Asthma
Conditions
Brief summary
The primary objective of this study is to determine the efficacy and safety of 4 doses of BI 1744 CL inhalation solution delivered by the Respimat® inhaler once daily for four weeks in patients with asthma in comparison to placebo.
Interventions
DRUGPlacebo
Determine efficacy and safety of Placebo inhaled once daily from the Respimat inhaler and/or twice daily from the Aerolizer inhaler
Determine efficacy and safety in 4 different doses of Olodaterol (BI 1744) inhaled once daily via the Respimat
DRUGOlodaterol (BI 1744) medium
Determination of efficacy in 4 different doses of Olodaterol (BI 1744) inhaled once daily via the Respimat
DRUGOlodaterol (BI 1744) very low
Determination of efficacy in 4 different doses of Olodaterol (BI 1744) inhaled once daily via the Respimat
Determine efficacy and safety of 12 mcg Formoterol dose inhaled orally twice daily from the Aerolizer in comparison to other treatment groups
Determine efficacy and safety of 4 different doses of Olodaterol (BI 1744) inhaled once daily via the Respimat
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. All patients must sign an informed consent consistent with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, i.e. prior to any study procedures which includes medication washout and restrictions. A separate informed consent is required for pharmacogenomic sampling. 2. Male or female patients, aged between 18 and 70 years of age, diurnally active 3. A history of asthma diagnosed by physician at least 3 months prior to Visit 1 at GINA treatment steps 3 or 4. The diagnosis of asthma must have been made before the age of 40. 4. Pre-bronchodilator FEV1 between 60% predicted and 90% predicted at Visit 1. 5. Increase in FEV1 greater or equal to 12% and 200 ml 15 minutes after 400mcg salbutamol (albuterol) at Visit 1. 6. Patient must have been taking inhaled corticosteroids (ICS) for at least 12 weeks prior to screening, and must have been receiving at a stable dose for at least 6 weeks prior to screening either: - a medium to high dose ICS or - a low to high dose ICS in combination with Long acting beta agonist (LABA). 7. All patients must be symptomatic.
Exclusion criteria
1. Patients with a significant disease other than asthma; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient's ability to participate in the study 2. Patients who have been hospitalised for an asthma exacerbation within 3 months or had an admission to an intensive care unit for asthma within 3 years of Visit 1 3. Patients will be excluded when they have: - an aspartate aminotransferase (AST) \>80 IU/L, alanine aminotransferase (ALT) \>80 IU/L, bilirubin \>1.5 X upper limit of normal (ULN) or creatinine \>1.5 X ULN - clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis 4. Patients with any of the following conditions: - a diagnosis of thyrotoxicosis * a diagnosis of paroxysmal tachycardia (\>100 beats per minute) * a marked baseline prolongation of QT/QTc interval at Visit 1 (e.g., repeated demonstration of a QTc interval \>450 ms) as recommended by ICH E14 * a history of additional risk factors for Torsade de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) as recommended by ICH E14. 5. Patients with any of the following conditions: - a history of myocardial infarction within 1 year of screening visit (Visit 1) * a diagnosis of clinically relevant cardiac arrhythmia * a history of cor pulmonale * known active tuberculosis * a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed) * a history of life-threatening pulmonary obstruction * a history of chronic obstructive pulmonary disease * history of cystic fibrosis * clinically evident bronchiectasis * a history of significant alcohol or drug abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. |
| Peak FEV1 Within 24 Hours Post-dose Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Peak FEV1 within 24 hours post dose measured following the evening trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. |
| Trough FEV1 Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. |
| Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h , 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres. |
| FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. |
| FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 min, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. |
| Peak FVC Within 24 Hours Post-dose Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Peak FVC within 24 hours post dose measured following the trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. |
| Trough FVC Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. |
| Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. |
| PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. |
| Mean Number of Puffs of Rescue Medication During the Whole Day | 2-4 weeks | Mean of daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Assessed by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. |
| Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. |
| Peak PEF Within 24 Hours Post-dose Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Peak PEF within 24 hours post-dose measured following the evening trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. |
| Trough PEF Response | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. |
| FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. |
| Mean Pre-dose Evening PEF (PEF p.m.) | 2-4 weeks | PEF p.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. |
| PEF Daily Variability | 2-4 weeks | PEF daily variability was assessed by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). PEF daily variability is the absolute difference between the morning and the evening PEF value divided by the mean of these two values, expressed as a percent. Means are adjusted for treatment, period, patient and study baseline. |
| Mean Pre-dose Morning FEV1 (FEV1 a.m.) | 2-4 weeks | FEV1 a.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. |
| Mean Pre-dose Evening FEV1 (FEV1 p.m.) | 2-4 weeks | FEV1 p.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. |
| Percentage of Asthma Symptom Free Days | 2-4 weeks | Percentage of asthma-symptom free days after the first 2 weeks of each treatment period was calculated as the number of symptom-free days divided by the number of days on treatment multiplied by 100. A symptom-free day was defined as a day in which no asthma symptoms were recorded, no rescue medication was recorded, activities during the day were not at all limited due to asthma, no shortness of breath during the day was recorded, no wheezing or coughing during the day and no night-time awakenings due to asthma were recorded. Assessed by patients at home using the AM2+ device. |
| Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | 2-4 weeks | Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment. |
| Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | 2-4 weeks | Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment. |
| Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | 2-4 weeks | Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment. |
| Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score | 4 weeks | Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ (s)) at the end of each 4 week treatment period. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items. |
| Total Asthma Control Questionnaire (ACQ) Score | 4 weeks | Control of asthma as assessed by the ACQ at the end of each 4-week treatment period.The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items. |
| Potassium 1 Hour Pre-dose | 4 weeks | Effect on potassium evaluated 1 hour pre-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale. |
| Potassium 1 Hour Post-dose | 4 weeks | Effect on potassium evaluated 1 hour post-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale. |
| Potassium 3 Hours Post-dose | 4 weeks | Effect on potassium evaluated 3 hours post-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale. |
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | 4 weeks | Clinical relevant abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. |
| Mean Pre-dose Morning PEF (PEF a.m.) | 2-4 weeks | PEF a.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. |
Countries
Austria, Germany, Poland, Romania, Slovakia, Slovenia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Study Total This was a randomised, double-blind, double dummy, placebo- and active-controlled, 6 treatment, 4 period incomplete crossover trial. 198 patients were assigned randomly to one of 30 treatment sequences, each sequence comprising 4 out of the 6 treatments listed: one of four doses (20 microgram (mcg), 10 mcg, 5 mcg or 2 mcg) of Olodaterol (Olo) once daily (qd) delivered via the Respimat inhaler or Foradil (Form) 12 mcg twice daily (bid) delivered via the Aerolizer inhaler or equivalent placebo. The duration of each treatment period was 4 weeks with no washout periods between treatments. | 198 |
| Total | 198 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Other | 2 |
| Overall Study | Protocol Violation | 3 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Study Total |
|---|---|
| Age, Continuous | 45.0 years STANDARD_DEVIATION 11.8 |
| Sex: Female, Male Female | 112 Participants |
| Sex: Female, Male Male | 86 Participants |
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 | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 125 | 0 / 121 | 0 / 130 | 0 / 127 | 0 / 124 | 0 / 125 |
| serious Total, serious adverse events | 0 / 125 | 0 / 121 | 0 / 130 | 1 / 127 | 0 / 124 | 0 / 125 |
Outcome results
Primary
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: Full analysis set (FAS). FAS is defined as all patients in the treated set for whom the baseline (pre-dose) value is available, and who have a value for the primary endpoint for at least one crossover period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period | -0.004 Liter | Standard Error 0.025 |
| Olo 2 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period | 0.135 Liter | Standard Error 0.025 |
| Olo 5 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period | 0.178 Liter | Standard Error 0.025 |
| Olo 10 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period | 0.201 Liter | Standard Error 0.025 |
| Olo 20 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period | 0.225 Liter | Standard Error 0.025 |
| Form 12 mcg Bid | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period | 0.164 Liter | Standard Error 0.025 |
p-value: <0.000195% CI: [0.097, 0.182]Mixed Models Analysis
p-value: <0.000195% CI: [0.14, 0.224]Mixed Models Analysis
p-value: <0.000195% CI: [0.163, 0.248]Mixed Models Analysis
p-value: <0.000195% CI: [0.186, 0.272]Mixed Models Analysis
p-value: <0.000195% CI: [0.126, 0.211]Mixed Models Analysis
Secondary
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
Clinical relevant abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events.
Time frame: 4 weeks
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrioventricular block first degree | 0 Participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase MB increased | 0 Participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase increased | 0 Participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood pressure increased | 0 Participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypothyroidism | 0 Participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypertension | 0 Participants |
| Olo 2 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase MB increased | 0 Participants |
| Olo 2 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood pressure increased | 1 Participants |
| Olo 2 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypertension | 0 Participants |
| Olo 2 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrioventricular block first degree | 0 Participants |
| Olo 2 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase increased | 0 Participants |
| Olo 2 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypothyroidism | 0 Participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypertension | 1 Participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypothyroidism | 1 Participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood pressure increased | 0 Participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase increased | 0 Participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrioventricular block first degree | 0 Participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase MB increased | 0 Participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood pressure increased | 0 Participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase MB increased | 1 Participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase increased | 1 Participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypertension | 1 Participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypothyroidism | 0 Participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrioventricular block first degree | 0 Participants |
| Olo 20 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrioventricular block first degree | 1 Participants |
| Olo 20 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypothyroidism | 0 Participants |
| Olo 20 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase MB increased | 0 Participants |
| Olo 20 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase increased | 0 Participants |
| Olo 20 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood pressure increased | 0 Participants |
