Asthma
Conditions
Brief summary
The primary objective of this study is to investigate safety and tolerability of three consecutive administrations, 12 hours apart, at three different dose-levels of BI 443651 administered via oral inhalation in male and female mild asthmatic subjects after a bolus methacholine challenge.
Interventions
DRUGBI 443651
Three doses, each 12 hours apart
DRUGPlacebo
Three doses, each 12 hours apart
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects must have a diagnosis of asthma by a physician at least 3 months prior to screening. The diagnosis of asthma must meet the following spirometric criteria: \-- Pre-bronchodilator clinic measured FEV1 \>=70% of predicted normal (calculated by the Global Lung Function Initiative equation (GLI)) measured \>= 8 hours after the last use of short acting bronchodilator at the screening visit and on the day of randomisation. * Age \>= 18 \<= 60 years. Subjects must be within the eligible age range on the day of signing informed consent. * Diagnosis of asthma must have been made before the subject's age of 40. Or If the subject is \>= 40 years and the diagnosis has not yet been recorded in the subject's medical files, the investigator should assess whether the subject's medical history (e.g. symptoms and prescribed medications) confirms the subject suffered from asthma since before the age of 40. If so, this subject may be considered for inclusion after consultation with the sponsor. * ACQ value \< 1.5 at the screening visit. * PD20 (Provocative dose causing at least a 20% decline in FEV1) at the screening visit of methacholine \<= 1mg * Body mass index (BMI) \>= 18.5 and \<= 32.0 kg/m2 at the screening visit * Subjects must be able to perform all study related procedures and assessments, including pulmonary function tests, as required by the protocol.
Exclusion criteria
* Significant pulmonary diseases other than asthma (up to GINA treatment step 2) or other medical conditions (as determined by medical history, examination and clinical investigations at screening) that may, in the opinion of the investigator result in any of the following: * Put the subject at risk because of participation in the study * Influence the results of the study * Cause concern regarding the subject's ability to participate in the study. * Respiratory tract infection or asthma exacerbation in the 4 weeks prior to the screening visit. Subjects can be rescreened 4 weeks after resolution of the infection or exacerbation. * Hospitalisation for asthma exacerbation within 3 months or intubation for asthma within 3 years of the screening visit. * Serum potassium measurement above the ULN at the screening visit. Any value about the ULN excludes the subject irrespective of clinical relevance. * Blood donation (more than 100mL within 30 days prior to the administration of trial medication or intended during the trial) * Subjects who have been treated with any of the following asthma medications in the given interval prior to Visit 1: * Non-approved asthma therapies such as methotrexate, * Intravenous, intramuscular or oral corticosteroids * Inhaled corticosteroids (iCS) other than low dose iCS (defined as equivalent to equal to, or less than 250 μg fluticasone / day) * A long acting beta agonist or anticholinergic bronchodilator (Visit 1), including fixed dose beta agonist/inhaled corticosteroid combinations and oral bronchodilators. * A biological based antagonist therapy including Omalizumab, or immune modulators * Asthma controller medications (e.g: leukotriene modifier, methylxanthines, nedocromil or cromolyn sodium) * Mucolytics * Systemically available immunomodulatory treatments for allergic rhinitis or atopic dermatitis. * Use of any diuretics (including loop diuretics or potassium sparing diuretics (such as amiloride), renin-angiotensin antihypertensive drugs in the 28 days prior to the screening visit (Visit 1) * Use of drugs that might reasonably influence the results of the trial or that might prolong the QT/QTc interval within 10 days prior to the randomisation visit. * A marked baseline prolongation of QT/QTcF interval (such as QTcF intervals that are repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or any other relevant ECG finding at screening and prior to randomisation * A history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalemia, or family history