Chronic Obstructive Pulmonary Disease, COPD
Conditions
Keywords
CHF 5259, Chronic Obstructive Pulmonary Disease (COPD), pMDI (pressurized metered dose inhaler), GLIMMER
Brief summary
The purpose of this study is to evaluate the dose-response of different doses of CHF 5259 pMDI on lung function and other clinical outcomes, to identify the optimal dose(s) in terms of benefit/ risk ratio for further development in the target subject population.
Detailed description
This is a phase II, multicenter, randomized, double-blind, placebo and active controlled dose-ranging 6-arm parallel group study to identify the optimal dose of CHF 5259 pMDI (pressurized metered dose inhaler) with respect to lung function as well as other clinical efficacy and safety outcomes. After a 2 week run-in period under rescue albuterol and background inhaled corticosteroid (ICS) as needed, patients were randomized to one of the 6 study treatment groups. Following randomization, subjects were assessed after 3 weeks and 6 weeks of study treatment at the study center. A follow-up phone was performed a week after the last visit. During the study, daily symptoms, rescue and background medication use and compliance with the study drug were recorded in a subject diary. Treatment-Emergent Adverse Events (TEAEs) were assessed and recorded throughout the study. At screening and subsequent visits, subjects underwent physical and vital signs examinations, spirometry measurements, and 12-lead electrocardiogram (ECG). Symptoms and chronic obstructive pulmonary disease (COPD) health status were assessed through validated questionnaires. Routine hematology, blood chemistry, and pregnancy testing were performed before enrollment and at end of study. 24-hour (24-H) digital recording of ECGs (Holter) was performed before and after the first dose and just before the last dose of study treatment.
Interventions
DRUGCHF 5259
Dose Response: Test one of four different doses of CHF 5259
DRUGPlacebo
Placebo Control
DRUGTiotropium Bromide 18 µg Inhalation Capsule
Active Control
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects aged ≥ 40 who have signed an Informed Consent Form prior to initiation of any study-related procedure. * Subjects with a diagnosis of COPD (according to GOLD 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD Report) at least 12 months before the screening visit. * Current smokers or ex-smokers who quit smoking at least 6 months prior to screening visit, with a smoking history of at least 10 pack years * A post-bronchodilator forced expiratory volume in the 1st second (FEV1) ≥50% and \<80% of the predicted normal value and, * a post-bronchodilator FEV1/ Forced Vital Capacity (FVC) \< 0.7 at screening and * a demonstrated reversibility to ipratropium defined as ΔFEV1 ≥ 5% over baseline 30-45 minutes after inhaling 4 puffs of ipratropium * Subjects under regular COPD therapy for at least 2 months prior to screening with either inhaled long-acting muscarinic antagonist (LAMA), inhaled ICS/ long-acting β2-agonist (LABA), inhaled ICS + LAMA * Symptomatic subjects at screening with a CAT score ≥10. This criterion must be confirmed at randomization * Symptomatic subjects with a BDI focal score ≤ 10. This criterion must be confirmed at randomization * A cooperative attitude and ability to demonstrate correct use of the inhalers and e-diary.
Exclusion criteria
* Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS they are willing to use highly effective birth control methods * Diagnosis of asthma or Asthma-COPD Overlap Syndrome (ACOS) as described in global initiative for asthma (GINA) Report 2016, history of allergic rhinitis or atopy (atopy which may raise contra-indications or impact the efficacy of the study treatment according to Investigator's judgment) * COPD Exacerbations: a moderate or severe COPD exacerbation that has not resolved ≤14 days prior to screening and ≤30 days following the last dose of any oral/systemic corticosteroid or antibiotic (whichever comes last). A Moderate or Severe COPD exacerbation during the run-in period * Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screening or during run-in * Subjects treated with non-cardio-selective β-blockers in the month preceding screening or during the run-in period * Subjects treated with long-acting anti-histamines unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study, or if taken as needed * Subjects requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia * Known respiratory disorders other than COPD which may impact the efficacy of the study treatment according the Investigator's judgment. * Subjects who have clinically significant cardiovascular condition * Subjects who have a clinically significant abnormal 12-lead ECG that results in active medical problem which may impact the safety of the subject according to Investigator's judgement * Subjects whose 12-lead ECG shows Fridericia corrected QT interval (QTcF) \>450 ms for males or QTcF \>470 ms for females at screening visit * Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that in the opinion of the Investigator would prevent use of anticholinergic agents * History of hypersensitivity to M3 receptor antagonists, β2-adrenergic receptor agonist, corticosteroids or any of the excipients contained in any of the formulations used in the study which may raise contra-indications or impact the efficacy of the study treatment according to the Investigator's judgement * Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study treatment according to Investigator's judgement * Subjects with serum potassium levels \<3.5 mEq/L (or 3.5 mmol/L) at screening * Use of potent cytochrome P450 2D6 and 3A4 inhibitors within 4 weeks prior to screening * Unstable or uncontrolled concurrent disease; fever, endocrine disease, gastrointestinal disease; neurological disease; hematological disease; autoimmune disorders, or other which may impact the feasibility of the results of the study according to Investigator's judgment * History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening * Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial. * Subjects who are mentally or legally incapacitated, or subjects accommodated in an establishment as a result of an official or judicial order. * Subjects who have undergone major surgery in the 3 months prior to screening visit or have a planned surgery during the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6 | Baseline, Week 6 | Change from baseline in FEV1 AUC(0-12h), normalized by time, at the end of treatment (Week 6). Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time; |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Baseline, Day 1, Week 6 | Change from baseline in FEV1 AUC(0-4h), normalized by time on Day 1 of treatment (Week 0). Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 and at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-4h)=Mean FEV1 after inhalation, measured at prespecified times for up to 4-h observation period (0-4h), normalized by time; |
| Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Baseline, Day 1, Week 6 | Change from baseline in FEV1 peak(0-4h) (L) on Day 1 and at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; Peak(0-4h)=Maximum FEV1 between 0 and 4 h. |
| Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Baseline, Day 1, Week 6 | Change from baseline in FVC AUC(0-12h), normalized by time, on Day 1 and at the end of treatment (Week 6). Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-12h)=Mean FVC after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time; |
| Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Baseline, Day 1, Week 6 | Change from baseline in FVC AUC(0-4h), normalized by time, on Day 1 and at the end of treatment (Week 6). Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-4)=Mean FVC after inhalation, measured at prespecified times for up to 4-h observation period (0-4 h), normalized by time; |
| Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Baseline, Day 1, Week 6 | Change from baseline in FVC peak(0-4h) (L) on Day 1 and at the end of treatment at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; Peak(0-4h)=Maximum FEV1 between 0 and 4 h. |
| Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1 | Day 1 | Time to onset of action is defined as the time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥100 mL. |
| Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1 | Day 1 | Number of patients achieving onset of action was defined as a change from baseline in post-dose FEV1 ≥100 mL on Day 1. These are the patients who contributed to the results, reported as median and 95% CI for 'time to onset of action' presented in Outcome Measure 8, above. |
| Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Baseline, Week 3, Week 6 | Change from baseline in FEV1 at treatment visit 3 (Week 3) and treatment visit 4 (Week 6) of treatment. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; |
| Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Baseline, Week 3, Week 6 | Change from baseline in IC at treatment Visit 3 (Week 3) and treatment Visit 4 (Week 6). Spirometry was used to measure IC and was performed according to internationally accepted standards. Definitions: Baseline: value of the measurement recorded at 45 mins pre-dose at Visit 2 (Week 0); IC=Inspiratory capacity; |
| Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Baseline, Week 3, Week 6 | Number of subjects achieving TDI focal score ≥1, at treatment visit 3 (Week 3) and at treatment visit 4 (Week 6). TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement); total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important. Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index; |
| Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Baseline, Week 3, Week 6 | Transitional Dyspnea Index (TDI) focal score at treatment visit 3 (Week 3) and treatment visit 4 (Week 6). TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement), with a total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important. Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index; |
| Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1 | Baseline, Day 1 | Change from baseline in FEV1 AUC(0-12h), normalized by time, on Day 1. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time; |
| Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period | Evaluate the change from baseline in average use of rescue medication (number of puffs/day) during the inter-visit periods and the entire treatment period. Results are shown as number of puffs/day; a decrease (implies improvement) from baseline in average use of rescue medication. Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3 (Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0); |
| Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period | Change from baseline in average EXACT-Respiratory Symptom (E-RS) total score during inter-visit periods and the entire treatment period E-RS in COPD uses 11 respiratory symptom items from the 14-item EXAcerbations of COPD tool (EXACT). E-RS total score quantifies respiratory symptom severity on a scale ranging from 0 to 40. Higher E-RS total scores indicate more severe symptoms and a declining total score indicates health improvement. E-RS questionnaire was completed by the patient each evening (e-diary). Definitions: For details on baseline, inter-visit periods, and the entire treatment period, please refer to outcome measure #15. |
| Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | Baseline, Day 1, Week 6 | Vital signs -- Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were measured at prespecified times, using a 12-Lead single ECGs were recorded at all study visits (pre-dose at V1 (Week -2) and V3 (Week 3), as well as at pre-dose and 1.5 hours post-dose at Visit 2 (Week 0) and Visit 4 (Week 6). Results are shown by treatment group, as change from baseline (in mmHg) for representative timepoints. Definitions: Baseline=Values recorded pre-dose (Visit 2, Week 0); Day 1=Day of the first dose of randomized study drug (Visit 2, Week 0); |
| Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | Baseline, Day 1, Week 6 | Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Heart rate (HR) Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5m, +55m, and at +2.5 h. |
| Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | Baseline, Day 1, Week 6 | Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - PR Interval Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h. |
| Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | Baseline, Day 1, Week 6 | Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - QRS Interval Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h. |
| Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | Baseline, Day 1, Week 6 | Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Fridericia-corrected QT interval (QTcF). Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h. |
| 24-hour Holter ECG - Prolonged QTcF - Male Subjects | Baseline, Day 1, Week 6 | 24-hour Holter ECG - Prolonged QTcF - Male subjects. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h. |
| 24-hour Holter ECG - Prolonged QTcF - Female Subjects | Baseline, Day 1, Week 6 | 24-hour Holter ECG - Prolonged QTcF - Female subjects. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h. |
| 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | Baseline, Day 1, Week 6 | 24-hour Holter ECG - Prolonged QTcF - Change from baseline. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h. Results are presented as the number of subjects who had a change from baseline in QTcF of: \> 30 msec, \> 60 msec, and no prolongation (by \> 30 msec or \> 60 msec). |
| Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period | Evaluate the number of rescue medication-free days compared with baseline. Results are shown as percentage (%) of rescue medication-free days; an increased value indicates improvement from baseline. Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3, Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment A CHF 5259 pMDI, 6.25 μg, 1 inhalation bid; 12.5 μg TDD
CHF 5259 Dose Response: Test one of 4 different doses of CHF 5259 | 121 |
| Treatment B CHF 5259 pMDI 12.5 μg, 1 inhalation bid; 25 μg TDD
CHF 5259 Dose Response: Test one of 4 different doses of CHF 5259 | 123 |
| Treatment C CHF 5259 pMDI 12.5 μg, 2 inhalations bid; 50 μg TDD
CHF 5259 Dose Response: Test one of 4 different doses of CHF 5259 | 121 |
| Treatment D CHF 5259 pMDI 25 μg, 2 inhalations bid; 100 μg TDD
CHF 5259 Dose Response: Test one of 4 different doses of CHF 5259 | 123 |
| Treatment E Placebo 2 inhalations of CHF 5259 pMDI-matched Placebo bid
Placebo: Placebo Control | 121 |
| Treatment F Tiotropium Bromide inhalation powder, 18 μg, SPIRIVA® HandiHaler®, 2 inhalations od of the content of 1 capsule; 18 µg TDD
Tiotropium Bromide Active Control, 18 µg Inhalation Capsule | 123 |
| Total | 732 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 | 6 | 2 | 3 | 5 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 1 | 3 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 | 1 | 1 |