| Olo 20 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypertension | 1 Participants |
| Form 12 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood pressure increased | 0 Participants |
| Form 12 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase increased | 0 Participants |
| Form 12 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypothyroidism | 0 Participants |
| Form 12 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Hypertension | 0 Participants |
| Form 12 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Blood creatine phosphokinase MB increased | 0 Participants |
| Form 12 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrioventricular block first degree | 1 Participants |
Secondary
FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period | -0.039 Liter | Standard Error 0.026 |
| Olo 2 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period | 0.124 Liter | Standard Error 0.026 |
| Olo 5 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period | 0.173 Liter | Standard Error 0.026 |
| Olo 10 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period | 0.194 Liter | Standard Error 0.026 |
| Olo 20 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period | 0.211 Liter | Standard Error 0.026 |
| Form 12 mcg Bid | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period | 0.145 Liter | Standard Error 0.026 |
p-value: <0.000195% CI: [0.116, 0.211]Mixed Models Analysis
p-value: <0.000195% CI: [0.166, 0.259]Mixed Models Analysis
p-value: <0.000195% CI: [0.186, 0.28]Mixed Models Analysis
p-value: <0.000195% CI: [0.203, 0.298]Mixed Models Analysis
p-value: <0.000195% CI: [0.137, 0.231]Mixed Models Analysis
Secondary
FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period | 0.031 Liter | Standard Error 0.026 |
| Olo 2 mcg qd | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period | 0.147 Liter | Standard Error 0.026 |
| Olo 5 mcg qd | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period | 0.183 Liter | Standard Error 0.025 |
| Olo 10 mcg qd | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period | 0.208 Liter | Standard Error 0.026 |
| Olo 20 mcg qd | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period | 0.238 Liter | Standard Error 0.026 |
| Form 12 mcg Bid | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period | 0.183 Liter | Standard Error 0.026 |
p-value: <0.000195% CI: [0.073, 0.158]Mixed Models Analysis
p-value: <0.000195% CI: [0.11, 0.193]Mixed Models Analysis
p-value: <0.000195% CI: [0.135, 0.219]Mixed Models Analysis
p-value: <0.000195% CI: [0.164, 0.25]Mixed Models Analysis
p-value: <0.000195% CI: [0.11, 0.194]Mixed Models Analysis
Secondary
Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h , 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | -0.047 Liter | Standard Error 0.029 |
| Olo 2 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.056 Liter | Standard Error 0.029 |
| Olo 5 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.109 Liter | Standard Error 0.029 |
| Olo 10 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.094 Liter | Standard Error 0.029 |
| Olo 20 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.122 Liter | Standard Error 0.029 |
| Form 12 mcg Bid | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.055 Liter | Standard Error 0.029 |
p-value: <0.000195% CI: [0.052, 0.154]Mixed Models Analysis
p-value: <0.000195% CI: [0.106, 0.207]Mixed Models Analysis
p-value: <0.000195% CI: [0.091, 0.192]Mixed Models Analysis
p-value: <0.000195% CI: [0.118, 0.221]Mixed Models Analysis
p-value: <0.000195% CI: [0.051, 0.153]Mixed Models Analysis
Secondary
FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 min, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | -0.026 Liter | Standard Error 0.028 |
| Olo 2 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.056 Liter | Standard Error 0.028 |
| Olo 5 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.109 Liter | Standard Error 0.028 |
| Olo 10 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.102 Liter | Standard Error 0.028 |
| Olo 20 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.131 Liter | Standard Error 0.028 |
| Form 12 mcg Bid | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.070 Liter | Standard Error 0.028 |
p-value: 0.000595% CI: [0.036, 0.128]Mixed Models Analysis
p-value: <0.000195% CI: [0.09, 0.181]Mixed Models Analysis
p-value: <0.000195% CI: [0.083, 0.174]Mixed Models Analysis
p-value: <0.000195% CI: [0.111, 0.203]Mixed Models Analysis
p-value: <0.000195% CI: [0.051, 0.143]Mixed Models Analysis
Secondary
FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | -0.005 Liter | Standard Error 0.029 |
| Olo 2 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.055 Liter | Standard Error 0.029 |
| Olo 5 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.109 Liter | Standard Error 0.028 |
| Olo 10 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.110 Liter | Standard Error 0.029 |
| Olo 20 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.139 Liter | Standard Error 0.029 |
| Form 12 mcg Bid | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.085 Liter | Standard Error 0.029 |
p-value: 0.010795% CI: [0.014, 0.107]Mixed Models Analysis
p-value: <0.000195% CI: [0.069, 0.16]Mixed Models Analysis
p-value: <0.000195% CI: [0.069, 0.161]Mixed Models Analysis
p-value: <0.000195% CI: [0.098, 0.191]Mixed Models Analysis
p-value: 0.000195% CI: [0.044, 0.137]Mixed Models Analysis
Secondary
Mean Number of Puffs of Rescue Medication During the Whole Day
Mean of daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Assessed by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Puffs of Rescue Medication During the Whole Day | 1.749 Number of Puffs | Standard Error 0.13 |
| Olo 2 mcg qd | Mean Number of Puffs of Rescue Medication During the Whole Day | 1.222 Number of Puffs | Standard Error 0.13 |
| Olo 5 mcg qd | Mean Number of Puffs of Rescue Medication During the Whole Day | 1.317 Number of Puffs | Standard Error 0.128 |
| Olo 10 mcg qd | Mean Number of Puffs of Rescue Medication During the Whole Day | 1.271 Number of Puffs | Standard Error 0.129 |
| Olo 20 mcg qd | Mean Number of Puffs of Rescue Medication During the Whole Day | 1.092 Number of Puffs | Standard Error 0.13 |
| Form 12 mcg Bid | Mean Number of Puffs of Rescue Medication During the Whole Day | 1.300 Number of Puffs | Standard Error 0.129 |
p-value: <0.000195% CI: [-0.77, -0.282]Mixed Models Analysis
p-value: 0.000495% CI: [-0.671, -0.192]Mixed Models Analysis
p-value: 0.000195% CI: [-0.72, -0.237]Mixed Models Analysis
p-value: <0.000195% CI: [-0.901, -0.413]Mixed Models Analysis
p-value: 0.000395% CI: [-0.691, -0.207]Mixed Models Analysis
Secondary
Mean Pre-dose Evening FEV1 (FEV1 p.m.)