of Long QT Syndrome) * History of relevant allergies/hypersensitivities (including allergy to the trial medication or its excipients) * Contraceptive measures for male and female patients may be required * Current smokers or ex-smokers who have given up smoking for \< 12 months and / or have a smoking pack history of \> 5 pack years (1 pack year = 20 cigarettes per day for 1 year of 5 cigarettes per day for 4 years) * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 1 | Baseline and Day 2 | Absolute change from baseline in maximum forced expiratory volume within 1 second (FEV1) reduction following bolus methacholine challenge in Part 1 was defined as the difference between the maximum reduction in FEV1 obtained during the treatment challenge and during the baseline challenge. |
| Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 2. | Baseline and Day 2 | Absolute change from baseline in maximum FEV1 reduction following bolus methacholine challenge in Part 2 was defined as the difference between the maximum reduction in FEV1 obtained during the treatment challenge and during the baseline challenge. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 1 | Baseline and Day 2 | Relative change from baseline in FEV1 area under the curve over the time interval from 0 to timepoint tz (FEV1 AUC0-tz) following bolus methacholine challenge in Part 1 was defined as the ratio of FEV1 AUC0-tz obtained during the treatment challenge and during the baseline challenge, where the time tz refers to the last time point before recovery of FEV1 to within 95% of post-diluent value. |
| Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 2 | Baseline and Day 2 | Relative change from baseline in FEV1 area under the curve over the time interval from 0 to timepoint tz (FEV1 AUC0-tz) following bolus methacholine challenge in Part 2 was defined as the ratio of FEV1 AUC0-tz obtained during the treatment challenge and during the baseline challenge, where the time tz refers to the last time point before recovery of FEV1 to within 95% of post-diluent value. Geometric mean is actually adjusted geometric mean. Standard error presented here is a geometric standard error. |
| Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 1 | Day 2 | Time to recovery of FEV1 to within 95% of post-diluent value in Part 1 was defined as the time from maximum reduction to last time before recovery to within 95% of the value obtained pre-methacholine challenge during the respective challenge. |
| Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 2 | Day 2 | Time to recovery of FEV1 to within 95% of post-diluent value in Part 2 was defined as the time from maximum reduction to last time before recovery to within 95% of the value obtained pre-methacholine challenge during the respective challenge. Median is actually model-based median. |
Countries
United Kingdom
Participant flow
Recruitment details
Patients with mild asthma were recruited in this trial, which was split into 2 parts. Part 1 was a multiple-dose, single-blind, double-dummy, randomized, 4-way crossover trial with dose ordered sequences. Part 2 was a multiple-dose, double-blind, double-dummy, randomized, 4-way crossover trial.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended a specialist site which ensured that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria was violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/BI 443651 100/400/1200 Micro Gram (μg) - Part 1 Patients were orally administered placebo matched to BI 443651 inhalation solution in period 1, followed by BI 443651 100 micro gram (μg) inhalation solution in period 2, BI 443651 400 μg inhalation solution in period 3 and BI 443651 1200 μg inhalation solution in period 4, each treatment was administered via Respimat® inhaler. All treatment periods were separated by a washout period of 14-28 days. | 1 |
| BI 443651 100 μg/Placebo/BI 443651 400/1200 μg - Part 1 Patients were orally administered BI 443651 100 μg inhalation solution in period 1, followed by placebo matched to BI 443651 inhalation solution in period 2, BI 443651 400 μg inhalation solution in period 3 and BI 443651 1200 μg inhalation solution in period 4, each treatment was administered via Respimat® inhaler. All treatment periods were separated by a washout period of 14-28 days. | 1 |
