BI 443651 Methacholine Challenge

Study Overview
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Brief Summary
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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.

Official Title
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A Two Part Phase I, Multiple-dose, Single- and Double-blind, Randomised, Double-dummy, Placebo-controlled, Four-way Crossover Study to Assess Safety and Tolerability of BI 443651 Via Respimat® Versus Placebo Via Respimat® in Subjects With Mild Asthma Following Methacholine Challenge.

Conditions
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Asthma

Intervention / Treatment
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* Drug: BI 443651
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 443651<br> | Drug: BI 443651<br>* Three doses, each 12 hours apart<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Three doses, each 12 hours apart<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Day 2 | 
| 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. | Baseline and Day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 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. | Baseline and Day 2 | 
| 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. | Day 2 | 
| 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. | Day 2 |