FEV1 p.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Evening FEV1 (FEV1 p.m.) | 2.378 L | Standard Error 0.027 |
| Olo 2 mcg qd | Mean Pre-dose Evening FEV1 (FEV1 p.m.) | 2.428 L | Standard Error 0.027 |
| Olo 5 mcg qd | Mean Pre-dose Evening FEV1 (FEV1 p.m.) | 2.460 L | Standard Error 0.027 |
| Olo 10 mcg qd | Mean Pre-dose Evening FEV1 (FEV1 p.m.) | 2.467 L | Standard Error 0.027 |
| Olo 20 mcg qd | Mean Pre-dose Evening FEV1 (FEV1 p.m.) | 2.495 L | Standard Error 0.027 |
| Form 12 mcg Bid | Mean Pre-dose Evening FEV1 (FEV1 p.m.) | 2.457 L | Standard Error 0.027 |
p-value: 0.036295% CI: [0.003, 0.097]Mixed Models Analysis
p-value: 0.000695% CI: [0.035, 0.127]Mixed Models Analysis
p-value: 0.000295% CI: [0.042, 0.135]Mixed Models Analysis
p-value: <0.000195% CI: [0.07, 0.164]Mixed Models Analysis
p-value: 0.00195% CI: [0.032, 0.125]Mixed Models Analysis
Secondary
Mean Pre-dose Evening PEF (PEF p.m.)
PEF p.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Evening PEF (PEF p.m.) | 379.44 Liter/min | Standard Error 4.398 |
| Olo 2 mcg qd | Mean Pre-dose Evening PEF (PEF p.m.) | 394.36 Liter/min | Standard Error 4.418 |
| Olo 5 mcg qd | Mean Pre-dose Evening PEF (PEF p.m.) | 404.28 Liter/min | Standard Error 4.368 |
| Olo 10 mcg qd | Mean Pre-dose Evening PEF (PEF p.m.) | 403.06 Liter/min | Standard Error 4.389 |
| Olo 20 mcg qd | Mean Pre-dose Evening PEF (PEF p.m.) | 407.89 Liter/min | Standard Error 4.41 |
| Form 12 mcg Bid | Mean Pre-dose Evening PEF (PEF p.m.) | 399.88 Liter/min | Standard Error 4.389 |
p-value: <0.000195% CI: [7.77, 22.071]Mixed Models Analysis
p-value: <0.000195% CI: [17.801, 31.866]Mixed Models Analysis
p-value: <0.000195% CI: [16.539, 30.686]Mixed Models Analysis
p-value: <0.000195% CI: [21.305, 35.594]Mixed Models Analysis
p-value: <0.000195% CI: [13.341, 27.538]Mixed Models Analysis
Secondary
Mean Pre-dose Morning FEV1 (FEV1 a.m.)
FEV1 a.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Morning FEV1 (FEV1 a.m.) | 2.309 L | Standard Error 0.028 |
| Olo 2 mcg qd | Mean Pre-dose Morning FEV1 (FEV1 a.m.) | 2.402 L | Standard Error 0.028 |
| Olo 5 mcg qd | Mean Pre-dose Morning FEV1 (FEV1 a.m.) | 2.438 L | Standard Error 0.028 |
| Olo 10 mcg qd | Mean Pre-dose Morning FEV1 (FEV1 a.m.) | 2.445 L | Standard Error 0.028 |
| Olo 20 mcg qd | Mean Pre-dose Morning FEV1 (FEV1 a.m.) | 2.479 L | Standard Error 0.028 |
| Form 12 mcg Bid | Mean Pre-dose Morning FEV1 (FEV1 a.m.) | 2.403 L | Standard Error 0.028 |
p-value: 0.000295% CI: [0.045, 0.141]Mixed Models Analysis
p-value: <0.000195% CI: [0.081, 0.176]Mixed Models Analysis
p-value: <0.000195% CI: [0.087, 0.183]Mixed Models Analysis
p-value: <0.000195% CI: [0.121, 0.217]Mixed Models Analysis
p-value: 0.000195% CI: [0.045, 0.141]Mixed Models Analysis
Secondary
Mean Pre-dose Morning PEF (PEF a.m.)
PEF a.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Morning PEF (PEF a.m.) | 361.89 Liter/min | Standard Error 4.548 |
| Olo 2 mcg qd | Mean Pre-dose Morning PEF (PEF a.m.) | 383.90 Liter/min | Standard Error 4.567 |
| Olo 5 mcg qd | Mean Pre-dose Morning PEF (PEF a.m.) | 390.91 Liter/min | Standard Error 4.519 |
| Olo 10 mcg qd | Mean Pre-dose Morning PEF (PEF a.m.) | 389.78 Liter/min | Standard Error 4.539 |
| Olo 20 mcg qd | Mean Pre-dose Morning PEF (PEF a.m.) | 394.82 Liter/min | Standard Error 4.56 |
| Form 12 mcg Bid | Mean Pre-dose Morning PEF (PEF a.m.) | 385.42 Liter/min | Standard Error 4.539 |
p-value: <0.000195% CI: [14.802, 29.223]Mixed Models Analysis
p-value: <0.000195% CI: [21.931, 36.114]Mixed Models Analysis
p-value: <0.000195% CI: [20.755, 35.019]Mixed Models Analysis
p-value: <0.000195% CI: [25.73, 40.139]Mixed Models Analysis
p-value: <0.000195% CI: [16.371, 30.686]Mixed Models Analysis
Secondary
Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall)
Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up 2-5 times | 26 Number of patients |
| Placebo | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up > 5 times | 3 Number of patients |
| Placebo | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Was awake all night | 1 Number of patients |
| Placebo | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up once | 37 Number of patients |
| Placebo | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Did not wake up | 55 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Was awake all night | 1 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up > 5 times | 5 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Did not wake up | 60 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up 2-5 times | 17 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up once | 36 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Did not wake up | 58 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up > 5 times | 2 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up once | 34 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up 2-5 times | 30 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Was awake all night | 2 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Was awake all night | 2 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Did not wake up | 56 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up once | 34 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up 2-5 times | 30 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up > 5 times | 1 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up once | 34 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Was awake all night | 1 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Did not wake up | 63 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up > 5 times | 2 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up 2-5 times | 20 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up 2-5 times | 33 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up once | 29 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Woke up > 5 times | 2 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Did not wake up | 59 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Was awake all night | 0 Number of patients |
Secondary
Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall)
Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Moderate asthma symptoms | 56 Number of patients |
| Placebo | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | No asthma symptoms | 20 Number of patients |
| Placebo | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Severe asthma symptoms | 15 Number of patients |