| BI 443651 100/400 μg/Placebo/BI 443651 1200 μg - Part 1 Patients were orally administered BI 443651 100 μg inhalation solution in period 1, followed by BI 443651 400 μg inhalation solution in period 2, placebo matched to BI 443651 inhalation solution in period 3 and BI 443651 1200 μg inhalation solution in period 4, each treatment was administered via Respimat® inhaler. All treatment periods were separated by a washout period of 14-28 days. | 1 |
| BI 443651 100/400/1200 μg/Placebo - Part 1 Patients were orally administered BI 443651 100 μg inhalation solution in period 1, followed by BI 443651 400 μg inhalation solution in period 2, BI 443651 1200 μg inhalation solution in period 3 and placebo matched to BI 443651 inhalation solution in period 4, each treatment was administered via Respimat® inhaler. All treatment periods were separated by a washout period of 14-28 days. | 1 |
| Placebo/BI 443651 100/400/1200 μg - Part 2 Patients were orally administered placebo matched to BI 443651 inhalation solution in period 1, followed by BI 443651 100 μg inhalation solution in period 2, BI 443651 400 μg inhalation solution in period 3 and BI 443651 1200 μg inhalation solution in period 4, each treatment was administered via Respimat® inhaler. All treatment periods were separated by a washout period of 14-28 days. | 8 |
| BI 443651 400/1200 μg/Placebo/BI 443651 100 μg - Part 2 Patients were orally administered BI 443651 400 μg inhalation solution in period 1, followed by BI 443651 1200 μg inhalation solution in period 2, placebo matched to BI 443651 inhalation solution in period 3 and BI 443651 100 μg inhalation solution in period 4, each treatment was administered via Respimat® inhaler. All treatment periods were separated by a washout period of 14-28 days. | 9 |
| BI 443651 100 μg/Placebo/BI 443651 1200/400 μg - Part 2 Patients were orally administered BI 443651 100 μg inhalation solution in period 1, followed by placebo matched to BI 443651 inhalation solution in period 2, BI 443651 1200 μg inhalation solution in period 3 and BI 443651 400 μg inhalation solution in period 4, each treatment was administered via Respimat® inhaler. All treatment periods were separated by a washout period of 14-28 days. | 8 |
| BI 443651 1200/400/100 μg/Placebo - Part 2 Patients were orally administered BI 443651 1200 μg inhalation solution in period 1, followed by BI 443651 400 μg inhalation solution in period 2, BI 443651 100 μg inhalation solution in period 3 and placebo matched to BI 443651 inhalation solution in period 4, each treatment was administered via Respimat® inhaler. All treatment periods were separated by a washout period of 14-28 days. | 8 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Failed spirometry,unable to repeat visit | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo/BI 443651 100/400/1200 Micro Gram (μg) - Part 1 | BI 443651 100 μg/Placebo/BI 443651 400/1200 μg - Part 1 | BI 443651 100/400 μg/Placebo/BI 443651 1200 μg - Part 1 | BI 443651 100/400/1200 μg/Placebo - Part 1 | Placebo/BI 443651 100/400/1200 μg - Part 2 | BI 443651 400/1200 μg/Placebo/BI 443651 100 μg - Part 2 | BI 443651 100 μg/Placebo/BI 443651 1200/400 μg - Part 2 | BI 443651 1200/400/100 μg/Placebo - Part 2 | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 42 Years | 41 Years | 59 Years | 35 Years | 39.1 Years STANDARD_DEVIATION 10.5 | 36.1 Years STANDARD_DEVIATION 10.3 | 35.4 Years STANDARD_DEVIATION 11.1 | 35.9 Years STANDARD_DEVIATION 11.7 | 37.4 Years STANDARD_DEVIATION 10.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 8 Participants | 9 Participants | 8 Participants | 8 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 7 Participants | 9 Participants | 4 Participants | 4 Participants | 28 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 6 Participants | 8 Participants | 8 Participants | 8 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 | 0 / 36 | 0 / 36 |
| other Total, other adverse events | 9 / 35 | 21 / 35 | 24 / 36 | 26 / 36 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 | 0 / 36 | 0 / 36 |
Outcome results
Primary
Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 1
Absolute change from baseline in maximum forced expiratory volume within 1 second (FEV1) reduction following bolus methacholine challenge in Part 1 was defined as the difference between the maximum reduction in FEV1 obtained during the treatment challenge and during the baseline challenge.
