Asthma
Conditions
Brief summary
To evaluate the dose-response of different doses of CHF 1531 pressurized metered dose inhaler (pMDI) containing formoterol fumarate, on lung function and other clinical outcomes and to identify the optimal dose(s) with regard to benefit/ risk ratio for further development in the target subject population.
Detailed description
This is a phase II, randomized, double-blind, placebo and active controlled dose-ranging, 6 arm incomplete block cross-over study to identify the optimal dose of CHF 1531 pMDI (containing formoterol fumarate), with regard to lung function and other clinical efficacy and safety outcome measures. After a 2 week run-in period under rescue albuterol 'as needed' and background inhaled corticosteroid (ICS), subjects qualifying for the study were required to complete 4 treatment intervals of 2 weeks each, separated by 2 week wash-out intervals. During each treatment interval, the subject were randomly assigned to take one of 5 double-blind study treatments twice daily (BID) i.e. one of 4 doses of CHF 1531 pMDI or a matching placebo or the open-label active control treatment (Perforomist® Inhalation Solution \[IS\]) also BID. During the entire study, all subjects concomitantly received ICS treatment with QVAR® inhaler (beclomethasone dipropionate 40 or 80 µg /actuation) twice daily at a dose that matches their pre-enrollment ICS and an albuterol inhaler to use as asthma rescue medication on 'as needed' basis. The subjects visited the study center every 2 weeks to undergo study procedures, and received a safety follow-up phone call one week after their last visit. In total, the study lasted 18 weeks and required 10 visits to the study center. During the study, daily asthma symptoms, peak expiratory flow, rescue and background medication use, and compliance with the study medication were recorded in a subject diary. Treatment-Emergent Adverse Events (TEAEs) were assessed and recorded throughout the study. A full physical exam, routine hematology, blood chemistry, spirometry, vital signs measurement, 12-lead ECG, and pregnancy testing were performed before enrollment and at the end of the study. Furthermore, on Day 1 and 14 of each treatment interval, serial spirometry, 12-lead ECGs, blood pressure measurements (BP), serum potassium, and serum glucose were measured at the study center for up to 12 hours post-dose.
Interventions
DRUGCHF 1531 pMDI
Dose Response: Test one of five different doses of CHF 1531
DRUGFormoterol Inhalation Solution
Active Control
DRUGPlacebo pMDI
Matched Placebo
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects aged ≥18 and ≤75 years who have signed an Informed Consent Form prior to initiation of any study-related procedure. * A diagnosis of asthma as defined in the Global Initiative for Asthma (GINA) Report, 2016, documented for at least 1 year prior to screening. * Poorly controlled or uncontrolled asthma evidenced by a score ≥1.5 on the Asthma Control Questionnaire 7 © (ACQ-7) * A pre-bronchodilator Forced Expiratory Volume in the 1st Second ( FEV1) ≥60% and \<85% of their predicted normal value, after appropriate washout from bronchodilators, at the screening and randomization visits * Subjects with a positive response to a reversibility test at screening, defined as change in FEV1 (ΔFEV1) ≥12% and ≥200 mL over baseline within 30 minutes after inhaling 4 puffs of albuterol hydrofluoroalkane(HFA) 90 µg/actuation. * Use of ICS (low/medium dose according to GINA Report, 2016) with or without a long-acting bronchodilator for 3 months (at a stable dose in the last 4 weeks) before screening visit. * A cooperative attitude and ability to demonstrate correct use of the diary, peak flow meter, and pMDI inhaler.
Exclusion criteria
* Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS they are willing to use a highly effective birth control methods * Subjects who suffer from Chronic Obstructive Pulmonary Disease (COPD) as defined by the Global Strategy for Prevention, Diagnosis and Management of COPD (GOLD) Report, 2017, or are suspected of having Asthma COPD Overlap Syndrome (ACOS) as described in the GINA Report, 2016. * Inability to carry out pulmonary function testing, to comply with study procedures or with study drug intake. * Current smokers or ex-smokers (tobacco, vapor cigarettes, marijuana) with a smoking history of \>10 pack-years or having stopped smoking one year or less prior to screening visit. * History of life-threatening asthma, clinically significant uncontrolled disease or respiratory infection. * An asthma exacerbation requiring oral/intravenous corticosteroids ≤ 30 days, intramuscular depot corticosteroid ≤3 months or hospitalization within 6 months prior to screening. * Subjects with unresolved bacterial or viral respiratory tract, sinus, or middle ear infection affecting asthma status within 2 weeks prior to screening. * Subjects who received a vaccination within 2 weeks prior to screening or during the run-in. * Subjects with oral candidiasis at screening and at randomization. * Subjects with any clinically significant, uncontrolled condition. * Subjects with serum potassium levels \<3.5 milliequivalents per litre (mEq/L) or (3.5 mmol/L) at screening. * 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 patient according to Investigator's judgment. * Subjects whose 12-lead ECG shows Fridericia's corrected QT interval (QTcF) \>450 ms for males or QTcF \>470 ms for females at screening or randomization visits. * Subjects with known intolerance/hypersensitivity or contra-indication to treatment with inhaled β2-adrenergic receptor agonists, corticosteroids or propellant gases/excipients. * Subjects with concomitant immunosuppressive therapy, use of oral or injected corticosteroids, anti- Immunoglobulin E (IgE), anti-Interleukin 5 (IL5) or other monoclonal or polyclonal antibodies within 12 weeks prior to screening. * Use of potent cytochrome P450 3A4 inhibitors and inducers within 4 weeks prior to screening. * 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 |
|---|---|---|
| FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14 | Baseline, Day 14 post-dose | Spirometry used to measure FEV1, was performed according to internationally accepted standards. Results show the change from baseline in FEV1 AUC(0-12h), normalized by time on Day 14; it was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Definitions: AUC=Area under the curve; AUC(0-12h)=AUC between 0 and 12 h; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; FEV1=Forced expiratory volume in the 1st second; |
| Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | Baseline, Day 14 post-dose | The primary analysis was repeated, considering patients as randomized and including only the first instance of each treatment. Patients receiving the same treatment in more than one period were included in the analysis with only data from the first instance of each treatment. |
| Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | Baseline, Day 14 post-dose | The primary analysis was repeated, considering only patients and treatment periods for which treatment was assigned on or after the randomization error occurred. The number of patients shown represents those with at least one post-baseline assessment available. |
| Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | Baseline, Day 14 post-dose | Patients receiving the same treatment during two treatment periods are considered twice in the ANCOVA model (once for each period attended). Patients considered in this analysis are those with at least one available post-baseline assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; |
| FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; |
| Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14 | Baseline, Day 14 post-dose | Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; |
| Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14 | Baseline, Day 14 post-dose | Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; |
| Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | Baseline, Day 1 post-dose | Spirometry, used to measure FEV1, was performed according to internationally accepted standards. For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment. Definitions: Time to onset of action=The time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; |
| Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | Baseline, Day 1 post-dose | Patients achieving onset of action, defined as a change from baseline in post-dose FEV1 ≥12% and ≥200 mL, on Day 1. These are the subjects who contributed to the results, reported as median and 95% CI for 'Time to onset of action' presented in the Outcome Measure 13, above. For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment. Definitions: Onset of action=Change from baseline in post-dose FEV1 ≥12% and ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose); |
| Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | Baseline, Day 1 and Day 14 post-dose | Vital signs -- Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) were measured at pre-specified times (at baseline - pre dose and on Day 14 of each treatment period or on the day of early study termination). Results are shown by treatment group, as change from baseline (in mmHg). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. Definitions: For safety variables, the baseline for each treatment period was defined as pre-dose measurements on Day 1 of each treatment period; Day 14=The day of the last dosing of a treatment period. Day 14 of the second, third, and fourth treatment periods (day of last dosing); treatments were separated by a 2-week wash-out interval; |