| Overall Study | Randomization error | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 5 | 2 | 1 | 3 | 0 |
Baseline characteristics
| Characteristic | Total | Treatment F | Treatment E | Treatment D | Treatment C | Treatment B | Treatment A |
|---|---|---|---|---|---|---|---|
| Age at first diagnosis of COPD | 55.50 years STANDARD_DEVIATION 9.25 | 55.65 years STANDARD_DEVIATION 10.19 | 55.12 years STANDARD_DEVIATION 8.85 | 56.40 years STANDARD_DEVIATION 9.41 | 55.38 years STANDARD_DEVIATION 8.46 | 55.45 years STANDARD_DEVIATION 9.29 | 54.98 years STANDARD_DEVIATION 9.31 |
| Age, Continuous | 64.7 years STANDARD_DEVIATION 9.05 | 63.8 years STANDARD_DEVIATION 9.55 | 64.9 years STANDARD_DEVIATION 9.25 | 64.9 years STANDARD_DEVIATION 9.11 | 65.3 years STANDARD_DEVIATION 8.16 | 65.3 years STANDARD_DEVIATION 9.1 | 64.1 years STANDARD_DEVIATION 9.13 |
| Age, Customized 65-84 years | 370 Participants | 59 Participants | 58 Participants | 60 Participants | 65 Participants | 68 Participants | 60 Participants |
| Age, Customized < 65 years | 352 Participants | 62 Participants | 60 Participants | 62 Participants | 56 Participants | 53 Participants | 59 Participants |
| Age, Customized > 85 years | 10 Participants | 2 Participants | 3 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants |
| BDI focal scores at randomization | 5.8 scores on a scale STANDARD_DEVIATION 1.71 | 5.7 scores on a scale STANDARD_DEVIATION 1.59 | 6.1 scores on a scale STANDARD_DEVIATION 1.43 | 5.8 scores on a scale STANDARD_DEVIATION 1.63 | 5.8 scores on a scale STANDARD_DEVIATION 1.77 | 5.9 scores on a scale STANDARD_DEVIATION 1.87 | 5.6 scores on a scale STANDARD_DEVIATION 1.88 |
| Body Mass Index (BMI) | 28.88 kg/m^2 STANDARD_DEVIATION 6.45 | 28.05 kg/m^2 STANDARD_DEVIATION 5.54 | 29.26 kg/m^2 STANDARD_DEVIATION 6.49 | 29.62 kg/m^2 STANDARD_DEVIATION 6.73 | 28.52 kg/m^2 STANDARD_DEVIATION 6.77 | 29.13 kg/m^2 STANDARD_DEVIATION 5.98 | 28.67 kg/m^2 STANDARD_DEVIATION 7.05 |
| CAT total score at randomization | 19.6 scores on a scale STANDARD_DEVIATION 5.8 | 20.3 scores on a scale STANDARD_DEVIATION 6.48 | 19.3 scores on a scale STANDARD_DEVIATION 5.73 | 20.0 scores on a scale STANDARD_DEVIATION 5.49 | 19.2 scores on a scale STANDARD_DEVIATION 5.83 | 19.2 scores on a scale STANDARD_DEVIATION 5.65 | 19.6 scores on a scale STANDARD_DEVIATION 5.6 |
| COPD medication category at study entry Inhaled ICS and LABA (free combination) | 6 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| COPD medication category at study entry Inhaled ICS and LAMA | 8 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| COPD medication category at study entry Inhaled ICS/LABA (fixed combination) | 491 Participants | 81 Participants | 78 Participants | 92 Participants | 74 Participants | 89 Participants | 77 Participants |
| COPD medication category at study entry Inhaled ICS+LABA+LAMA (free or fixed combination) | 52 Participants | 8 Participants | 13 Participants | 6 Participants | 11 Participants | 3 Participants | 11 Participants |
| COPD medication category at study entry Inhaled LABA/LAMA (fixed combination) | 24 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 8 Participants | 6 Participants |
| COPD medication category at study entry Inhaled LAMA | 151 Participants | 27 Participants | 25 Participants | 22 Participants | 31 Participants | 22 Participants | 24 Participants |
| Duration of smoking | 41.80 years STANDARD_DEVIATION 10.3 | 40.79 years STANDARD_DEVIATION 10.83 | 41.34 years STANDARD_DEVIATION 10.39 | 42.78 years STANDARD_DEVIATION 10.44 | 40.71 years STANDARD_DEVIATION 10.46 | 42.98 years STANDARD_DEVIATION 9.86 | 42.19 years STANDARD_DEVIATION 9.74 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 51 Participants | 7 Participants | 5 Participants | 11 Participants | 12 Participants | 9 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 680 Participants | 116 Participants | 115 Participants | 112 Participants | 109 Participants | 114 Participants | 114 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| FEV1 (L) at baseline | 1.430 litres STANDARD_DEVIATION 0.446 | 1.443 litres STANDARD_DEVIATION 0.487 | 1.415 litres STANDARD_DEVIATION 0.433 | 1.420 litres STANDARD_DEVIATION 0.419 | 1.434 litres STANDARD_DEVIATION 0.472 | 1.428 litres STANDARD_DEVIATION 0.439 | 1.440 litres STANDARD_DEVIATION 0.432 |
| FVC at baseline | 2.694 litres STANDARD_DEVIATION 0.752 | 2.746 litres STANDARD_DEVIATION 0.809 | 2.683 litres STANDARD_DEVIATION 0.736 | 2.630 litres STANDARD_DEVIATION 0.719 | 2.669 litres STANDARD_DEVIATION 0.725 | 2.719 litres STANDARD_DEVIATION 0.775 | 2.717 litres STANDARD_DEVIATION 0.754 |
| Height | 169.10 cm STANDARD_DEVIATION 9.48 | 169.53 cm STANDARD_DEVIATION 9.67 | 169.34 cm STANDARD_DEVIATION 9.56 | 168.17 cm STANDARD_DEVIATION 9.57 | 169.21 cm STANDARD_DEVIATION 9.67 | 169.38 cm STANDARD_DEVIATION 9.74 | 168.95 cm STANDARD_DEVIATION 8.76 |
| IC at baseline | 2.078 litres STANDARD_DEVIATION 0.612 | 2.175 litres STANDARD_DEVIATION 0.624 | 2.053 litres STANDARD_DEVIATION 0.628 | 2.066 litres STANDARD_DEVIATION 0.572 | 2.089 litres STANDARD_DEVIATION 0.683 | 2.065 litres STANDARD_DEVIATION 0.533 | 2.020 litres STANDARD_DEVIATION 0.622 |
| Number of pack-years | 45.0 pack-years | 43.0 pack-years | 45.0 pack-years | 45.0 pack-years | 45.0 pack-years | 49.0 pack-years | 45.0 pack-years |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 69 Participants | 10 Participants | 12 Participants | 14 Participants | 10 Participants | 10 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 646 Participants | 110 Participants | 104 Participants | 108 Participants | 107 Participants | 110 Participants | 107 Participants |
| Region of Enrollment United States | 732 Participants | 123 Participants | 121 Participants | 123 Participants | 121 Participants | 123 Participants | 121 Participants |
| Sex: Female, Male Female | 367 Participants | 57 Participants | 52 Participants | 65 Participants | 67 Participants | 68 Participants | 58 Participants |
| Sex: Female, Male Male | 365 Participants | 66 Participants | 69 Participants | 58 Participants | 54 Participants | 55 Participants | 63 Participants |
| Smoking habits Current smoker | 369 Participants | 67 Participants | 55 Participants | 68 Participants | 59 Participants | 59 Participants | 61 Participants |
| Smoking habits Ex-smoker | 363 Participants | 56 Participants | 66 Participants | 55 Participants | 62 Participants | 64 Participants | 60 Participants |
| Time since first diagnosis of COPD | 94.55 months | 74.40 months | 103.40 months | 94.00 months | 97.40 months | 99.60 months | 92.80 months |
| Weight | 82.85 kg STANDARD_DEVIATION 20.77 | 80.67 kg STANDARD_DEVIATION 17.4 | 84.43 kg STANDARD_DEVIATION 21.82 | 84.23 kg STANDARD_DEVIATION 22.41 | 82.12 kg STANDARD_DEVIATION 22.7 | 83.82 kg STANDARD_DEVIATION 19.33 | 81.81 kg STANDARD_DEVIATION 20.64 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 121 | 0 / 123 | 0 / 121 | 0 / 123 | 0 / 121 | 0 / 123 |
| other Total, other adverse events | 16 / 121 | 14 / 123 | 8 / 121 | 15 / 123 | 11 / 121 | 9 / 123 |
| serious Total, serious adverse events | 2 / 121 | 5 / 123 | 1 / 121 | 1 / 123 | 1 / 121 | 1 / 123 |
Outcome results
Primary
Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6
Change from baseline in FEV1 AUC(0-12h), normalized by time, at the end of treatment (Week 6). Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;
Time frame: Baseline, Week 6
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6 | 0.070 Litres |
| Treatment B | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6 | 0.118 Litres |
| Treatment C | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6 | 0.153 Litres |
| Treatment D | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6 | 0.147 Litres |
| Treatment E | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6 | 0.002 Litres |
| Treatment F | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6 | 0.213 Litres |
Comparison: Comparison groups were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.~Adjusted for multiplicity based on the parametric simulation method by Edwards and Berry.p-value: 0.03795% CI: [0.003, 0.132]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis for was performed as described for the statistical analysis 1 for this outcome measure.~Adjusted for multiplicity based on the parametric simulation method by Edwards and Berry.p-value: <0.00195% CI: [0.051, 0.181]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis for was performed as described for the statistical analysis 1 for this outcome measure.~Adjusted for multiplicity based on the parametric simulation method by Edwards and Berry.p-value: <0.00195% CI: [0.086, 0.216]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis for was performed as described for the statistical analysis 1 for this outcome measure.~Adjusted for multiplicity based on the parametric simulation method by Edwards and Berry.p-value: <0.00195% CI: [0.081, 0.209]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West) and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.p-value: <0.00195% CI: [0.159, 0.263]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West) and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.p-value: 0.06695% CI: [-0.003, 0.1]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West) and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.p-value: 0.00295% CI: [0.031, 0.135]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West) and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.p-value: 0.00395% CI: [0.026, 0.128]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD.~Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West) and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.p-value: 0.18995% CI: [-0.017, 0.087]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West) and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.p-value: 0.27395% CI: [-0.023, 0.08]Mixed Models Analysis
Comparison: Comparison treatment groups were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West) and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.p-value: 0.81395% CI: [-0.058, 0.045]Mixed Models Analysis
Secondary
24-hour Holter ECG - Prolonged QTcF - Change From Baseline
24-hour Holter ECG - Prolonged QTcF - Change from baseline. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h. Results are presented as the number of subjects who had a change from baseline in QTcF of: \> 30 msec, \> 60 msec, and no prolongation (by \> 30 msec or \> 60 msec).
Time frame: Baseline, Day 1, Week 6
Population: Safety population:~All randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 113 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 30 msec | 19 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | No change from baseline (> 30 msec or > 60 msec) | 102 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 30 msec | 5 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 30 msec | 6 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 116 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 30 msec | 5 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 116 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 60 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 30 msec | 2 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 116 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 115 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 119 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 30 msec | 5 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 30 msec | 8 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 30 msec | 20 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 30 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 30 msec | 6 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 123 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 30 msec | 4 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | No change from baseline (> 30 msec or > 60 msec) | 102 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 119 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 119 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 30 msec | 12 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 60 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 111 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 30 msec | 3 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 117 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 60 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 119 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 30 msec | 4 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 60 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 116 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 118 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | No change from baseline (> 30 msec or > 60 msec) | 100 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 30 msec | 5 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 30 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 30 msec | 9 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 30 msec | 7 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 114 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 121 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 30 msec | 21 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 112 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 30 msec | 6 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 30 msec | 3 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 115 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 116 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 121 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 30 msec | 6 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 60 msec | 1 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 116 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 30 msec | 5 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 60 msec | 1 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 117 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 30 msec | 3 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 120 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 30 msec | 7 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 30 msec | 20 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 30 msec | 6 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 117 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 60 msec | 2 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | No change from baseline (> 30 msec or > 60 msec) | 101 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 30 msec | 2 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 30 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 30 msec | 3 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 121 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 118 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 118 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 114 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 60 msec | 1 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 30 msec | 16 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 30 msec | 6 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 60 msec | 2 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 116 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 60 msec | 1 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 30 msec | 3 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | No change from baseline (> 30 msec or > 60 msec) | 103 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 30 msec | 4 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 118 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 30 msec | 3 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 30 msec | 5 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 118 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 30 msec | 7 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | No change from baseline (> 30 msec or > 60 msec) | 118 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | Change from baseline: > 30 msec | 4 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 60 msec | 1 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | Change from baseline: > 30 msec | 3 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 60 msec | 1 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 115 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 55 min post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 55 min post dose | Change from baseline: > 30 msec | 4 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 2.5 h post dose | No change from baseline (> 30 msec or > 60 msec) | 116 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 119 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 60 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day before Week 6, 5 min post dose | No change from baseline (> 30 msec or > 60 msec) | 120 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | No change from baseline (> 30 msec or > 60 msec) | 104 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Any post dose time point | Change from baseline: > 30 msec | 18 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Change From Baseline | QTcF, Day 1, 2.5 h post dose | Change from baseline: > 30 msec | 8 Participants |