| Placebo | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Mild asthma symptoms | 31 Number of patients |
| Placebo | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Very severe asthma symptoms | 0 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Very severe asthma symptoms | 0 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Moderate asthma symptoms | 37 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | No asthma symptoms | 26 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Severe asthma symptoms | 10 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Mild asthma symptoms | 46 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Moderate asthma symptoms | 51 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | No asthma symptoms | 29 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Mild asthma symptoms | 29 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Very severe asthma symptoms | 5 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Severe asthma symptoms | 12 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Moderate asthma symptoms | 52 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Mild asthma symptoms | 37 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | No asthma symptoms | 23 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Severe asthma symptoms | 10 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Very severe asthma symptoms | 1 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Severe asthma symptoms | 6 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | No asthma symptoms | 21 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Very severe asthma symptoms | 1 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Mild asthma symptoms | 38 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Moderate asthma symptoms | 54 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | No asthma symptoms | 24 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Severe asthma symptoms | 12 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Mild asthma symptoms | 37 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Very severe asthma symptoms | 1 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Moderate asthma symptoms | 49 Number of patients |
Secondary
Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall)
Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Severe asthma symptoms | 14 Number of patients |
| Placebo | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Mild asthma symptoms | 32 Number of patients |
| Placebo | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Moderate asthma symptoms | 49 Number of patients |
| Placebo | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Very severe asthma symptoms | 0 Number of patients |
| Placebo | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | No asthma symptoms | 27 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Severe asthma symptoms | 10 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | No asthma symptoms | 31 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Mild asthma symptoms | 47 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Moderate asthma symptoms | 29 Number of patients |
| Olo 2 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Very severe asthma symptoms | 2 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Very severe asthma symptoms | 0 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Severe asthma symptoms | 11 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Moderate asthma symptoms | 45 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | No asthma symptoms | 22 Number of patients |
| Olo 5 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Mild asthma symptoms | 48 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Severe asthma symptoms | 10 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | No asthma symptoms | 25 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Very severe asthma symptoms | 2 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Moderate asthma symptoms | 46 Number of patients |
| Olo 10 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Mild asthma symptoms | 40 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Severe asthma symptoms | 5 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | No asthma symptoms | 27 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Mild asthma symptoms | 45 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Moderate asthma symptoms | 43 Number of patients |
| Olo 20 mcg qd | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Very severe asthma symptoms | 0 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Mild asthma symptoms | 39 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | No asthma symptoms | 26 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Severe asthma symptoms | 10 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Very severe asthma symptoms | 2 Number of patients |
| Form 12 mcg Bid | Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Moderate asthma symptoms | 46 Number of patients |
Secondary
Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response | -0.117 Liter/sec | Standard Error 0.076 |
| Olo 2 mcg qd | Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.291 Liter/sec | Standard Error 0.077 |
| Olo 5 mcg qd | Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.449 Liter/sec | Standard Error 0.076 |
| Olo 10 mcg qd | Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.495 Liter/sec | Standard Error 0.077 |
| Olo 20 mcg qd | Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.553 Liter/sec | Standard Error 0.077 |
| Form 12 mcg Bid | Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.471 Liter/sec | Standard Error 0.076 |
p-value: <0.000195% CI: [0.277, 0.539]Mixed Models Analysis
p-value: <0.000195% CI: [0.438, 0.695]Mixed Models Analysis
p-value: <0.000195% CI: [0.482, 0.743]Mixed Models Analysis
p-value: <0.000195% CI: [0.539, 0.801]Mixed Models Analysis
p-value: <0.000195% CI: [0.457, 0.718]Mixed Models Analysis
Secondary
Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response | -0.038 Liter/sec | Standard Error 0.074 |
| Olo 2 mcg qd | Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.336 Liter/sec | Standard Error 0.074 |
| Olo 5 mcg qd | Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.489 Liter/sec | Standard Error 0.074 |
| Olo 10 mcg qd | Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.534 Liter/sec | Standard Error 0.074 |
| Olo 20 mcg qd | Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.623 Liter/sec | Standard Error 0.074 |