| 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Results are shown by treatment group, as change from baseline (in bpm). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. |
| FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 | Baseline, Day 1 post-dose | Spirometry used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; |
| Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Heart rate (HR) peak(0-4h) normalized by time. Results are shown by treatment group, as change from baseline (in bpm). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. Definitions: HR=Heart rate; HR peak(0-4h)=The maximum observed value over 4 hours following dosing; |
| Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | Baseline, Day 14 post-dose | Heart rate (HR) AUC(0-4h) and HR peak(0-4h), normalized by time (in bpm). Results are shown as change from pre-dose on Day 14 (in bpm). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. Definitions: HR=Heart rate; HR AUC(0-4h)=Area under the curve between 0 and 4 h for heart rate; HR peak(0-4h)=The maximum observed value over 4 h after dosing; |
| 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | 12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. |
| 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | 12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. |
| 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | 12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. |
| Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Serum potassium level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. |
| Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Serum glucose level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. |
| Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Heart rate HR AUC(0-4h) normalized by time. Results are shown by treatment group, as change from baseline (in bpm). The HR AUC(0-4h) normalized by time is calculated based on the actual times, using the linear trapezoidal rule. For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. |
| FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Spirometry used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; |
| FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; |
| FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Baseline, Day 1, Day 14 post-dose | Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; |
Countries
United States
Participant flow
Recruitment details
Adult patients with confirmed diagnosis of asthma were recruited into the study according to the trial inclusion and exclusion criteria and were randomized into one of the 6 treatment groups. The total daily dose (TDD) of the trial investigational drug CHF 1531 pressurized metered dose Inhaler (pMDI), inhalation solution (IS) of the direct comparator, or matched placebo is indicated for each treatment group.
Participants by arm
| Arm | Count |
|---|---|
| Trial Participants All trial participants had diagnosed asthma and were randomized to 6 treatments in a cross-over study design. | 67 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Study Participants | Lost to Follow-up | 2 |
| Study Participants | Protocol Violation | 1 |
| Study Participants | Withdrawal by Subject | 6 |
| Treatment A | Lost to Follow-up | 1 |
| Treatment A | Protocol Violation | 1 |
| Treatment A | Withdrawal by Subject | 2 |
| Treatment C | Withdrawal by Subject | 2 |
| Treatment E | Lost to Follow-up | 1 |
| Treatment E | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Trial Participants |
|---|---|
| Age at first diagnosis of asthma | 17.3 years STANDARD_DEVIATION 17.4 |
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 55 Participants |
| Age, Continuous | 46.0 years STANDARD_DEVIATION 15.8 |
| Asthma medication category at study entry ICS/LABA/LAMA | 0 Participants |
| Asthma medication category at study entry ICS/Long-acting muscarinic antagonist (LABA), (free or fixed combination) | 39 Participants |
| Asthma medication category at study entry ICS/Long-acting muscarinic antagonist (LAMA), (free combination) | 1 Participants |
| Asthma medication category at study entry Inhaled corticosteroid (ICS) alone | 27 Participants |
| Asthma medication category at study entry Leukotriene modifiers (LTRM) | 7 Participants |
| Asthma medication category at study entry Short-acting beta2-agonist (SABA [albuterol]) | 62 Participants |
| Asthma medication category at study entry Theophylline | 0 Participants |
| Body Mass Index (BMI) | 32.0 kg/m^2 STANDARD_DEVIATION 8.1 |
| Duration of smoking | 8.0 years STANDARD_DEVIATION 4.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| FEV1 at screening (post-bronchodilator) | 2.548 Litre STANDARD_DEVIATION 0.738 |
| FEV1 at screening (pre-bronchodilator) | 2.128 Litre STANDARD_DEVIATION 0.62 |
| FEV1 % of the normal predicted value (post-bronchodilator) | 84.2 percent STANDARD_DEVIATION 8.1 |
| FEV1 % of the normal predicted value (pre-bronchodilator) | 70.2 percent STANDARD_DEVIATION 6.3 |
| FVC at screening (post-bronchodilator) | 3.450 Litre STANDARD_DEVIATION 1.028 |
| FVC at screening (pre-bronchodilator) | 3.066 Litre STANDARD_DEVIATION 0.993 |
| Height | 167.6 cm STANDARD_DEVIATION 10.1 |
| Number of pack-years | 2.5 pack-years |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 34 Participants |
| Region of Enrollment United States | 67 participants |
| Reversibility FEV1 (%) at screening | 20.1 percent STANDARD_DEVIATION 7.1 |
| Reversibility FEV1 (mL) at screening | 420 millilitre STANDARD_DEVIATION 178 |
| Sex: Female, Male Female | 42 Participants |
| Sex: Female, Male Male | 25 Participants |
| Smoking habits Current smoker | 0 Participants |
| Smoking habits Ex-smoker | 9 Participants |
| Smoking habits Non-smoker | 58 Participants |
| Time since first diagnosis of asthma | 335.2 months |
| Weight | 89.8 kg STANDARD_DEVIATION 23.1 |
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 / 43 | 0 / 36 | 0 / 40 | 0 / 44 | 0 / 45 | 0 / 41 |
| other Total, other adverse events | 2 / 43 | 1 / 36 | 2 / 40 | 2 / 44 | 0 / 45 | 1 / 41 |
| serious Total, serious adverse events | 0 / 43 | 0 / 36 | 0 / 40 | 0 / 44 | 0 / 45 | 0 / 41 |
Outcome results
Primary
FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14
Spirometry used to measure FEV1, was performed according to internationally accepted standards. Results show the change from baseline in FEV1 AUC(0-12h), normalized by time on Day 14; it was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Definitions: AUC=Area under the curve; AUC(0-12h)=AUC between 0 and 12 h; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; FEV1=Forced expiratory volume in the 1st second;
Time frame: Baseline, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A | FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.174 Litres |
| Treatment B | FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.221 Litres |
| Treatment C | FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.197 Litres |
| Treatment D | FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.231 Litres |
| Treatment E | FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.064 Litres |
| Treatment F | FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.208 Litres |
Comparison: Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~The primary endpoint was analyzed using an analysis of covariance (ANCOVA) including treatment, period, and patient as fixed effects and baseline as a covariate. The confidence intervals (CIs) and the p-values of the comparisons between each dose of CHF 1531 pMDI and Placebo at Day 14 were adjusted for multiplicity, based on the parametric simulation method of Edwards and Berry.p-value: <0.00195% CI: [0.05, 0.171]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [0.095, 0.22]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.072, 0.194]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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, 0.225]ANCOVA
Comparison: Comparison groups were:~Treatment F ( Perforomist® IS 40 μg TDD) versus Treatment E (Placebo).~The statistical analysis was performed using an analysis of covariance (ANCOVA) including treatment, period, and patient as fixed effects, and baseline as a covariate.p-value: <0.00195% CI: [0.098, 0.19]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~The statistical analysis was performed using an analysis of covariance (ANCOVA) including treatment, period, and patient as fixed effects, and baseline as a covariate.p-value: 0.05995% CI: [-0.002, 0.095]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.36195% CI: [-0.026, 0.07]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.01695% CI: [0.011, 0.102]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.3495% CI: [-0.075, 0.026]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.6995% CI: [-0.038, 0.058]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.15595% CI: [-0.013, 0.082]ANCOVA
Primary
Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14
The primary analysis was repeated, considering patients as randomized and including only the first instance of each treatment. Patients receiving the same treatment in more than one period were included in the analysis with only data from the first instance of each treatment.