Secondary
24-hour Holter ECG - Prolonged QTcF - Female Subjects
24-hour Holter ECG - Prolonged QTcF - Female subjects. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time frame: Baseline, Day 1, Week 6
Population: Safety population:~All randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 470 msec | 3 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 470 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 470 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | No prolongation (> 470 msec or > 500 msec) | 58 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 470 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 470 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | No prolongation (> 470 msec or > 500 msec) | 55 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 470 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 470 msec | 2 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 56 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 470 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 58 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 470 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 58 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 470 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 470 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 66 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 65 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | No prolongation (> 470 msec or > 500 msec) | 64 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 470 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 470 msec or > 500 msec) | 66 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 470 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 66 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 470 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 65 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 470 msec | 3 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 470 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 470 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | No prolongation (> 470 msec or > 500 msec) | 64 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 470 msec | 3 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 66 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 470 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 67 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 64 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 470 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 470 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 65 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 65 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | No prolongation (> 470 msec or > 500 msec) | 65 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 65 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 65 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 65 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | No prolongation (> 470 msec or > 500 msec) | 64 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 470 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 470 msec | 1 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 470 msec or > 500 msec) | 65 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 470 msec | 1 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | No prolongation (> 470 msec or > 500 msec) | 64 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 470 msec | 1 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 470 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 470 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 470 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 470 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 470 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 52 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 470 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 470 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 55 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 470 msec | 1 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 470 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | Actual value > 470 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 56 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day 1, 5 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | No prolongation (> 470 msec or > 500 msec) | 56 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Any post dose time point | Actual value > 470 msec | 1 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 2.5 h | Actual value > 470 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 55 min | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 470 msec or > 500 msec) | 57 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 470 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Female Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
Secondary
24-hour Holter ECG - Prolonged QTcF - Male Subjects
24-hour Holter ECG - Prolonged QTcF - Male subjects. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time frame: Baseline, Day 1, Week 6
Population: Safety population:~All randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 62 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 480 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 450 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 450 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 450 msec | 3 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 62 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 480 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 450 msec | 2 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 59 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 480 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 450 msec | 3 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 61 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 60 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 480 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 450 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 450 msec | 2 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 60 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 480 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 480 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 450 msec | 2 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 59 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 450 msec | 1 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 480 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 60 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 450 msec | 3 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 62 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment A | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 62 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 54 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 450 msec | 4 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 55 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 450 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 450 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 450 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 51 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 450 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 450 msec | 1 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 54 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 54 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 53 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 450 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 52 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 450 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 54 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 450 msec | 3 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 53 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 53 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 480 msec | 0 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 450 msec | 2 Participants |
| Treatment B | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 54 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 450 msec | 6 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 480 msec | 1 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 450 msec | 2 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 52 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 450 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 450 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 480 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 54 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 450 msec | 1 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 480 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 53 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 450 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 480 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 54 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 480 msec | 1 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 47 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 450 msec | 3 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 51 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 450 msec | 3 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 50 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 450 msec | 3 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 51 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 450 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment C | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 54 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 450 msec | 2 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 55 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 450 msec | 4 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 450 msec | 3 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 57 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 56 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 55 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 55 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 450 msec | 1 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 450 msec | 3 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 450 msec | 2 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 450 msec | 1 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 55 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 450 msec | 3 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 56 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 57 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 450 msec | 2 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 54 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 56 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment D | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 450 msec | 3 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 68 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 480 msec | 1 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 450 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 480 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 66 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 450 msec | 2 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 450 msec | 2 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 480 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 69 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 67 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 450 msec | 1 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 450 msec | 1 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 450 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 68 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 450 msec | 1 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 69 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 450 msec | 1 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 480 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 450 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 68 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 480 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 69 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 68 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 67 Participants |