Time frame: Baseline and Day 2
Population: Methacholine set (MCS): The MCS included all patients in the TS who provided at least one pair (baseline and end-of-treatment) of evaluable measures of spirometry parameters that were not excluded due to use of rescue medication within 3 hours (h) after start of bolus methacholine challenge.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Part 1 | Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 1 | 0.018 Litres (L) | Standard Deviation 0.554 |
| BI 443651 100 μg - Part 1 | Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 1 | 0.390 Litres (L) | Standard Deviation 0.261 |
| BI 443651 400 μg - Part 1 | Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 1 | -0.195 Litres (L) | Standard Deviation 0.431 |
| BI 443651 1200 μg - Part 1 | Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 1 | 0.272 Litres (L) | Standard Deviation 0.268 |
Primary
Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 2.
Absolute change from baseline in maximum FEV1 reduction following bolus methacholine challenge in Part 2 was defined as the difference between the maximum reduction in FEV1 obtained during the treatment challenge and during the baseline challenge.
Time frame: Baseline and Day 2
Population: MCS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Part 1 | Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 2. | 0.005 Litres (L) | Standard Error 0.056 |
| BI 443651 100 μg - Part 1 | Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 2. | 0.064 Litres (L) | Standard Error 0.056 |
| BI 443651 400 μg - Part 1 | Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 2. | -0.032 Litres (L) | Standard Error 0.055 |
| BI 443651 1200 μg - Part 1 | Absolute Change From Baseline in Maximum Forced Expiratory Volume Within 1 Second (FEV1) Reduction Following Bolus Methacholine Challenge in Part 2. | -0.152 Litres (L) | Standard Error 0.056 |
Comparison: The mixed effects model included 'treatment' and 'period' as fixed effects, 'patient' as a random effect, and 'period baseline' as well as 'patient baseline' as covariates. No hypothesis was tested. The patient baseline was obtained by calculating the mean of the period baselines for each patient. Covariance structure variance component (VC) was used for random subject effect.90% CI: [-0.048, 0.165]Mixed Models Analysis
Comparison: The mixed effects model included 'treatment' and 'period' as fixed effects, 'patient' as a random effect, and 'period baseline' as well as 'patient baseline' as covariates. No hypothesis was tested. The patient baseline was obtained by calculating the mean of the period baselines for each patient. Covariance structure variance component (VC) was used for random subject effect.90% CI: [-0.144, 0.07]Mixed Models Analysis
Comparison: The mixed effects model included 'treatment' and 'period' as fixed effects, 'patient' as a random effect, and 'period baseline' as well as 'patient baseline' as covariates. No hypothesis was tested. The patient baseline was obtained by calculating the mean of the period baselines for each patient. Covariance structure variance component (VC) was used for random subject effect.90% CI: [-0.266, -0.047]Mixed Models Analysis
Secondary
Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 1
Relative change from baseline in FEV1 area under the curve over the time interval from 0 to timepoint tz (FEV1 AUC0-tz) following bolus methacholine challenge in Part 1 was defined as the ratio of FEV1 AUC0-tz obtained during the treatment challenge and during the baseline challenge, where the time tz refers to the last time point before recovery of FEV1 to within 95% of post-diluent value.
Time frame: Baseline and Day 2
Population: MCS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Part 1 | Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 1 | 1.097 Ratio | Standard Deviation 0.849 |
| BI 443651 100 μg - Part 1 | Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 1 | 0.625 Ratio | Standard Deviation 0.262 |
| BI 443651 400 μg - Part 1 | Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 1 | 0.925 Ratio | Standard Deviation 0.364 |
| BI 443651 1200 μg - Part 1 | Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 1 | 0.296 Ratio | Standard Deviation 0.218 |
Secondary
Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 2
Relative change from baseline in FEV1 area under the curve over the time interval from 0 to timepoint tz (FEV1 AUC0-tz) following bolus methacholine challenge in Part 2 was defined as the ratio of FEV1 AUC0-tz obtained during the treatment challenge and during the baseline challenge, where the time tz refers to the last time point before recovery of FEV1 to within 95% of post-diluent value. Geometric mean is actually adjusted geometric mean. Standard error presented here is a geometric standard error.