Time frame: Baseline, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A | Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.169 Litres |
| Treatment B | Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.224 Litres |
| Treatment C | Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.196 Litres |
| Treatment D | Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.232 Litres |
| Treatment E | Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.058 Litres |
| Treatment F | Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.206 Litres |
Comparison: Comparison groups:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~Analysis of covariance model: treatment, subject, and period as fixed effects; baseline FEV1 value as covariates. CIs and p-values for CHF 1531 pMDI vs Placebo are adjusted for multiplicity (parametric simulation method by Edwards and Berry). Subjects receiving the same treatment in more than one period are included in the primary efficacy model with only data from the first instance of each treatment.p-value: <0.00195% CI: [0.049, 0.175]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [0.101, 0.23]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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, 0.203]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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, 0.235]ANCOVA
Comparison: Comparison groups were:~Treatment F ( Perforomist® IS 40 μg TDD) versus Treatment E (Placebo).~Analysis of covariance model: treatment, subject, and period as fixed effects; baseline FEV1 value as covariates. Subjects receiving the same treatment in more than one period are included in the primary efficacy model with only data from the first instance of each treatment.p-value: <0.00195% CI: [0.101, 0.197]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Analysis of covariance model: treatment, subject, and period as fixed effects; baseline FEV1 value as covariates. Subjects receiving the same treatment in more than one period are included in the primary efficacy model with only data from the first instance of each treatment.p-value: 0.03595% CI: [0.004, 0.104]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.30195% CI: [-0.024, 0.076]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.01195% CI: [0.014, 0.11]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.29495% CI: [-0.08, 0.024]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.74795% CI: [-0.042, 0.058]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.15595% CI: [-0.014, 0.086]ANCOVA
Primary
Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14
The primary analysis was repeated, considering only patients and treatment periods for which treatment was assigned on or after the randomization error occurred. The number of patients shown represents those with at least one post-baseline assessment available.
Time frame: Baseline, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A | Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.129 Litres |
| Treatment B | Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.180 Litres |
| Treatment C | Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.159 Litres |
| Treatment D | Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.179 Litres |
| Treatment E | Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | -0.006 Litres |
| Treatment F | Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.170 Litres |
Comparison: Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~Analysis of covariance model: treatment, subject, and period as fixed effects; baseline FEV1 value as covariates. CIs and p-values for CHF 1531 pMDI vs Placebo are adjusted for multiplicity (parametric simulation method by Edwards and Berry). Subjects receiving the same treatment in more than one period are included in the model with only data for the instance of each treatment, which occurred after the randomization error.p-value: <0.00195% CI: [0.065, 0.207]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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, 0.258]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.092, 0.238]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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, 0.252]ANCOVA
Comparison: Comparison groups were:~Treatment F ( Perforomist® IS 40 μg TDD) versus Treatment E (Placebo).~Analysis of covariance model: treatment, subject, and period as fixed effects; baseline FEV1 value as covariates. Subjects receiving the same treatment in more than one period are included in the model with only data for the instance of each treatment which occurred after the randomization error.p-value: <0.00195% CI: [0.121, 0.231]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Analysis of covariance model: treatment, subject, and period as fixed effects; baseline FEV1 value as covariates. Subjects receiving the same treatment in more than one period are included in the model with only data for the instance of each treatment which occurred after the randomization error.p-value: 0.08895% CI: [-0.008, 0.108]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.32395% CI: [-0.029, 0.088]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.07395% CI: [-0.005, 0.103]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.48995% CI: [-0.08, 0.039]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.97895% CI: [-0.057, 0.056]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.48495% CI: [-0.037, 0.077]ANCOVA
Primary
Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14
Patients receiving the same treatment during two treatment periods are considered twice in the ANCOVA model (once for each period attended). Patients considered in this analysis are those with at least one available post-baseline assessment.
Time frame: Baseline, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A | Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.144 Litres |
| Treatment B | Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.194 Litres |
| Treatment C | Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.170 Litres |
| Treatment D | Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.198 Litres |
| Treatment E | Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.037 Litres |
| Treatment F | Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | 0.184 Litres |
Comparison: Comparison groups:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~Analysis of covariance model: treatment and period as fixed effects, subject as random effect, baseline FEV1 value as covariate. CIs and p-values for CHF 1531 pMDI vs Placebo are adjusted for multiplicity (parametric simulation method by Edwards and Berry). Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).p-value: <0.00195% CI: [0.048, 0.166]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [0.096, 0.217]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.073, 0.193]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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, 0.217]ANCOVA
Comparison: Comparison groups were:~Treatment F ( Perforomist® IS 40 μg TDD) versus Treatment E (Placebo).~Analysis of covariance model: treatment and period as fixed effects, subject as random effect, baseline FEV1 value as covariate. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).p-value: <0.00195% CI: [0.102, 0.192]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Analysis of covariance model: treatment and period as fixed effects, subject as random effect, baseline FEV1 value as covariate. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).p-value: 0.04195% CI: [0.002, 0.098]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.27595% CI: [-0.021, 0.073]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.02195% CI: [0.008, 0.098]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.3595% CI: [-0.073, 0.026]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.88695% CI: [-0.044, 0.051]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #6 of this outcome measure.p-value: 0.25495% CI: [-0.02, 0.074]ANCOVA
Secondary
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14
Results are shown by treatment group, as change from baseline (in bpm). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period.