| Treatment E | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 450 msec | 2 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 450 msec | 4 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 450 msec | 1 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 450 msec | 4 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 480 msec | 1 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 63 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 450 msec | 3 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 58 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 65 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 66 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 450 msec | 2 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 62 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 480 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 5 min | Actual value > 480 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 63 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 63 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 480 msec | 3 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 450 msec | 4 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 62 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 480 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 480 msec | 1 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 61 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 450 msec | 3 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 55 min | Actual value > 450 msec | 3 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 55 min post dose | Actual value > 500 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 5 min post dose | Actual value > 480 msec | 1 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day before Week 6, 2.5 h post dose | Actual value > 480 msec | 0 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 55 min post dose | No prolongation (> 450 msec or > 480 msec or > 500 msec) | 61 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Any post dose time point | Actual value > 450 msec | 5 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day 1, 5 min post dose | Actual value > 480 msec | 1 Participants |
| Treatment F | 24-hour Holter ECG - Prolonged QTcF - Male Subjects | QTcF, Day -1, 2.5 h | Actual value > 450 msec | 0 Participants |
Secondary
Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF)
Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Fridericia-corrected QT interval (QTcF). Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time frame: Baseline, Day 1, Week 6
Population: Safety population:~All randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 5 min post dose | 3.62 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 55 min post dose | 8.37 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 2.5 h post dose | 7.15 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 5 min post dose | 1.61 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 55 min post dose | 2.38 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 2.5 h post dose | 4.13 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 2.5 h post dose | 0.85 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 2.5 h post dose | 8.65 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 5 min post dose | 1.14 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 55 min post dose | 5.41 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 5 min post dose | 5.37 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 55 min post dose | 0.09 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 2.5 h post dose | -0.97 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 5 min post dose | -0.60 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 5 min post dose | 6.81 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 55 min post dose | 6.72 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 2.5 h post dose | 7.20 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 55 min post dose | 1.41 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 5 min post dose | 1.67 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 55 min post dose | 9.90 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 2.5 h post dose | 5.45 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 2.5 h post dose | 1.73 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 55 min post dose | 4.15 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 5 min post dose | 6.25 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 5 min post dose | 3.59 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 55 min post dose | 1.02 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 55 min post dose | 6.04 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 2.5 h post dose | 4.81 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 5 min post dose | -3.56 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 2.5 h post dose | 0.14 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 5 min post dose | 1.41 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 2.5 h post dose | 6.77 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 55 min post dose | 3.19 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day before Week 6, 2.5 h post dose | 2.50 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 55 min post dose | 5.43 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) | QTcF, Day 1, 5 min post dose | 5.56 msec |
Secondary
Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR)
Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Heart rate (HR) Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5m, +55m, and at +2.5 h.
Time frame: Baseline, Day 1, Week 6
Population: Safety population:~All randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 55 min post dose | -7.19 bpm |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 5 min post dose | -1.72 bpm |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 5 min post dose | -8.85 bpm |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 2.5 h post dose | -2.30 bpm |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 55 min post dose | -1.52 bpm |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 2.5 h post dose | -7.57 bpm |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 5 min post dose | -6.62 bpm |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 5 min post dose | -1.06 bpm |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 55 min post dose | -8.29 bpm |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 55 min post dose | 0.41 bpm |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 2.5 h post dose | -6.75 bpm |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 2.5 h post dose | -0.01 bpm |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 55 min post dose | -1.10 bpm |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 5 min post dose | -7.78 bpm |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 2.5 h post dose | -9.20 bpm |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 2.5 h post dose | -1.13 bpm |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 5 min post dose | -1.61 bpm |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 55 min post dose | -8.28 bpm |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 5 min post dose | -7.64 bpm |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 2.5 h post dose | -0.73 bpm |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 55 min post dose | -9.59 bpm |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 2.5 h post dose | -7.46 bpm |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 5 min post dose | -1.85 bpm |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 55 min post dose | -1.40 bpm |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 2.5 h post dose | -6.12 bpm |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 55 min post dose | -7.44 bpm |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 5 min post dose | -4.84 bpm |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 2.5 h post dose | 2.49 bpm |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 55 min post dose | 1.12 bpm |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 5 min post dose | 3.92 bpm |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 2.5 h post dose | -1.47 bpm |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 55 min post dose | -7.19 bpm |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 2.5 h post dose | -8.96 bpm |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 5 min post dose | 1.70 bpm |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day before Week 6, 55 min post dose | 1.22 bpm |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) | HR, Day 1, 5 min post dose | -5.54 bpm |
Secondary
Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval
Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - PR Interval Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time frame: Baseline, Day 1, Week 6
Population: Safety population:~All randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 5 min post dose | 7.24 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 55 min post dose | 7.20 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 2.5 h post dose | 8.48 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 5 min post dose | 0.44 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 55 min post dose | 0.88 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 2.5 h post dose | 2.50 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 55 min post dose | 6.89 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 5 min post dose | 1.36 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 2.5 h post dose | 3.01 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 5 min post dose | 6.53 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 2.5 h post dose | 9.38 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 55 min post dose | 2.37 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 2.5 h post dose | 0.16 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 55 min post dose | 1.91 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 5 min post dose | -0.11 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 2.5 h post dose | 7.58 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 5 min post dose | 6.08 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 55 min post dose | 8.21 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 5 min post dose | 3.88 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 55 min post dose | 6.77 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 2.5 h post dose | 6.16 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 2.5 h post dose | 0.84 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 55 min post dose | 0.82 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 5 min post dose | 6.71 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 5 min post dose | 3.06 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 55 min post dose | -1.13 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 55 min post dose | 4.38 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 2.5 h post dose | 5.84 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 5 min post dose | -1.36 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 2.5 h post dose | -1.22 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 5 min post dose | 0.82 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 2.5 h post dose | 4.25 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 55 min post dose | -1.66 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day before Week 6, 2.5 h post dose | -1.94 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 55 min post dose | 4.77 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval | PR Interval, Day 1, 5 min post dose | 4.90 msec |
Secondary
Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval
Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - QRS Interval Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time frame: Baseline, Day 1, Week 6
Population: Safety population:~All randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 55 min post dose | 0.97 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 2.5 h post dose | 1.49 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 2.5 h post dose | 1.38 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 55 min post dose | 1.12 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 5 min post dose | 0.61 msec |
| Treatment A | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 5 min post dose | 1.18 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 5 min post dose | -1.76 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 5 min post dose | 0.05 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 55 min post dose | 1.19 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 2.5 h post dose | 2.40 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 55 min post dose | -0.09 msec |
| Treatment B | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 2.5 h post dose | 0.74 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 55 min post dose | 0.85 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 55 min post dose | 1.21 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 5 min post dose | 0.43 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 2.5 h post dose | 1.80 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 2.5 h post dose | 0.30 msec |
| Treatment C | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 5 min post dose | 1.50 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 5 min post dose | 1.99 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 2.5 h post dose | 2.18 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 2.5 h post dose | 1.50 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 5 min post dose | 2.00 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 55 min post dose | 2.38 msec |
| Treatment D | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 55 min post dose | 1.56 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 55 min post dose | 0.14 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 55 min post dose | 0.77 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 2.5 h post dose | 0.64 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 2.5 h post dose | 1.14 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 5 min post dose | 0.45 msec |
| Treatment E | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 5 min post dose | 0.45 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 5 min post dose | 0.69 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 5 min post dose | 1.50 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 55 min post dose | 0.42 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 2.5 h post dose | 0.86 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day before Week 6, 2.5 h post dose | 1.35 msec |
| Treatment F | Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval | QRS Interval, Day 1, 55 min post dose | 1.70 msec |
Secondary
Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period
Change from baseline in average EXACT-Respiratory Symptom (E-RS) total score during inter-visit periods and the entire treatment period E-RS in COPD uses 11 respiratory symptom items from the 14-item EXAcerbations of COPD tool (EXACT). E-RS total score quantifies respiratory symptom severity on a scale ranging from 0 to 40. Higher E-RS total scores indicate more severe symptoms and a declining total score indicates health improvement. E-RS questionnaire was completed by the patient each evening (e-diary). Definitions: For details on baseline, inter-visit periods, and the entire treatment period, please refer to outcome measure #15.