| Form 12 mcg Bid | Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.532 Liter/sec | Standard Error 0.074 |
p-value: <0.000195% CI: [0.253, 0.493]Mixed Models Analysis
p-value: <0.000195% CI: [0.409, 0.645]Mixed Models Analysis
p-value: <0.000195% CI: [0.453, 0.692]Mixed Models Analysis
p-value: <0.000195% CI: [0.54, 0.781]Mixed Models Analysis
p-value: <0.000195% CI: [0.451, 0.689]Mixed Models Analysis
Secondary
Peak FEV1 Within 24 Hours Post-dose Response
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Peak FEV1 within 24 hours post dose measured following the evening trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FEV1 Within 24 Hours Post-dose Response | 0.224 Liter | Standard Error 0.026 |
| Olo 2 mcg qd | Peak FEV1 Within 24 Hours Post-dose Response | 0.326 Liter | Standard Error 0.027 |
| Olo 5 mcg qd | Peak FEV1 Within 24 Hours Post-dose Response | 0.359 Liter | Standard Error 0.026 |
| Olo 10 mcg qd | Peak FEV1 Within 24 Hours Post-dose Response | 0.385 Liter | Standard Error 0.027 |
| Olo 20 mcg qd | Peak FEV1 Within 24 Hours Post-dose Response | 0.404 Liter | Standard Error 0.027 |
| Form 12 mcg Bid | Peak FEV1 Within 24 Hours Post-dose Response | 0.390 Liter | Standard Error 0.026 |
p-value: <0.000195% CI: [0.056, 0.148]Mixed Models Analysis
p-value: <0.000195% CI: [0.09, 0.18]Mixed Models Analysis
p-value: <0.000195% CI: [0.116, 0.207]Mixed Models Analysis
p-value: <0.000195% CI: [0.134, 0.226]Mixed Models Analysis
p-value: <0.000195% CI: [0.12, 0.211]Mixed Models Analysis
Secondary
Peak FVC Within 24 Hours Post-dose Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Peak FVC within 24 hours post dose measured following the trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FVC Within 24 Hours Post-dose Response | 0.253 Liter | Standard Error 0.031 |
| Olo 2 mcg qd | Peak FVC Within 24 Hours Post-dose Response | 0.300 Liter | Standard Error 0.031 |
| Olo 5 mcg qd | Peak FVC Within 24 Hours Post-dose Response | 0.356 Liter | Standard Error 0.031 |
| Olo 10 mcg qd | Peak FVC Within 24 Hours Post-dose Response | 0.342 Liter | Standard Error 0.031 |
| Olo 20 mcg qd | Peak FVC Within 24 Hours Post-dose Response | 0.380 Liter | Standard Error 0.031 |
| Form 12 mcg Bid | Peak FVC Within 24 Hours Post-dose Response | 0.326 Liter | Standard Error 0.031 |
p-value: 0.095295% CI: [-0.008, 0.103]Mixed Models Analysis
p-value: 0.000395% CI: [0.048, 0.158]Mixed Models Analysis
p-value: 0.001695% CI: [0.034, 0.145]Mixed Models Analysis
p-value: <0.000195% CI: [0.071, 0.183]Mixed Models Analysis
p-value: 0.009695% CI: [0.018, 0.129]Mixed Models Analysis
Secondary
Peak PEF Within 24 Hours Post-dose Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Peak PEF within 24 hours post-dose measured following the evening trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak PEF Within 24 Hours Post-dose Response | 0.664 Liter/sec | Standard Error 0.079 |
| Olo 2 mcg qd | Peak PEF Within 24 Hours Post-dose Response | 0.966 Liter/sec | Standard Error 0.079 |
| Olo 5 mcg qd | Peak PEF Within 24 Hours Post-dose Response | 1.093 Liter/sec | Standard Error 0.078 |
| Olo 10 mcg qd | Peak PEF Within 24 Hours Post-dose Response | 1.130 Liter/sec | Standard Error 0.079 |
| Olo 20 mcg qd | Peak PEF Within 24 Hours Post-dose Response | 1.198 Liter/sec | Standard Error 0.079 |
| Form 12 mcg Bid | Peak PEF Within 24 Hours Post-dose Response | 1.168 Liter/sec | Standard Error 0.079 |
p-value: <0.000195% CI: [0.371, 0.637]Mixed Models Analysis
p-value: <0.000195% CI: [0.168, 0.436]Mixed Models Analysis
p-value: <0.000195% CI: [0.297, 0.561]Mixed Models Analysis
p-value: <0.000195% CI: [0.333, 0.599]Mixed Models Analysis
p-value: <0.000195% CI: [0.4, 0.669]Mixed Models Analysis
Secondary
PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.043 Liter/sec | Standard Error 0.075 |
| Olo 2 mcg qd | PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.380 Liter/sec | Standard Error 0.075 |
| Olo 5 mcg qd | PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.528 Liter/sec | Standard Error 0.075 |
| Olo 10 mcg qd | PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.575 Liter/sec | Standard Error 0.075 |
| Olo 20 mcg qd | PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.692 Liter/sec | Standard Error 0.075 |
| Form 12 mcg Bid | PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.594 Liter/sec | Standard Error 0.075 |
p-value: <0.000195% CI: [0.213, 0.461]Mixed Models Analysis
p-value: <0.000195% CI: [0.363, 0.606]Mixed Models Analysis
p-value: <0.000195% CI: [0.408, 0.655]Mixed Models Analysis
p-value: <0.000195% CI: [0.524, 0.772]Mixed Models Analysis
p-value: <0.000195% CI: [0.428, 0.674]Mixed Models Analysis
Secondary
PEF Daily Variability
PEF daily variability was assessed by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). PEF daily variability is the absolute difference between the morning and the evening PEF value divided by the mean of these two values, expressed as a percent. Means are adjusted for treatment, period, patient and study baseline.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PEF Daily Variability | 11.688 Percentage | Standard Error 0.48 |
| Olo 2 mcg qd | PEF Daily Variability | 9.694 Percentage | Standard Error 0.484 |
| Olo 5 mcg qd | PEF Daily Variability | 9.593 Percentage | Standard Error 0.475 |
| Olo 10 mcg qd | PEF Daily Variability | 9.851 Percentage | Standard Error 0.48 |
| Olo 20 mcg qd | PEF Daily Variability | 9.899 Percentage | Standard Error 0.483 |
| Form 12 mcg Bid | PEF Daily Variability | 10.417 Percentage | Standard Error 0.479 |
p-value: <0.000195% CI: [-2.989, -0.999]Mixed Models Analysis
p-value: <0.000195% CI: [-3.073, -1.116]Mixed Models Analysis
p-value: 0.000395% CI: [-2.824, -0.849]Mixed Models Analysis
p-value: 0.000495% CI: [-2.783, -0.795]Mixed Models Analysis
p-value: 0.011895% CI: [-2.258, -0.283]Mixed Models Analysis
Secondary
Percentage of Asthma Symptom Free Days
Percentage of asthma-symptom free days after the first 2 weeks of each treatment period was calculated as the number of symptom-free days divided by the number of days on treatment multiplied by 100. A symptom-free day was defined as a day in which no asthma symptoms were recorded, no rescue medication was recorded, activities during the day were not at all limited due to asthma, no shortness of breath during the day was recorded, no wheezing or coughing during the day and no night-time awakenings due to asthma were recorded. Assessed by patients at home using the AM2+ device.