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 5.0 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 2.5 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 7.4 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 0.3 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 5.1 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | -1.3 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 1.9 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 2.9 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 5.5 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 2.1 bpm |
| Treatment A | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 2.8 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 2.4 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 2.3 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.2 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 0.3 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 5.5 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | -1.2 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 0.1 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 3.5 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 7.5 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | -0.8 bpm |
| Treatment B | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 1.5 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 1.6 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 6.7 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 2.7 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 6.7 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 3.3 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 5.0 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 5.5 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 3.1 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 4.9 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 1.6 bpm |
| Treatment C | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.7 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 2.0 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 5.3 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 3.4 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 1.5 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 5.4 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 2.5 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 4.3 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 7.6 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 3.8 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 3.9 bpm |
| Treatment D | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 3.2 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 0.5 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | -2.4 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | -1.8 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 0.2 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 2.4 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 0.7 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | -1.5 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | -1.2 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 1.8 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 1.6 bpm |
| Treatment E | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 0.5 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 1.3 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 0.4 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 5.2 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 5.1 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 2.6 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 2.1 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 3.2 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | -1.2 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | -0.3 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 2.3 bpm |
| Treatment F | 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 0.4 bpm |
Secondary
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14
12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period.
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | -1.9 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 1.3 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | -3.4 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | -2.6 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 1.1 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | -5.0 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | -1.5 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 1.0 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | -1.2 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | -0.1 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | -0.2 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 1.6 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 1.7 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 3.7 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 1.5 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | -2.3 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 5.7 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | -0.5 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.6 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 2.5 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 4.5 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 2.2 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | -1.5 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | -1.3 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | -4.8 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | -1.1 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | -1.5 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | -3.0 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | -3.8 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | -1.7 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 0.1 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | -2.5 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | -3.2 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | -2.6 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | -3.1 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | -4.0 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | -1.6 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | -3.0 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | -2.9 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | -0.7 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | -3.6 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | -5.4 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | -3.2 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | -1.4 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 0.8 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 3.4 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | -1.1 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 0.1 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | -2.6 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | -2.4 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 0.4 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.0 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 5.2 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 0.1 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | -1.6 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | -1.7 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 3.2 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 2.2 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 1.9 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 5.1 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 2.0 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 6.1 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 1.3 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | -0.3 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | -0.0 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 0.8 msec |
Secondary
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14
12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period.
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 1.4 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 0.5 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 0.8 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 2.0 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 0.5 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 1.3 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.2 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 1.2 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 0.6 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 1.3 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 0.7 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 1.2 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 1.6 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 0.9 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 1.0 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 2.1 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 0.4 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 1.8 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 0.9 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.2 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 1.0 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 1.0 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | -0.5 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 0.4 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 0.5 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 1.2 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.7 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 2.2 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 0.1 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 1.3 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 0.3 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 0.6 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 1.0 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 1.4 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.1 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 1.6 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 2.1 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 0.5 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 0.9 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 1.7 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 2.4 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 2.3 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 2.8 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 1.4 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 0.0 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 1.0 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | -1.0 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | -0.8 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | -0.2 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 1.0 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 0.4 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 0.8 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | -0.2 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | -0.3 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | -0.9 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 0.8 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 0.5 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 1.0 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 0.8 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 0.5 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 1.1 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 1.1 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 1.4 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 0.9 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.3 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 1.7 msec |
Secondary
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14
12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period.
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 1.5 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 2.0 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 2.4 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 3.4 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 3.9 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 2.1 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 3.7 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 4.0 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 4.4 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 2.5 msec |
| Treatment A | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 3.8 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 1.0 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 0.9 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 1.0 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | -0.4 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 1.1 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 1.7 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 1.4 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 1.5 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 3.8 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 1.7 msec |
| Treatment B | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 0.9 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 1.9 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 3.5 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 2.7 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 3.9 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 0.8 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 0.6 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | -0.3 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 1.6 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 1.1 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 1.7 msec |