Time frame: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -2.030 score on a scale |
| Treatment A | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -1.855 score on a scale |
| Treatment A | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -1.681 score on a scale |
| Treatment B | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -1.840 score on a scale |
| Treatment B | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -1.689 score on a scale |
| Treatment B | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -1.539 score on a scale |
| Treatment C | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -2.044 score on a scale |
| Treatment C | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -1.941 score on a scale |
| Treatment C | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -2.147 score on a scale |
| Treatment D | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -1.663 score on a scale |
| Treatment D | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -2.077 score on a scale |
| Treatment D | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -1.870 score on a scale |
| Treatment E | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -0.698 score on a scale |
| Treatment E | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -0.714 score on a scale |
| Treatment E | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -0.681 score on a scale |
| Treatment F | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -1.505 score on a scale |
| Treatment F | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -1.280 score on a scale |
| Treatment F | Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -1.393 score on a scale |
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, inter-visit period, treatment by inter-visit period interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by inter-visit period interaction as covariates.p-value: 0.01695% CI: [-1.753, -0.181]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.03995% CI: [-1.606, -0.043]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00295% CI: [-2.012, -0.441]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01895% CI: [-1.733, -0.164]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.16995% CI: [-1.374, 0.242]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.7295% CI: [-0.638, 0.923]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.51595% CI: [-1.043, 0.523]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.96395% CI: [-0.764, 0.8]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.31195% CI: [-1.182, 0.377]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.75495% CI: [-0.903, 0.654]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.48595% CI: [-0.503, 1.06]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00595% CI: [-2.294, -0.403]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01695% CI: [-2.1, -0.218]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00395% CI: [-2.416, -0.516]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00495% CI: [-2.337, -0.454]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.09795% CI: [-1.797, 0.15]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.6995% CI: [-0.746, 1.126]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.80895% CI: [-1.061, 0.827]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.92295% CI: [-0.983, 0.889]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.52295% CI: [-1.248, 0.634]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.61895% CI: [-1.17, 0.696]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.88495% CI: [-0.871, 1.012]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00695% CI: [-1.978, -0.337]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01795% CI: [-1.808, -0.175]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00195% CI: [-2.168, -0.524]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00595% CI: [-1.991, -0.353]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.10795% CI: [-1.539, 0.149]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.68995% CI: [-0.648, 0.98]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.65195% CI: [-1.007, 0.63]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.97395% CI: [-0.83, 0.801]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.39395% CI: [-1.17, 0.461]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.66395% CI: [-0.993, 0.632]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.67695% CI: [-0.643, 0.991]Mixed Models Analysis
Secondary
Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period
Evaluate the change from baseline in average use of rescue medication (number of puffs/day) during the inter-visit periods and the entire treatment period. Results are shown as number of puffs/day; a decrease (implies improvement) from baseline in average use of rescue medication. Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3 (Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0);
Time frame: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -0.59 Number of puffs/day |
| Treatment A | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -0.72 Number of puffs/day |
| Treatment A | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -0.66 Number of puffs/day |
| Treatment B | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -0.50 Number of puffs/day |
| Treatment B | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -0.58 Number of puffs/day |
| Treatment B | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -0.54 Number of puffs/day |
| Treatment C | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -0.51 Number of puffs/day |
| Treatment C | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -0.53 Number of puffs/day |
| Treatment C | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -0.52 Number of puffs/day |
| Treatment D | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -0.69 Number of puffs/day |
| Treatment D | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -0.71 Number of puffs/day |
| Treatment D | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -0.70 Number of puffs/day |
| Treatment E | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -0.17 Number of puffs/day |
| Treatment E | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -0.30 Number of puffs/day |
| Treatment E | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -0.23 Number of puffs/day |
| Treatment F | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | -0.52 Number of puffs/day |
| Treatment F | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | -0.46 Number of puffs/day |
| Treatment F | Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | -0.40 Number of puffs/day |
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed, using linear mixed model repeated for measurements (MMRM), including treatment, inter-visit period, treatment by inter-visit period interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by inter-visit period interaction as covariates.p-value: <0.00195% CI: [-0.67, -0.18]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.02395% CI: [-0.53, -0.04]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.06795% CI: [-0.47, 0.02]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [-0.66, -0.17]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.08495% CI: [-0.47, 0.03]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.24395% CI: [-0.1, 0.39]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.11295% CI: [-0.05, 0.44]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.92995% CI: [-0.23, 0.26]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.66895% CI: [-0.19, 0.3]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.28195% CI: [-0.38, 0.11]Mixed Models Analysis
Comparison: Inter-visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.13495% CI: [-0.43, 0.06]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00395% CI: [-0.7, -0.14]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.0295% CI: [-0.61, -0.05]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01795% CI: [-0.62, -0.06]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [-0.8, -0.24]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.11595% CI: [-0.52, 0.06]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.53295% CI: [-0.19, 0.36]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.60395% CI: [-0.21, 0.35]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.4695% CI: [-0.38, 0.17]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD.~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.92195% CI: [-0.29, 0.26]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.17295% CI: [-0.47, 0.08]Mixed Models Analysis
Comparison: Inter-visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.2195% CI: [-0.46, 0.1]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [-0.67, -0.17]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01695% CI: [-0.55, -0.06]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.02595% CI: [-0.54, -0.04]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [-0.72, -0.22]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.08395% CI: [-0.48, 0.03]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.35595% CI: [-0.13, 0.36]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.28395% CI: [-0.11, 0.38]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.71295% CI: [-0.29, 0.2]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.87795% CI: [-0.23, 0.27]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.19595% CI: [-0.41, 0.08]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.1595% CI: [-0.43, 0.07]Mixed Models Analysis
Secondary
Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1
Change from baseline in FEV1 AUC(0-12h), normalized by time, on Day 1. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;
Time frame: Baseline, Day 1
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1 | 0.067 Litres |
| Treatment B | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1 | 0.086 Litres |
| Treatment C | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1 | 0.135 Litres |
| Treatment D | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1 | 0.149 Litres |
| Treatment E | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1 | 0.009 Litres |
| Treatment F | Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1 | 0.192 Litres |
Comparison: Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model for repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: 0.00295% CI: [0.022, 0.095]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: <0.00195% CI: [0.04, 0.113]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: <0.00195% CI: [0.089, 0.163]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: <0.00195% CI: [0.104, 0.177]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: <0.00195% CI: [0.147, 0.22]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: 0.32295% CI: [-0.018, 0.055]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: <0.00195% CI: [0.031, 0.104]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: <0.00195% CI: [0.045, 0.118]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD.~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: 0.00895% CI: [0.013, 0.086]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: <0.00195% CI: [0.027, 0.1]Mixed Models Analysis
Comparison: Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.p-value: 0.44395% CI: [-0.022, 0.051]Mixed Models Analysis
Secondary
Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6
Change from baseline in FEV1 AUC(0-4h), normalized by time on Day 1 of treatment (Week 0). Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 and at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-4h)=Mean FEV1 after inhalation, measured at prespecified times for up to 4-h observation period (0-4h), normalized by time;
Time frame: Baseline, Day 1, Week 6
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.116 Litres |
| Treatment A | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.101 Litres |
| Treatment B | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.157 Litres |
| Treatment B | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.115 Litres |
| Treatment C | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.173 Litres |
| Treatment C | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.198 Litres |
| Treatment D | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.190 Litres |
| Treatment D | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.204 Litres |
| Treatment E | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.024 Litres |
| Treatment E | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.030 Litres |
| Treatment F | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.194 Litres |
| Treatment F | Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.253 Litres |
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model for repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: <0.00195% CI: [0.038, 0.105]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.052, 0.119]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.109, 0.177]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.127, 0.194]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.131, 0.198]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.41895% CI: [-0.02, 0.048]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.038, 0.105]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.055, 0.122]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.024, 0.091]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.041, 0.108]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.30895% CI: [-0.016, 0.051]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: <0.00195% CI: [0.038, 0.147]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Analyzed, using linear mixed model repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: <0.00195% CI: [0.079, 0.188]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.12, 0.229]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.127, 0.235]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.175, 0.284]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.14195% CI: [-0.013, 0.095]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00395% CI: [0.028, 0.137]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00195% CI: [0.035, 0.142]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.13795% CI: [-0.013, 0.096]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.08295% CI: [-0.006, 0.101]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.82395% CI: [-0.048, 0.06]Mixed Models Analysis
Secondary
Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6
Change from baseline in FEV1 peak(0-4h) (L) on Day 1 and at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.