Time frame: 2-4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Asthma Symptom Free Days | 18.502 Percentage of asthma symptom free days | Standard Error 2.494 |
| Olo 2 mcg qd | Percentage of Asthma Symptom Free Days | 26.430 Percentage of asthma symptom free days | Standard Error 2.973 |
| Olo 5 mcg qd | Percentage of Asthma Symptom Free Days | 22.348 Percentage of asthma symptom free days | Standard Error 2.835 |
| Olo 10 mcg qd | Percentage of Asthma Symptom Free Days | 23.624 Percentage of asthma symptom free days | Standard Error 2.951 |
| Olo 20 mcg qd | Percentage of Asthma Symptom Free Days | 21.326 Percentage of asthma symptom free days | Standard Error 2.803 |
| Form 12 mcg Bid | Percentage of Asthma Symptom Free Days | 23.664 Percentage of asthma symptom free days | Standard Error 2.797 |
Secondary
Potassium 1 Hour Post-dose
Effect on potassium evaluated 1 hour post-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale.
Time frame: 4 weeks
Population: Treated set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Potassium 1 Hour Post-dose | 4.097 mmol/L |
| Olo 2 mcg qd | Potassium 1 Hour Post-dose | 4.069 mmol/L |
| Olo 5 mcg qd | Potassium 1 Hour Post-dose | 4.013 mmol/L |
| Olo 10 mcg qd | Potassium 1 Hour Post-dose | 4.004 mmol/L |
| Olo 20 mcg qd | Potassium 1 Hour Post-dose | 4.015 mmol/L |
| Form 12 mcg Bid | Potassium 1 Hour Post-dose | 4.059 mmol/L |
p-value: 0.442395% CI: [0.975, 1.011]Mixed Models Analysis
p-value: 0.021895% CI: [0.962, 0.997]Mixed Models Analysis
p-value: 0.010995% CI: [0.96, 0.995]Mixed Models Analysis
p-value: 0.028395% CI: [0.962, 0.998]Mixed Models Analysis
p-value: 0.308595% CI: [0.973, 1.009]Mixed Models Analysis
Secondary
Potassium 1 Hour Pre-dose
Effect on potassium evaluated 1 hour pre-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale.
Time frame: 4 weeks
Population: Treated set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Potassium 1 Hour Pre-dose | 4.067 mmol/L |
| Olo 2 mcg qd | Potassium 1 Hour Pre-dose | 4.051 mmol/L |
| Olo 5 mcg qd | Potassium 1 Hour Pre-dose | 4.051 mmol/L |
| Olo 10 mcg qd | Potassium 1 Hour Pre-dose | 4.061 mmol/L |
| Olo 20 mcg qd | Potassium 1 Hour Pre-dose | 4.057 mmol/L |
| Form 12 mcg Bid | Potassium 1 Hour Pre-dose | 4.080 mmol/L |
p-value: 0.618795% CI: [0.981, 1.011]Mixed Models Analysis
p-value: 0.602295% CI: [0.981, 1.011]Mixed Models Analysis
p-value: 0.864195% CI: [0.984, 1.014]Mixed Models Analysis
p-value: 0.766495% CI: [0.983, 1.013]Mixed Models Analysis
p-value: 0.675795% CI: [0.988, 1.018]Mixed Models Analysis
Secondary
Potassium 3 Hours Post-dose
Effect on potassium evaluated 3 hours post-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale.
Time frame: 4 weeks
Population: Treated set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Potassium 3 Hours Post-dose | 4.029 mmol/L |
| Olo 2 mcg qd | Potassium 3 Hours Post-dose | 4.026 mmol/L |
| Olo 5 mcg qd | Potassium 3 Hours Post-dose | 3.997 mmol/L |
| Olo 10 mcg qd | Potassium 3 Hours Post-dose | 3.979 mmol/L |
| Olo 20 mcg qd | Potassium 3 Hours Post-dose | 3.992 mmol/L |
| Form 12 mcg Bid | Potassium 3 Hours Post-dose | 4.007 mmol/L |
p-value: 0.911295% CI: [0.984, 1.015]Mixed Models Analysis
p-value: 0.295595% CI: [0.977, 1.007]Mixed Models Analysis
p-value: 0.102995% CI: [0.973, 1.003]Mixed Models Analysis
p-value: 0.255295% CI: [0.975, 1.007]Mixed Models Analysis
p-value: 0.480395% CI: [0.979, 1.01]Mixed Models Analysis
Secondary
Total Asthma Control Questionnaire (ACQ) Score
Control of asthma as assessed by the ACQ at the end of each 4-week treatment period.The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items.