| Treatment C | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | -0.9 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 10.4 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 2.2 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | 5.0 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 4.2 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 7.7 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | 1.1 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 4.9 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 5.8 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | 0.8 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | 3.7 msec |
| Treatment D | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | 2.4 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | -2.4 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | -1.5 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 0.9 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | -2.3 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | 0.4 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 1.9 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | -0.2 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | -1.1 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | -0.6 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 1.5 msec |
| Treatment E | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | -0.2 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 4h post-dose | -1.1 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 12h post-dose | -1.6 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 8h post-dose | -2.4 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, pre-dose | 1.2 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 1h post-dose | -0.9 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 4h post-dose | -1.3 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 12h post-dose | -2.2 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 1h post-dose | 0.6 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1, 30 min post-dose | 1.4 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 30 min post-dose | 1.7 msec |
| Treatment F | 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14, 8h post-dose | 0.4 msec |
Secondary
FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1
Spirometry used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;
Time frame: Baseline, Day 1 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A | FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 | 0.181 Litres |
| Treatment B | FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 | 0.221 Litres |
| Treatment C | FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 | 0.260 Litres |
| Treatment D | FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 | 0.282 Litres |
| Treatment E | FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 | 0.067 Litres |
| Treatment F | FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 | 0.239 Litres |
Comparison: Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~This secondary efficacy variable was analyzed using the ANCOVA model that was also used for the primary efficacy analysis, without adjusting for multiplicity.p-value: <0.00195% CI: [0.06, 0.169]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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, 0.208]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.138, 0.247]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [0.163, 0.268]ANCOVA
Comparison: Comparison groups were:~Treatment F ( Perforomist® IS 40 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, 0.224]ANCOVA
Comparison: Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.16595% CI: [-0.016, 0.095]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.00595% CI: [0.024, 0.132]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: <0.00195% CI: [0.049, 0.153]ANCOVA
Comparison: Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.18795% CI: [-0.019, 0.097]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.02895% CI: [0.007, 0.116]ANCOVA
Comparison: Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.40695% CI: [-0.031, 0.076]ANCOVA
Secondary
FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14
Spirometry used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.~Due to an error in the randomization system during the trial, some patients received the same treatment in several treatment period, as summarized in section Participant Flow.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.220 Litres |
| Treatment A | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.214 Litres |
| Treatment B | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.250 Litres |
| Treatment B | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.251 Litres |
| Treatment C | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.270 Litres |
| Treatment C | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.231 Litres |
| Treatment D | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.317 Litres |
| Treatment D | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.278 Litres |
| Treatment E | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.047 Litres |
| Treatment E | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.061 Litres |
| Treatment F | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.288 Litres |
| Treatment F | FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.259 Litres |
Comparison: Day 1~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~This secondary efficacy variable was analyzed using the ANCOVA model that was also used for the primary efficacy analysis, without adjusting for multiplicity.p-value: <0.00195% CI: [0.116, 0.23]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [0.146, 0.26]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.166, 0.28]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [0.216, 0.325]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.187, 0.295]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.30895% CI: [-0.028, 0.089]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.08295% CI: [-0.006, 0.107]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: <0.00195% CI: [0.043, 0.152]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.5295% CI: [-0.041, 0.08]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.02295% CI: [0.01, 0.124]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.09895% CI: [-0.009, 0.103]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 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: [0.095, 0.21]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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, 0.249]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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, 0.228]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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, 0.272]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.144, 0.252]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.20395% CI: [-0.02, 0.095]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.54295% CI: [-0.039, 0.074]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.02195% CI: [0.01, 0.119]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.5195% CI: [-0.08, 0.04]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.35295% CI: [-0.03, 0.084]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.09895% CI: [-0.009, 0.103]ANCOVA
Secondary
FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14
Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.359 Litres |
| Treatment A | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.346 Litres |
| Treatment B | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.370 Litres |
| Treatment B | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.373 Litres |
| Treatment C | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.393 Litres |
| Treatment C | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.349 Litres |
| Treatment D | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.430 Litres |
| Treatment D | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.389 Litres |
| Treatment E | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.178 Litres |
| Treatment E | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.183 Litres |
| Treatment F | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.416 Litres |
| Treatment F | FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.367 Litres |
Comparison: Day 1~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~This secondary efficacy variable was analyzed using the ANCOVA model that was also used for the primary efficacy analysis, without adjusting for multiplicity.p-value: <0.00195% CI: [0.122, 0.241]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [0.133, 0.251]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.156, 0.275]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [0.195, 0.309]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.182, 0.295]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.72395% CI: [-0.049, 0.071]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.25795% CI: [-0.025, 0.093]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.01695% CI: [0.014, 0.128]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.46495% CI: [-0.039, 0.086]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.04895% CI: [0, 0.12]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.21995% CI: [-0.022, 0.095]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 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: [0.1, 0.226]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [0.126, 0.254]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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, 0.229]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [0.146, 0.266]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.125, 0.243]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.495% CI: [-0.036, 0.09]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.93195% CI: [-0.059, 0.064]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.1695% CI: [-0.017, 0.102]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.46495% CI: [-0.09, 0.041]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.62395% CI: [-0.047, 0.078]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.19795% CI: [-0.021, 0.101]ANCOVA
Secondary
FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14
Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.111 Litres |
| Treatment A | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.103 Litres |
| Treatment B | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.156 Litres |
| Treatment B | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.134 Litres |
| Treatment C | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.160 Litres |
| Treatment C | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.120 Litres |
| Treatment D | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.182 Litres |
| Treatment D | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.142 Litres |
| Treatment E | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.059 Litres |
| Treatment E | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.060 Litres |
| Treatment F | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.172 Litres |
| Treatment F | FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.134 Litres |
Comparison: Day 1~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~This secondary efficacy variable was analyzed using the ANCOVA model that was also used for the primary efficacy analysis, without adjusting for multiplicity.p-value: 0.09895% CI: [-0.01, 0.113]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [0.035, 0.159]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.039, 0.163]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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, 0.182]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.054, 0.171]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.16295% CI: [-0.018, 0.108]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.11795% CI: [-0.012, 0.11]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.0295% CI: [0.011, 0.13]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.90995% CI: [-0.062, 0.07]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.41995% CI: [-0.037, 0.088]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.48395% CI: [-0.039, 0.083]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.12695% CI: [-0.012, 0.099]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.01295% CI: [0.017, 0.131]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.03795% CI: [0.004, 0.116]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [0.028, 0.136]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.021, 0.127]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.28295% CI: [-0.025, 0.087]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.55495% CI: [-0.039, 0.072]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.14995% CI: [-0.014, 0.091]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.63695% CI: [-0.072, 0.044]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.77595% CI: [-0.047, 0.063]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.42595% CI: [-0.032, 0.077]ANCOVA
Secondary
FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14
Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.158 Litres |
| Treatment A | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.135 Litres |
| Treatment B | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.186 Litres |
| Treatment B | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.146 Litres |
| Treatment C | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.159 Litres |
| Treatment C | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.136 Litres |
| Treatment D | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.215 Litres |
| Treatment D | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.194 Litres |
| Treatment E | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.036 Litres |
| Treatment E | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.050 Litres |
| Treatment F | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.213 Litres |