Time frame: Baseline, Day 1, Week 6
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Day 1 | 0.197 Litres |
| Treatment A | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Week 6 | 0.212 Litres |
| Treatment B | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Day 1 | 0.211 Litres |
| Treatment B | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Week 6 | 0.255 Litres |
| Treatment C | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Day 1 | 0.260 Litres |
| Treatment C | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Week 6 | 0.305 Litres |
| Treatment D | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Day 1 | 0.288 Litres |
| Treatment D | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Week 6 | 0.301 Litres |
| Treatment E | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Day 1 | 0.136 Litres |
| Treatment E | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Week 6 | 0.143 Litres |
| Treatment F | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Day 1 | 0.299 Litres |
| Treatment F | Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 | Week 6 | 0.356 Litres |
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: 0.00295% CI: [0.022, 0.1]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.036, 0.113]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.085, 0.163]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.113, 0.19]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.124, 0.202]MMRM
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.48595% CI: [-0.025, 0.052]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00195% CI: [0.025, 0.102]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.053, 0.13]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01295% CI: [0.011, 0.088]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.039, 0.116]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.15795% CI: [-0.011, 0.066]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.02195% CI: [0.011, 0.128]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.053, 0.17]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.103, 0.22]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.099, 0.215]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.154, 0.271]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.14995% CI: [-0.015, 0.101]Mixed Models Analysis
Comparison: week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00295% CI: [0.034, 0.151]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00395% CI: [0.031, 0.146]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.09695% CI: [-0.009, 0.108]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.12295% CI: [-0.012, 0.103]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.88695% CI: [-0.062, 0.054]Mixed Models Analysis
Secondary
Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6
Change from baseline in FVC AUC(0-12h), normalized by time, on Day 1 and at the end of treatment (Week 6). Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-12h)=Mean FVC after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;
Time frame: Baseline, Day 1, Week 6
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.086 Litres |
| Treatment A | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.084 Litres |
| Treatment B | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.133 Litres |
| Treatment B | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.145 Litres |
| Treatment C | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.195 Litres |
| Treatment C | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.190 Litres |
| Treatment D | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.220 Litres |
| Treatment D | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.184 Litres |
| Treatment E | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.011 Litres |
| Treatment E | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Week 6 | -0.029 Litres |
| Treatment F | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.305 Litres |
| Treatment F | Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.298 Litres |
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: 0.02995% CI: [0.008, 0.141]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.055, 0.188]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.117, 0.25]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.142, 0.275]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.227, 0.36]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.16195% CI: [-0.019, 0.113]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00195% CI: [0.043, 0.176]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.068, 0.201]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.06695% CI: [-0.004, 0.128]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.0195% CI: [0.021, 0.153]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.46595% CI: [-0.042, 0.091]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00895% CI: [0.03, 0.195]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.091, 0.256]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.136, 0.302]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.131, 0.295]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.244, 0.409]McNemar
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.14495% CI: [-0.021, 0.143]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01195% CI: [0.024, 0.189]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01695% CI: [0.019, 0.182]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.2895% CI: [-0.037, 0.128]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.34295% CI: [-0.042, 0.121]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.88695% CI: [-0.088, 0.076]Mixed Models Analysis
Secondary
Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6
Change from baseline in FVC AUC(0-4h), normalized by time, on Day 1 and at the end of treatment (Week 6). Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-4)=Mean FVC after inhalation, measured at prespecified times for up to 4-h observation period (0-4 h), normalized by time;
Time frame: Baseline, Day 1, Week 6
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.133 Litres |
| Treatment A | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.149 Litres |
| Treatment B | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.192 Litres |
| Treatment B | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.203 Litres |
| Treatment C | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.244 Litres |
| Treatment C | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.248 Litres |
| Treatment D | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.273 Litres |
| Treatment D | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.253 Litres |
| Treatment E | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.036 Litres |
| Treatment E | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.000 Litres |
| Treatment F | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Day 1 | 0.311 Litres |
| Treatment F | Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 | Week 6 | 0.353 Litres |
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: 0.00395% CI: [0.032, 0.163]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.091, 0.221]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.143, 0.273]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.172, 0.302]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.211, 0.341]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.07695% CI: [-0.006, 0.124]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.046, 0.176]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.075, 0.205]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.11695% CI: [-0.013, 0.117]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01495% CI: [0.016, 0.146]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.38495% CI: [-0.036, 0.094]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.064, 0.236]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.118, 0.29]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.162, 0.335]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.168, 0.339]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.268, 0.439]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.21495% CI: [-0.031, 0.14]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.02595% CI: [0.012, 0.184]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01695% CI: [0.019, 0.189]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.31395% CI: [-0.042, 0.13]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.2595% CI: [-0.035, 0.135]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.89895% CI: [-0.08, 0.091]Mixed Models Analysis
Secondary
Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6
Change from baseline in FVC peak(0-4h) (L) on Day 1 and at the end of treatment at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.
Time frame: Baseline, Day 1, Week 6
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Day 1 | 0.293 Litres |
| Treatment A | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Week 6 | 0.322 Litres |
| Treatment B | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Day 1 | 0.372 Litres |
| Treatment B | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Week 6 | 0.379 Litres |
| Treatment C | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Day 1 | 0.414 Litres |
| Treatment C | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Week 6 | 0.431 Litres |
| Treatment D | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Day 1 | 0.455 Litres |
| Treatment D | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Week 6 | 0.427 Litres |
| Treatment E | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Day 1 | 0.213 Litres |
| Treatment E | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Week 6 | 0.182 Litres |
| Treatment F | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Day 1 | 0.491 Litres |
| Treatment F | Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 | Week 6 | 0.530 Litres |
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed, using linear mixed model for repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: 0.03595% CI: [0.006, 0.153]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.085, 0.232]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.127, 0.275]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.168, 0.315]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.204, 0.351]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.03595% CI: [0.005, 0.152]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00195% CI: [0.048, 0.195]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.088, 0.235]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.25695% CI: [-0.031, 0.116]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.02795% CI: [0.01, 0.156]Mixed Models Analysis
Comparison: Day 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.28195% CI: [-0.033, 0.114]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00395% CI: [0.05, 0.232]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.106, 0.288]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.157, 0.34]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.155, 0.336]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.258, 0.439]Mixed Models Analysis
Comparison: week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.22295% CI: [-0.034, 0.147]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.0295% CI: [0.017, 0.199]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.02295% CI: [0.015, 0.195]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.26295% CI: [-0.039, 0.143]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.2995% CI: [-0.041, 0.138]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.93895% CI: [-0.094, 0.087]Mixed Models Analysis
Secondary
Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period
Evaluate the number of rescue medication-free days compared with baseline. Results are shown as percentage (%) of rescue medication-free days; an increased value indicates improvement from baseline. Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3, Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0).