Time frame: 4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Asthma Control Questionnaire (ACQ) Score | 1.882 units on a scale | Standard Error 0.058 |
| Olo 2 mcg qd | Total Asthma Control Questionnaire (ACQ) Score | 1.561 units on a scale | Standard Error 0.058 |
| Olo 5 mcg qd | Total Asthma Control Questionnaire (ACQ) Score | 1.589 units on a scale | Standard Error 0.057 |
| Olo 10 mcg qd | Total Asthma Control Questionnaire (ACQ) Score | 1.556 units on a scale | Standard Error 0.058 |
| Olo 20 mcg qd | Total Asthma Control Questionnaire (ACQ) Score | 1.488 units on a scale | Standard Error 0.058 |
| Form 12 mcg Bid | Total Asthma Control Questionnaire (ACQ) Score | 1.536 units on a scale | Standard Error 0.058 |
p-value: <0.000195% CI: [-0.432, -0.21]Mixed Models Analysis
p-value: <0.000195% CI: [-0.403, -0.184]Mixed Models Analysis
p-value: <0.000195% CI: [-0.436, -0.215]Mixed Models Analysis
p-value: <0.000195% CI: [-0.505, -0.282]Mixed Models Analysis
p-value: <0.000195% CI: [-0.457, -0.235]Mixed Models Analysis
Secondary
Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score
Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ (s)) at the end of each 4 week treatment period. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items.
Time frame: 4 weeks
Population: FAS including all patients who contributed data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score | 5.174 units on a scale | Standard Error 0.063 |
| Olo 2 mcg qd | Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score | 5.463 units on a scale | Standard Error 0.064 |
| Olo 5 mcg qd | Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score | 5.383 units on a scale | Standard Error 0.063 |
| Olo 10 mcg qd | Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score | 5.437 units on a scale | Standard Error 0.063 |
| Olo 20 mcg qd | Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score | 5.491 units on a scale | Standard Error 0.064 |
| Form 12 mcg Bid | Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score | 5.489 units on a scale | Standard Error 0.063 |
p-value: <0.000195% CI: [0.178, 0.4]Mixed Models Analysis
p-value: 0.000295% CI: [0.099, 0.318]Mixed Models Analysis
p-value: <0.000195% CI: [0.151, 0.374]Mixed Models Analysis
p-value: <0.000195% CI: [0.205, 0.429]Mixed Models Analysis
p-value: <0.000195% CI: [0.203, 0.426]Mixed Models Analysis
Secondary
Trough FEV1 Response
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response | 0.013 Liter | Standard Error 0.026 |
| Olo 2 mcg qd | Trough FEV1 Response | 0.116 Liter | Standard Error 0.026 |
| Olo 5 mcg qd | Trough FEV1 Response | 0.146 Liter | Standard Error 0.026 |
| Olo 10 mcg qd | Trough FEV1 Response | 0.182 Liter | Standard Error 0.026 |
| Olo 20 mcg qd | Trough FEV1 Response | 0.211 Liter | Standard Error 0.026 |
| Form 12 mcg Bid | Trough FEV1 Response | 0.115 Liter | Standard Error 0.026 |
p-value: <0.000195% CI: [0.058, 0.148]Mixed Models Analysis
p-value: <0.000195% CI: [0.088, 0.177]Mixed Models Analysis
p-value: <0.000195% CI: [0.124, 0.214]Mixed Models Analysis
p-value: <0.000195% CI: [0.153, 0.244]Mixed Models Analysis
p-value: <0.000195% CI: [0.058, 0.147]Mixed Models Analysis
Secondary
Trough FVC Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response | -0.022 Liter | Standard Error 0.029 |
| Olo 2 mcg qd | Trough FVC Response | 0.015 Liter | Standard Error 0.029 |
| Olo 5 mcg qd | Trough FVC Response | 0.069 Liter | Standard Error 0.029 |
| Olo 10 mcg qd | Trough FVC Response | 0.088 Liter | Standard Error 0.029 |
| Olo 20 mcg qd | Trough FVC Response | 0.107 Liter | Standard Error 0.029 |
| Form 12 mcg Bid | Trough FVC Response | 0.029 Liter | Standard Error 0.029 |
p-value: 0.14795% CI: [-0.013, 0.088]Mixed Models Analysis
p-value: 0.000395% CI: [0.042, 0.141]Mixed Models Analysis
p-value: <0.000195% CI: [0.06, 0.16]Mixed Models Analysis
p-value: <0.000195% CI: [0.078, 0.179]Mixed Models Analysis
p-value: 0.044895% CI: [0.001, 0.101]Mixed Models Analysis
Secondary
Trough PEF Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough PEF Response | 0.031 Liter/sec | Standard Error 0.078 |
| Olo 2 mcg qd | Trough PEF Response | 0.295 Liter/sec | Standard Error 0.078 |
| Olo 5 mcg qd | Trough PEF Response | 0.499 Liter/sec | Standard Error 0.077 |
| Olo 10 mcg qd | Trough PEF Response | 0.515 Liter/sec | Standard Error 0.078 |
| Olo 20 mcg qd | Trough PEF Response | 0.655 Liter/sec | Standard Error 0.078 |
| Form 12 mcg Bid | Trough PEF Response | 0.478 Liter/sec | Standard Error 0.078 |
p-value: 0.000295% CI: [0.127, 0.401]Mixed Models Analysis
p-value: <0.000195% CI: [0.333, 0.602]Mixed Models Analysis
p-value: <0.000195% CI: [0.348, 0.62]Mixed Models Analysis
p-value: <0.000195% CI: [0.487, 0.761]Mixed Models Analysis
p-value: <0.000195% CI: [0.311, 0.583]Mixed Models Analysis