| Treatment F | FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.177 Litres |
Comparison: Day 1~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~This secondary efficacy variable was analyzed using the ANCOVA model that was also used for the primary efficacy analysis, without adjusting for multiplicity.p-value: <0.00195% CI: [0.058, 0.187]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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, 0.215]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.059, 0.189]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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, 0.242]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.115, 0.238]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.4195% CI: [-0.039, 0.094]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.96195% CI: [-0.063, 0.066]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.0795% CI: [-0.005, 0.119]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.45495% CI: [-0.095, 0.043]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.3795% CI: [-0.035, 0.095]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.08695% CI: [-0.008, 0.12]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.01195% CI: [0.02, 0.151]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [0.029, 0.164]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.0195% CI: [0.021, 0.153]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [0.081, 0.208]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.065, 0.189]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.7495% CI: [-0.055, 0.078]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.97395% CI: [-0.064, 0.066]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.06495% CI: [-0.003, 0.122]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.77495% CI: [-0.079, 0.059]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.15195% CI: [-0.018, 0.113]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.07695% CI: [-0.006, 0.122]ANCOVA
Secondary
FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14
Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.331 Litres |
| Treatment A | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.310 Litres |
| Treatment B | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.347 Litres |
| Treatment B | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.331 Litres |
| Treatment C | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.354 Litres |
| Treatment C | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.304 Litres |
| Treatment D | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.367 Litres |
| Treatment D | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.350 Litres |
| Treatment E | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.216 Litres |
| Treatment E | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.198 Litres |
| Treatment F | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 1 | 0.385 Litres |
| Treatment F | FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Day 14 | 0.340 Litres |
Comparison: Day 1~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~This secondary efficacy variable was analyzed using the ANCOVA model that was also used for the primary efficacy analysis, without adjusting for multiplicity.p-value: 0.00395% CI: [0.039, 0.19]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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, 0.206]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.061, 0.213]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [0.078, 0.223]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.097, 0.24]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.67995% CI: [-0.061, 0.093]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.54995% CI: [-0.052, 0.098]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.32395% CI: [-0.036, 0.109]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.86695% CI: [-0.073, 0.087]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.59695% CI: [-0.055, 0.096]ANCOVA
p-value: 0.7295% CI: [-0.061, 0.088]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 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: [0.038, 0.185]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [0.057, 0.209]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [0.032, 0.18]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [0.081, 0.223]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [0.072, 0.212]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.57395% CI: [-0.053, 0.096]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.88195% CI: [-0.078, 0.067]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.26195% CI: [-0.03, 0.11]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.49395% CI: [-0.104, 0.051]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.61695% CI: [-0.055, 0.092]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.21295% CI: [-0.026, 0.118]ANCOVA
Secondary
Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14
Heart rate (HR) AUC(0-4h) and HR peak(0-4h), normalized by time (in bpm). Results are shown as change from pre-dose on Day 14 (in bpm). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. Definitions: HR=Heart rate; HR AUC(0-4h)=Area under the curve between 0 and 4 h for heart rate; HR peak(0-4h)=The maximum observed value over 4 h after dosing;
Time frame: Baseline, Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR AUC(0-4h) | -0.4 bpm |
| Treatment A | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR peak(0-4h) | 3.5 bpm |
| Treatment B | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR peak(0-4h) | 5.1 bpm |
| Treatment B | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR AUC(0-4h) | 0.5 bpm |
| Treatment C | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR peak(0-4h) | 5.1 bpm |
| Treatment C | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR AUC(0-4h) | 0.4 bpm |
| Treatment D | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR AUC(0-4h) | 1.3 bpm |
| Treatment D | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR peak(0-4h) | 5.3 bpm |
| Treatment E | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR AUC(0-4h) | -0.2 bpm |
| Treatment E | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR peak(0-4h) | 4.3 bpm |
| Treatment F | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR peak(0-4h) | 4.8 bpm |
| Treatment F | Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | HR AUC(0-4h) | 0.9 bpm |
Secondary
Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14
Heart rate HR AUC(0-4h) normalized by time. Results are shown by treatment group, as change from baseline (in bpm). The HR AUC(0-4h) normalized by time is calculated based on the actual times, using the linear trapezoidal rule. For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period.
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 0.2 bpm |
| Treatment A | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 2.3 bpm |
| Treatment B | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 0.8 bpm |
| Treatment B | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 0.2 bpm |
| Treatment C | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 2.7 bpm |
| Treatment C | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 3.5 bpm |
| Treatment D | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 3.0 bpm |
| Treatment D | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 3.3 bpm |
| Treatment E | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | -1.0 bpm |
| Treatment E | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | -0.1 bpm |
| Treatment F | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 0.3 bpm |
| Treatment F | Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 1.2 bpm |
Secondary
Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14
Heart rate (HR) peak(0-4h) normalized by time. Results are shown by treatment group, as change from baseline (in bpm). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. Definitions: HR=Heart rate; HR peak(0-4h)=The maximum observed value over 4 hours following dosing;
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 4.7 bpm |
| Treatment A | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 6.1 bpm |
| Treatment B | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 4.4 bpm |
| Treatment B | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 4.8 bpm |
| Treatment C | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 6.5 bpm |
| Treatment C | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 8.3 bpm |
| Treatment D | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 7.5 bpm |
| Treatment D | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 7.3 bpm |
| Treatment E | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 2.9 bpm |
| Treatment E | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 4.4 bpm |
| Treatment F | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1 | 5.1 bpm |
| Treatment F | Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14 | 5.2 bpm |
Secondary
Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1
Patients achieving onset of action, defined as a change from baseline in post-dose FEV1 ≥12% and ≥200 mL, on Day 1. These are the subjects who contributed to the results, reported as median and 95% CI for 'Time to onset of action' presented in the Outcome Measure 13, above. For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment. Definitions: Onset of action=Change from baseline in post-dose FEV1 ≥12% and ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose);
Time frame: Baseline, Day 1 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A | Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 23 Participants |
| Treatment B | Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 22 Participants |
| Treatment C | Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 30 Participants |
| Treatment D | Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 29 Participants |
| Treatment E | Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 11 Participants |
| Treatment F | Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 31 Participants |
Secondary
Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14
Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;
Time frame: Baseline, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A | Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14 | 0.071 Litres |
| Treatment B | Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14 | 0.102 Litres |
| Treatment C | Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14 | 0.073 Litres |
| Treatment D | Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14 | 0.149 Litres |
| Treatment E | Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14 | 0.037 Litres |
| Treatment F | Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14 | 0.126 Litres |
Comparison: Day 1~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~This secondary efficacy variable was analyzed using the ANCOVA model that was also used for the primary efficacy analysis, without adjusting for multiplicity.p-value: 0.36195% CI: [-0.039, 0.106]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.08595% CI: [-0.009, 0.138]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.32895% CI: [-0.037, 0.109]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [0.042, 0.182]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment F ( Perforomist® IS 40 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.01195% CI: [0.02, 0.158]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.40495% CI: [-0.042, 0.104]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.94295% CI: [-0.069, 0.074]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.02795% CI: [0.009, 0.147]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.46395% CI: [-0.104, 0.048]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.295% CI: [-0.025, 0.119]ANCOVA
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.03795% CI: [0.005, 0.146]ANCOVA
Secondary
Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14
Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;
Time frame: Baseline, Day 14 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A | Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14 | 0.048 Litres |
| Treatment B | Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14 | 0.044 Litres |
| Treatment C | Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14 | 0.048 Litres |
| Treatment D | Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14 | 0.114 Litres |
| Treatment E | Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14 | 0.053 Litres |
| Treatment F | Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14 | 0.114 Litres |
Comparison: Day 14~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~This secondary efficacy variable was analyzed using the ANCOVA model that was also used for the primary efficacy analysis, without adjusting for multiplicity.p-value: 0.89695% CI: [-0.083, 0.073]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.8195% CI: [-0.089, 0.07]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.88295% CI: [-0.084, 0.073]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [-0.015, 0.136]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment F ( Perforomist® IS 40 μg TDD) versus Treatment E (Placebo).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.11195% CI: [-0.014, 0.134]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.91195% CI: [-0.083, 0.074]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.98595% CI: [-0.078, 0.077]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.08495% CI: [-0.009, 0.14]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.92895% CI: [-0.078, 0.086]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.07895% CI: [-0.008, 0.148]ANCOVA
Comparison: Day 14~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment C (CHF 1531 pMDI 24 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.08995% CI: [-0.01, 0.143]ANCOVA
Secondary
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14
Serum glucose level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period.