Time frame: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | 13.83 % of of rescue medication-free days |
| Treatment A | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | 16.78 % of of rescue medication-free days |
| Treatment A | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | 15.30 % of of rescue medication-free days |
| Treatment B | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | 15.51 % of of rescue medication-free days |
| Treatment B | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | 15.67 % of of rescue medication-free days |
| Treatment B | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | 15.59 % of of rescue medication-free days |
| Treatment C | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | 14.03 % of of rescue medication-free days |
| Treatment C | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | 15.55 % of of rescue medication-free days |
| Treatment C | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | 14.79 % of of rescue medication-free days |
| Treatment D | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | 18.15 % of of rescue medication-free days |
| Treatment D | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | 18.19 % of of rescue medication-free days |
| Treatment D | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | 18.17 % of of rescue medication-free days |
| Treatment E | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | 7.07 % of of rescue medication-free days |
| Treatment E | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | 8.90 % of of rescue medication-free days |
| Treatment E | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | 7.98 % of of rescue medication-free days |
| Treatment F | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 1 | 13.51 % of of rescue medication-free days |
| Treatment F | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Entire treatment period | 12.39 % of of rescue medication-free days |
| Treatment F | Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period | Inter-visit period 2 | 11.27 % of of rescue medication-free days |
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model repeated for measurements (MMRM), including inter-visit period, treatment by inter-visit period interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by inter-visit period interaction as covariates.p-value: 0.02295% CI: [1.13, 14.63]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.04895% CI: [0.07, 13.48]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.05395% CI: [-0.09, 13.4]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00795% CI: [2.55, 16.04]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.19195% CI: [-2.31, 11.53]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.74795% CI: [-7.8, 5.6]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.7295% CI: [-7.96, 5.5]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.6895% CI: [-5.31, 8.14]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.97195% CI: [-6.82, 6.57]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.4695% CI: [-4.17, 9.21]Mixed Models Analysis
Comparison: Inter-Visit period 1~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.44195% CI: [-4.09, 9.37]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.0795% CI: [-0.55, 14.08]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.02395% CI: [1.16, 15.72]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.06495% CI: [-0.4, 14.31]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00395% CI: [3.79, 18.38]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.27495% CI: [-3.32, 11.72]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.64995% CI: [-5.57, 8.93]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.95895% CI: [-7.12, 7.51]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.24295% CI: [-2.93, 11.58]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.6995% CI: [-8.77, 5.81]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.47395% CI: [-4.58, 9.87]Mixed Models Analysis
Comparison: Inter-Visit period 2~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.26795% CI: [-3.17, 11.43]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.03295% CI: [0.65, 13.99]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.02595% CI: [0.97, 14.24]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.04695% CI: [0.12, 13.49]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00395% CI: [3.52, 16.85]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.20795% CI: [-2.45, 11.25]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.93295% CI: [-6.33, 6.91]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.87995% CI: [-7.17, 6.14]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.39695% CI: [-3.77, 9.5]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.81295% CI: [-7.44, 5.83]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.44495% CI: [-4.03, 9.19]Mixed Models Analysis
Comparison: Entire treatment period~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.31995% CI: [-3.27, 10.04]Mixed Models Analysis
Secondary
Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6
Change from baseline in FEV1 at treatment visit 3 (Week 3) and treatment visit 4 (Week 6) of treatment. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second;
Time frame: Baseline, Week 3, Week 6
Population: Intention to treat All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 3 | 0.059 Litres |
| Treatment A | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 6 | 0.020 Litres |
| Treatment B | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 3 | 0.080 Litres |
| Treatment B | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 6 | 0.088 Litres |
| Treatment C | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 3 | 0.122 Litres |
| Treatment C | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 6 | 0.107 Litres |
| Treatment D | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 3 | 0.111 Litres |
| Treatment D | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 6 | 0.130 Litres |
| Treatment E | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 3 | 0.000 Litres |
| Treatment E | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 6 | -0.012 Litres |
| Treatment F | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 3 | 0.122 Litres |
| Treatment F | Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 | Week 6 | 0.112 Litres |
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: 0.01795% CI: [0.011, 0.107]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00195% CI: [0.032, 0.128]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.074, 0.17]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.063, 0.159]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.074, 0.17]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.37795% CI: [-0.026, 0.069]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.0195% CI: [0.015, 0.111]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.03195% CI: [0.005, 0.1]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.08595% CI: [-0.006, 0.089]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.19995% CI: [-0.016, 0.079]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.65795% CI: [-0.058, 0.037]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.24695% CI: [-0.022, 0.086]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.046, 0.154]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.064, 0.173]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.088, 0.196]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.07, 0.178]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01495% CI: [0.014, 0.121]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00295% CI: [0.032, 0.141]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.057, 0.163]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.49395% CI: [-0.035, 0.073]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.11995% CI: [-0.011, 0.096]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.39295% CI: [-0.03, 0.077]Mixed Models Analysis
Secondary
Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6
Change from baseline in IC at treatment Visit 3 (Week 3) and treatment Visit 4 (Week 6). Spirometry was used to measure IC and was performed according to internationally accepted standards. Definitions: Baseline: value of the measurement recorded at 45 mins pre-dose at Visit 2 (Week 0); IC=Inspiratory capacity;
Time frame: Baseline, Week 3, Week 6
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 3 | 0.156 Litres |
| Treatment A | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 6 | 0.045 Litres |
| Treatment B | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 3 | 0.137 Litres |
| Treatment B | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 6 | 0.090 Litres |
| Treatment C | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 3 | 0.106 Litres |
| Treatment C | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 6 | 0.136 Litres |
| Treatment D | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 3 | 0.140 Litres |
| Treatment D | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 6 | 0.105 Litres |
| Treatment E | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 3 | 0.047 Litres |
| Treatment E | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 6 | 0.025 Litres |
| Treatment F | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 3 | 0.090 Litres |
| Treatment F | Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 | Week 6 | 0.099 Litres |
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model for repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.p-value: 0.02395% CI: [0.015, 0.203]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.05895% CI: [-0.003, 0.184]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.21595% CI: [-0.035, 0.153]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.05195% CI: [-0.001, 0.187]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.36495% CI: [-0.051, 0.138]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.69495% CI: [-0.112, 0.074]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.29795% CI: [-0.143, 0.044]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.73495% CI: [-0.109, 0.077]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.51495% CI: [-0.124, 0.062]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.95795% CI: [-0.09, 0.095]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.47995% CI: [-0.06, 0.127]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.68795% CI: [-0.079, 0.12]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.19595% CI: [-0.034, 0.165]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.0395% CI: [0.011, 0.212]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.11295% CI: [-0.019, 0.179]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.14795% CI: [-0.026, 0.174]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.3795% CI: [-0.054, 0.144]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.07495% CI: [-0.009, 0.19]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.23395% CI: [-0.039, 0.158]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.36995% CI: [-0.054, 0.145]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.77395% CI: [-0.084, 0.112]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.53695% CI: [-0.13, 0.068]Mixed Models Analysis
Secondary
Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1
Number of patients achieving onset of action was defined as a change from baseline in post-dose FEV1 ≥100 mL on Day 1. These are the patients who contributed to the results, reported as median and 95% CI for 'time to onset of action' presented in Outcome Measure 8, above.
Time frame: Day 1
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A | Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1 | 90 Participants |
| Treatment B | Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1 | 103 Participants |
| Treatment C | Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1 | 103 Participants |
| Treatment D | Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1 | 110 Participants |
| Treatment E | Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1 | 74 Participants |
| Treatment F | Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1 | 113 Participants |
Secondary
Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1
Time to onset of action is defined as the time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥100 mL.