Time frame: Baseline and Day 2
Population: MCS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Part 1 | Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 2 | 0.863 Ratio | Standard Error 1.152 |
| BI 443651 100 μg - Part 1 | Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 2 | 0.665 Ratio | Standard Error 1.152 |
| BI 443651 400 μg - Part 1 | Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 2 | 0.799 Ratio | Standard Error 1.15 |
| BI 443651 1200 μg - Part 1 | Relative Change From Baseline in FEV1 Area Under the Curve Over the Time Interval From 0 to Timepoint tz (FEV1 AUC0-tz) Following Bolus Methacholine Challenge in Part 2 | 0.729 Ratio | Standard Error 1.152 |
Comparison: The mixed effects model included 'treatment' and 'period' as fixed effects, 'patient' as a random effect, and 'period baseline' as well as 'patient baseline' as covariates. No hypothesis was tested. The patient baseline was obtained by calculating the mean of the period baselines for each patient. Covariance structure variance component (VC) was used for random subject effect.90% CI: [0.595, 0.977]Mixed Models Analysis
Comparison: The mixed effects model included 'treatment' and 'period' as fixed effects, 'patient' as a random effect, and 'period baseline' as well as 'patient baseline' as covariates. No hypothesis was tested. The patient baseline was obtained by calculating the mean of the period baselines for each patient. Covariance structure variance component (VC) was used for random subject effect.90% CI: [0.715, 1.199]Mixed Models Analysis
Comparison: The mixed effects model included 'treatment' and 'period' as fixed effects, 'patient' as a random effect, and 'period baseline' as well as 'patient baseline' as covariates. No hypothesis was tested. The patient baseline was obtained by calculating the mean of the period baselines for each patient. Covariance structure variance component (VC) was used for random subject effect.90% CI: [0.651, 1.095]Mixed Models Analysis
Secondary
Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 1
Time to recovery of FEV1 to within 95% of post-diluent value in Part 1 was defined as the time from maximum reduction to last time before recovery to within 95% of the value obtained pre-methacholine challenge during the respective challenge.
Time frame: Day 2
Population: MCS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo - Part 1 | Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 1 | 0.775 hours (h) |
| BI 443651 100 μg - Part 1 | Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 1 | 0.452 hours (h) |
| BI 443651 400 μg - Part 1 | Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 1 | 0.751 hours (h) |
| BI 443651 1200 μg - Part 1 | Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 1 | 0.597 hours (h) |
Secondary
Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 2
Time to recovery of FEV1 to within 95% of post-diluent value in Part 2 was defined as the time from maximum reduction to last time before recovery to within 95% of the value obtained pre-methacholine challenge during the respective challenge. Median is actually model-based median.
Time frame: Day 2
Population: MCS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo - Part 1 | Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 2 | 0.65 h |
| BI 443651 100 μg - Part 1 | Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 2 | 0.48 h |
| BI 443651 400 μg - Part 1 | Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 2 | 0.44 h |
| BI 443651 1200 μg - Part 1 | Time to Recovery of FEV1 to Within 95% of Post-diluent Value in Part 2 | 0.32 h |
Comparison: The cox proportional hazard model included treatment and period as fixed effect and patient baseline as covariate. No hypothesis was tested. The patient baseline was obtained by calculating the median of the period baselines for each patient. A hazard ratio greater than 1 gives that active treatment is not-inferior to placebo.95% CI: [1.31, 3.95]Regression, Cox
Comparison: The cox proportional hazard model included treatment and period as fixed effect and patient baseline as covariate. No hypothesis was tested. The patient baseline was obtained by calculating the median of the period baselines for each patient. A hazard ratio greater than 1 gives that active treatment is not-inferior to placebo.95% CI: [1.22, 3.53]Regression, Cox
Comparison: The cox proportional hazard model included treatment and period as fixed effect and patient baseline as covariate. No hypothesis was tested. The patient baseline was obtained by calculating the median of the period baselines for each patient. A hazard ratio greater than 1 gives that active treatment is not-inferior to placebo.95% CI: [1.5, 4.47]Regression, Cox