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 1.5h post-dose | 0.49 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 3h post-dose | 0.45 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 11h post-dose | 0.98 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 5h post-dose | 0.04 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; pre-dose | -0.34 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 11h post-dose | 0.39 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 3h post-dose | 0.09 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 5h post-dose | 0.83 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 1.5h post-dose | 0.09 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 7h post-dose | -0.04 mmol/L |
| Treatment A | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 7h post-dose | 0.81 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 1.5h post-dose | 0.26 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 7h post-dose | 0.60 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 5h post-dose | 0.90 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 7h post-dose | 0.42 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 11h post-dose | 1.08 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 3h post-dose | 0.54 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 3h post-dose | 0.77 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 5h post-dose | 1.12 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 1.5h post-dose | 0.34 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 11h post-dose | 1.30 mmol/L |
| Treatment B | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; pre-dose | 0.00 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 1.5h post-dose | 0.57 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 1.5h post-dose | 0.97 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 3h post-dose | 1.10 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 7h post-dose | 0.73 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 5h post-dose | 1.11 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; pre-dose | 0.49 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 7h post-dose | 1.24 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 5h post-dose | 1.12 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 11h post-dose | 1.89 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 11h post-dose | 1.50 mmol/L |
| Treatment C | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 3h post-dose | 1.31 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 7h post-dose | 1.09 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 1.5h post-dose | 1.19 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 3h post-dose | 1.79 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 5h post-dose | 1.58 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 7h post-dose | 1.37 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 11h post-dose | 1.42 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; pre-dose | 0.49 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 1.5h post-dose | 1.21 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 3h post-dose | 1.51 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 5h post-dose | 1.16 mmol/L |
| Treatment D | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 11h post-dose | 1.47 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; pre-dose | 0.37 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 3h post-dose | 0.25 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 11h post-dose | 1.40 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 7h post-dose | 0.84 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 11h post-dose | 1.03 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 5h post-dose | 0.32 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 5h post-dose | 0.51 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 7h post-dose | 0.25 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 3h post-dose | 0.26 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 1.5h post-dose | 0.47 mmol/L |
| Treatment E | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 1.5h post-dose | 0.35 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 1.5h post-dose | -0.06 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 11h post-dose | 0.90 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 11h post-dose | 0.68 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 3h post-dose | 0.39 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 3h post-dose | 0.16 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 5h post-dose | 0.53 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 7h post-dose | 0.61 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 1.5h post-dose | -0.03 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; 7h post-dose | 0.18 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 14; pre-dose | -0.03 mmol/L |
| Treatment F | Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Day 1; 5h post-dose | 0.44 mmol/L |
Secondary
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14
Serum potassium level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period.
Time frame: Baseline, Day 1, Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 11h post-dose | 0.11 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; pre-dose | 0.06 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 11h post-dose | 0.07 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 3h post-dose | -0.06 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 1.5h post-dose | -0.01 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 7h post-dose | 0.05 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 5h post-dose | -0.02 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 5h post-dose | -0.14 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 3h post-dose | -0.04 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 7h post-dose | -0.02 mmol/L |
| Treatment A | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 1.5h post-dose | -0.02 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 1.5h post-dose | -0.03 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; pre-dose | -0.02 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 7h post-dose | -0.00 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 5h post-dose | -0.03 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 11h post-dose | 0.02 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 7h post-dose | 0.06 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 1.5h post-dose | -0.05 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 3h post-dose | -0.08 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 3h post-dose | -0.09 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 11h post-dose | 0.05 mmol/L |
| Treatment B | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 5h post-dose | -0.05 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 3h post-dose | -0.23 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 1.5h post-dose | -0.08 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 5h post-dose | -0.12 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 1.5h post-dose | -0.10 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 7h post-dose | -0.05 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 11h post-dose | -0.08 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; pre-dose | 0.08 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 3h post-dose | -0.13 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 5h post-dose | -0.01 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 7h post-dose | 0.09 mmol/L |
| Treatment C | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 11h post-dose | 0.03 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 3h post-dose | -0.28 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 3h post-dose | -0.24 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 7h post-dose | -0.16 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 5h post-dose | -0.26 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 11h post-dose | -0.06 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 11h post-dose | -0.10 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 1.5h post-dose | -0.23 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; pre-dose | -0.14 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 7h post-dose | -0.19 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 1.5h post-dose | -0.17 mmol/L |
| Treatment D | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 5h post-dose | -0.19 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 7h post-dose | 0.04 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; pre-dose | 0.05 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 1.5h post-dose | -0.03 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 5h post-dose | -0.04 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 3h post-dose | -0.00 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 3h post-dose | 0.03 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 5h post-dose | 0.00 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 11h post-dose | 0.01 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 7h post-dose | 0.02 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 1.5h post-dose | -0.06 mmol/L |
| Treatment E | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 11h post-dose | 0.01 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 1.5h post-dose | -0.18 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; pre-dose | -0.13 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 1.5h post-dose | -0.15 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 11h post-dose | -0.13 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 7h post-dose | -0.09 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 7h post-dose | -0.14 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 3h post-dose | -0.21 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 3h post-dose | -0.15 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 1; 5h post-dose | -0.20 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 5h post-dose | -0.15 mmol/L |
| Treatment F | Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Day 14; 11h post-dose | -0.02 mmol/L |
Secondary
Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1
Spirometry, used to measure FEV1, was performed according to internationally accepted standards. For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment. Definitions: Time to onset of action=The time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;
Time frame: Baseline, Day 1 post-dose
Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 358.8 minutes |
| Treatment B | Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 60.3 minutes |
| Treatment C | Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 33.6 minutes |
| Treatment D | Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 44.3 minutes |
| Treatment E | Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | NA minutes |
| Treatment F | Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | 45.5 minutes |
Comparison: Day 1~Comparison groups were:~Treatment A (CHF 1531 pMDI 6 μg TDD) versus Treatment E (Placebo).~Time to onset of action was analyzed using a Cox proportional hazard model stratified by patient, including treatment and period as a factor, and baseline FEV1 as covariate.~For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment.p-value: <0.00195% CI: [4.25, 76.37]Regression, Cox
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 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: [7.52, 133.47]Regression, Cox
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 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: [10.23, 191.34]Regression, Cox
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 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: [9.54, 170.45]Regression, Cox