Time frame: Day 1
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A | Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1 | 45.1 minutes |
| Treatment B | Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1 | 32.6 minutes |
| Treatment C | Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1 | 29.5 minutes |
| Treatment D | Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1 | 27.3 minutes |
| Treatment E | Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1 | 240.1 minutes |
| Treatment F | Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1 | 28.1 minutes |
Comparison: Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using Cox proportional hazards model, including treatment, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and baseline FEV1 value as covariate.p-value: 0.00295% CI: [1.21, 2.24]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [1.61, 2.94]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [2.07, 3.78]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [2.27, 4.15]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [2.3, 4.17]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.05295% CI: [1, 1.76]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [1.28, 2.26]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [1.41, 2.48]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.07495% CI: [0.98, 1.69]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01395% CI: [1.08, 1.85]Regression, Cox
Comparison: Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.49495% CI: [0.84, 1.44]Regression, Cox
Secondary
Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6
Transitional Dyspnea Index (TDI) focal score at treatment visit 3 (Week 3) and treatment visit 4 (Week 6). TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement), with a total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important. Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;
Time frame: Baseline, Week 3, Week 6
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 3 | 1.29 score on a scale |
| Treatment A | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 6 | 1.65 score on a scale |
| Treatment B | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 3 | 1.55 score on a scale |
| Treatment B | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 6 | 2.02 score on a scale |
| Treatment C | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 3 | 1.54 score on a scale |
| Treatment C | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 6 | 2.05 score on a scale |
| Treatment D | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 3 | 1.94 score on a scale |
| Treatment D | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 6 | 2.55 score on a scale |
| Treatment E | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 6 | 1.03 score on a scale |
| Treatment E | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 3 | 1.14 score on a scale |
| Treatment F | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 6 | 2.11 score on a scale |
| Treatment F | Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 | Week 3 | 1.66 score on a scale |
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.07195% CI: [-0.05, 1.28]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the BDI, BDI by visit interaction as covariates.p-value: 0.66695% CI: [-0.52, 0.81]Mixed Models Analysis
Comparison: week 3~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.22495% CI: [-0.25, 1.07]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.23995% CI: [-0.27, 1.06]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.01995% CI: [0.13, 1.46]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.12495% CI: [-0.14, 1.19]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.43295% CI: [-0.39, 0.92]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.45495% CI: [-0.41, 0.91]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.05395% CI: [-0.01, 1.31]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.97395% CI: [-0.67, 0.65]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.24795% CI: [-0.27, 1.04]Mixed Models Analysis
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.23595% CI: [-0.26, 1.06]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00495% CI: [0.32, 1.64]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00395% CI: [0.35, 1.68]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [0.86, 2.18]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00295% CI: [0.41, 1.75]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.27195% CI: [-0.29, 1.03]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.23595% CI: [-0.26, 1.06]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00795% CI: [0.25, 1.56]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.92395% CI: [-0.63, 0.69]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.10895% CI: [-0.12, 1.19]Mixed Models Analysis
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.13495% CI: [-0.16, 1.16]Mixed Models Analysis
Secondary
Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6
Number of subjects achieving TDI focal score ≥1, at treatment visit 3 (Week 3) and at treatment visit 4 (Week 6). TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement); total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important. Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;
Time frame: Baseline, Week 3, Week 6
Population: Intention to treat:~All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 3 Focal Score ≥ 1 | 70 Participants |
| Treatment A | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 6 Focal Score ≥ 1 | 74 Participants |
| Treatment B | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 3 Focal Score ≥ 1 | 78 Participants |
| Treatment B | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 6 Focal Score ≥ 1 | 83 Participants |
| Treatment C | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 3 Focal Score ≥ 1 | 75 Participants |
| Treatment C | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 6 Focal Score ≥ 1 | 82 Participants |
| Treatment D | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 3 Focal Score ≥ 1 | 84 Participants |
| Treatment D | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 6 Focal Score ≥ 1 | 91 Participants |
| Treatment E | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 3 Focal Score ≥ 1 | 67 Participants |
| Treatment E | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 6 Focal Score ≥ 1 | 55 Participants |
| Treatment F | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 3 Focal Score ≥ 1 | 74 Participants |
| Treatment F | Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 | Week 6 Focal Score ≥ 1 | 80 Participants |
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Analysis based on logistic regression model - multiple logistic regression model, with treatment, US regions, smoking status at screening, and BDI as covariates.p-value: 0.84895% CI: [0.62, 1.77]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.26495% CI: [0.8, 2.28]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.34395% CI: [0.76, 2.18]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.04295% CI: [1.02, 2.98]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.50395% CI: [0.71, 2.02]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.35495% CI: [0.76, 2.16]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.44795% CI: [0.73, 2.07]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.06495% CI: [0.97, 2.83]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.86795% CI: [0.57, 1.62]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.34795% CI: [0.76, 2.22]Regression, Logistic
Comparison: Week 3~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.26995% CI: [0.79, 2.32]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.~Analysis based on logistic regression model - multiple logistic regression model, with treatment, US regions, smoking status at screening, and BDI as covariates.p-value: 0.01895% CI: [1.12, 3.3]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [1.5, 4.49]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [1.75, 5.44]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: <0.00195% CI: [1.94, 6.02]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.00195% CI: [1.41, 4.26]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.28495% CI: [0.78, 2.35]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.10395% CI: [0.91, 2.84]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.04595% CI: [1.01, 3.14]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.55795% CI: [0.67, 2.12]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.34595% CI: [0.74, 2.34]Regression, Logistic
Comparison: Week 6~Comparison treatment groups for this analysis were:~Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD).~Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.p-value: 0.73295% CI: [0.61, 2]Regression, Logistic
Secondary
Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP)
Vital signs -- Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were measured at prespecified times, using a 12-Lead single ECGs were recorded at all study visits (pre-dose at V1 (Week -2) and V3 (Week 3), as well as at pre-dose and 1.5 hours post-dose at Visit 2 (Week 0) and Visit 4 (Week 6). Results are shown by treatment group, as change from baseline (in mmHg) for representative timepoints. Definitions: Baseline=Values recorded pre-dose (Visit 2, Week 0); Day 1=Day of the first dose of randomized study drug (Visit 2, Week 0);
Time frame: Baseline, Day 1, Week 6
Population: Safety population:~All randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 30 min post dose | -1.4 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 11 h post dose | -0.9 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 11 h post dose | 1.1 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 1,5 h post dose | -0.7 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 1,5 h post dose | 0.3 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 11 h post dose | 0.2 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 1,5 h post dose | -1.0 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 1,5 h post dose | -1.3 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 30 min post dose | -0.7 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 30 min post dose | -0.7 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 11 h post dose | -0.9 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 30 min post dose | -1.6 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, pre-dose | 0.4 mmHg |
| Treatment A | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, pre-dose | 0.4 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 1,5 h post dose | -1.8 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 30 min post dose | -0.4 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 30 min post dose | -0.6 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 1,5 h post dose | -1.1 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 11 h post dose | 2.0 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 11 h post dose | 0.3 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, pre-dose | 0.8 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, pre-dose | 0.5 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 30 min post dose | -0.9 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 30 min post dose | -0.9 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 1,5 h post dose | -0.6 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 1,5 h post dose | -2.7 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 11 h post dose | 1.5 mmHg |
| Treatment B | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 11 h post dose | -2.0 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 11 h post dose | -0.0 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 30 min post dose | -0.5 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, pre-dose | -0.3 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 11 h post dose | 0.5 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 11 h post dose | -1.6 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 30 min post dose | -2.1 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 1,5 h post dose | -1.7 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 30 min post dose | -2.0 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 1,5 h post dose | -2.0 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 1,5 h post dose | -0.5 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, pre-dose | 0.4 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 1,5 h post dose | -0.6 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 11 h post dose | -2.3 mmHg |
| Treatment C | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 30 min post dose | -1.5 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 1,5 h post dose | -2.3 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 11 h post dose | 2.2 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 11 h post dose | -1.4 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, pre-dose | -1.0 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 30 min post dose | -1.4 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, pre-dose | -1.0 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 30 min post dose | -2.5 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 30 min post dose | -2.0 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 1,5 h post dose | -2.3 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 30 min post dose | -1.9 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 11 h post dose | -1.4 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 11 h post dose | 1.7 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 1,5 h post dose | -1.6 mmHg |
| Treatment D | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 1,5 h post dose | -1.8 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 1,5 h post dose | -1.1 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, pre-dose | 1.6 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 11 h post dose | 3.2 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 11 h post dose | -1.0 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 30 min post dose | -0.8 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 1,5 h post dose | 0.2 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 1,5 h post dose | 0.1 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, pre-dose | 0.0 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 11 h post dose | -1.0 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 1,5 h post dose | -1.7 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 30 min post dose | 0.5 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 30 min post dose | -0.9 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 30 min post dose | -0.8 mmHg |
| Treatment E | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 11 h post dose | 1.9 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 11 h post dose | -0.7 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 30 min post dose | -1.2 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 11 h post dose | 0.9 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 1,5 h post dose | 0.5 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 1,5 h post dose | -1.5 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, 1,5 h post dose | -0.6 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 11 h post dose | -1.2 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 1,5 h post dose | -1.5 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Week 6, pre-dose | -0.2 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 11 h post dose | 2.0 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | DBP, Day 1, 30 min post dose | 0.1 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, 30 min post dose | 0.1 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Day 1, 30 min post dose | -1.2 mmHg |
| Treatment F | Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) | SBP, Week 6, pre-dose | 1.3 mmHg |