Comparison: Day 1~Comparison groups were:~Treatment F ( Perforomist® IS 40 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: [5.7, 92.06]Regression, Cox
Comparison: Day 1~Comparison groups were:~Treatment B (CHF 1531 pMDI 12 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.19595% CI: [0.75, 4.13]Regression, Cox
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.03795% CI: [1.06, 5.72]Regression, Cox
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment A (CHF 1531 pMDI 6 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.04295% CI: [1.03, 4.86]Regression, Cox
Comparison: Day 1~Comparison groups were:~Treatment C (CHF 1531 pMDI 24 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.43595% CI: [0.6, 3.23]Regression, Cox
Comparison: Day 1~Comparison groups were:~Treatment D (CHF 1531 pMDI 48 μg TDD) versus Treatment B (CHF 1531 pMDI 12 μg TDD).~Statistical analysis was performed as described for the statistical analysis #1 of this outcome measure.p-value: 0.56495% CI: [0.56, 2.89]Regression, Cox
p-value: 0.81895% CI: [0.41, 2.01]Regression, Cox
Secondary
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14
Vital signs -- Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) were measured at pre-specified times (at baseline - pre dose and on Day 14 of each treatment period or on the day of early study termination). Results are shown by treatment group, as change from baseline (in mmHg). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. Definitions: For safety variables, the baseline for each treatment period was defined as pre-dose measurements on Day 1 of each treatment period; Day 14=The day of the last dosing of a treatment period. Day 14 of the second, third, and fourth treatment periods (day of last dosing); treatments were separated by a 2-week wash-out interval;
Time frame: Baseline, Day 1 and Day 14 post-dose
Population: Safety population:~All randomized patients who received at least one dose of study treatment within the given period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 1 h post-dose | 0.1 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 1 h post-dose | -0.1 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 12 h post-dose | 1.2 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 4 h post-dose | 0.9 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 8 h post-dose | 0.7 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 30 min post-dose | -1.2 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 4 h post-dose | -1.0 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 4 h post-dose | 1.7 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 1 h post-dose | -0.3 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 30 min post-dose | -0.2 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 8 h post-dose | 0.8 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, pre-dose | -1.2 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 12 h post-dose | 1.8 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 12 h post-dose | 0.0 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 12 h post-dose | -0.5 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, pre-dose | 1.0 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 8 h post-dose | -1.5 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 4 h post-dose | -0.6 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 30 min post-dose | 0.3 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 8 h post-dose | -1.1 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 1 h post-dose | 0.0 mmHg |
| Treatment A | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 30 min post-dose | -2.1 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 12 h post-dose | -0.7 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 1 h post-dose | -1.8 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 30 min post-dose | -1.5 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 12 h post-dose | 1.0 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, pre-dose | 0.1 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 8 h post-dose | 1.3 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, pre-dose | -1.8 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 4 h post-dose | 0.1 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 1 h post-dose | 0.5 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 8 h post-dose | -1.0 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 12 h post-dose | 2.1 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 4 h post-dose | -1.5 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 1 h post-dose | -1.9 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 1 h post-dose | -2.4 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 12 h post-dose | -0.1 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 4 h post-dose | 0.4 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 30 min post-dose | 0.2 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 4 h post-dose | -1.4 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 30 min post-dose | -2.1 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 8 h post-dose | -0.9 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 30 min post-dose | -3.1 mmHg |
| Treatment B | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 8 h post-dose | 0.2 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, pre-dose | 1.1 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 30 min post-dose | -0.8 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 1 h post-dose | -0.6 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 4 h post-dose | -0.9 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 8 h post-dose | 1.1 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 12 h post-dose | 3.0 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, pre-dose | 0.0 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 30 min post-dose | -0.7 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 1 h post-dose | -1.8 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 4 h post-dose | -1.4 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 8 h post-dose | 1.1 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 12 h post-dose | 1.5 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 30 min post-dose | -1.2 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 1 h post-dose | -0.4 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 4 h post-dose | -0.4 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 8 h post-dose | -0.4 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 12 h post-dose | 0.4 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 30 min post-dose | -0.8 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 1 h post-dose | -0.5 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 4 h post-dose | -1.7 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 8 h post-dose | 0.3 mmHg |
| Treatment C | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 12 h post-dose | 0.7 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 4 h post-dose | -1.0 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 30 min post-dose | -2.0 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 30 min post-dose | -0.7 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 8 h post-dose | -2.6 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 1 h post-dose | -1.6 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, pre-dose | -0.4 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 8 h post-dose | -1.9 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 12 h post-dose | 1.4 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 30 min post-dose | -1.2 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 12 h post-dose | -1.0 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 8 h post-dose | 0.7 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, pre-dose | -0.1 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 30 min post-dose | -2.9 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 4 h post-dose | 0.9 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 1 h post-dose | -2.4 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 1 h post-dose | -0.6 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 12 h post-dose | -0.6 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 4 h post-dose | -2.5 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 4 h post-dose | 1.0 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 8 h post-dose | 0.6 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 1 h post-dose | -1.9 mmHg |
| Treatment D | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 12 h post-dose | 4.4 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 1 h post-dose | -2.5 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 8 h post-dose | -1.7 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 12 h post-dose | -0.1 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 4 h post-dose | 0.4 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 12 h post-dose | -0.3 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 8 h post-dose | 0.5 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 4 h post-dose | -0.5 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, pre-dose | -0.6 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 4 h post-dose | 0.2 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 1 h post-dose | -1.7 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 30 min post-dose | -1.5 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 12 h post-dose | 1.4 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 30 min post-dose | -0.3 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 30 min post-dose | -3.6 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 1 h post-dose | -1.8 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 1 h post-dose | -0.8 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 8 h post-dose | -3.3 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, pre-dose | -2.5 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 8 h post-dose | -1.7 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 12 h post-dose | -0.3 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 4 h post-dose | -1.6 mmHg |
| Treatment E | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 30 min post-dose | -0.5 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 12 h post-dose | -0.1 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 12 h post-dose | 2.5 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 8 h post-dose | 0.4 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 30 min post-dose | -2.5 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 8 h post-dose | 0.6 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 8 h post-dose | -1.3 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 4 h post-dose | -2.3 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 30 min post-dose | -0.8 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 12 h post-dose | 0.0 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 8 h post-dose | 2.5 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 1 h post-dose | -1.7 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 30 min post-dose | -1.2 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 4 h post-dose | -0.8 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, pre-dose | -0.3 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, pre-dose | -0.7 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 4 h post-dose | 0.5 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 12 h post-dose | 3.4 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 1 h post-dose | -1.6 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 1, 4 h post-dose | -1.0 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | DBP, Day 14, 30 min post-dose | -2.0 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 14, 1 h post-dose | -1.1 mmHg |
| Treatment F | Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | SBP, Day 1, 1 h post-dose | -0.8 mmHg |