Safety, Tolerability and Pharmacokinetics of the Fixed Dose Combination of BI 1744 CL Plus BI 54903 XX Via Respimat® B Versus the Mono Products of BI 1744 CL Via Respimat® A and BI 54903 XX Via Respimat® B in Healthy Male and Female Volunteers

Study Overview
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Brief Summary
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The primary objective of this study was to compare the systemic exposure of BI 1744 BS and CD 1857 XX (the active metabolite of the pro-drug BI 54903 XX) at steady state following inhalation of the fixed dose combination (FDC) of 6.2 μg BI 1744 CL plus 727.3 μg BI 54903 XX (as ethanolic solution for inhalation, EIS) with the systemic exposure following inhalation of the mono compounds of 10 μg BI 1744 CL (as aqueous solution for inhalation, AIS) and 727.3 μg BI 54903 XX (EIS), respectively, when administered once-daily via Respimat® Inhaler (Respimat® A for AIS and Respimat® B for EIS) for 14 days in healthy volunteers. Secondary objectives were to compare exposure to BI 1744 BS and CD 1857 XX after a single dose of the BI 1744 CL/BI 54903 XX (6.2 μg/727.3 μg) FDC and the mono compounds, respectively; to compare exposure to BI 54903 XX after a single dose and at steady state after multiple doses of the BI 1744 CL/BI 54903 XX (6.2 μg/727.3 μg) FDC and the mono compounds, respectively; to compare the safety and tolerability of BI 1744 CL and BI 54903 XX when administered as BI 1744 CL/BI 54903 XX (6.2 μg/727.3 μg) FDC and as the mono compounds, respectively.

Official Title
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An Open Label, Randomised, Three-way Crossover Phase I Study to Assess Safety, Tolerability and Pharmacokinetics of the Fixed Dose Combination of BI 1744 CL Plus BI 54903 XX Via Respimat® B Versus the Mono Products of BI 1744 CL Via Respimat® A and BI 54903 XX Via Respimat® B in Healthy Male and Female Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 1744 CL/BI 54903 XX FDC
* Drug: BI 54903 XX
* Drug: BI 1744 CL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (Blood pressure (BP), Pulse Rate (PR)), 12-lead Electrocardiogram (ECG), clinical laboratory tests Age >= 21 and Age <= 50 years Body mass index (BMI) >= 18.5 and <= 29.9 kg/m2 Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation Exclusion Criteria: Any finding of the medical examination (including Blood pressure (BP), Pulse Rate (PR) and Electrocardiogram (ECG)) deviating from normal and of clinical relevance Any evidence of a clinically relevant concomitant disease Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Surgery of the gastrointestinal tract (except appendectomy) Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders History of relevant orthostatic hypotension, fainting spells or blackouts Chronic or relevant acute infections History of relevant allergy/hypersensitivity (including allergy to drug or its excipients) Intake of drugs with a long half-life (>24 h) within at least 1 month or less than 10 half-lives of the respective drug prior to administration or during the trial Use of drugs which might reasonably influence the results of the trial or that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial Participation in another trial with an investigational drug within 2 months prior to administration or during the trial Smoker (>10 cigarettes or >3 cigars or >3 pipes/day) Inability to refrain from smoking on trial days Alcohol abuse (more than 40 g/day) Drug abuse Blood donation (more than 100 mL within 4 weeks prior to administration or during the trial) Excessive physical activities (within 1 week prior to administration or during the trial) Any laboratory value outside the reference range of clinical relevance Inability to comply with dietary regimen of trial site For female subjects: Pregnancy or planning to become pregnant within 2 months of study completion Positive pregnancy test No adequate contraception e.g., sterilization, intrauterine device (IUD), oral contraception for at least 3 months prior to participation in the study Inability to maintain this adequate contraception during the whole trial period Lactation period Asthma or history of pulmonary hyperreactivity Hyperthyrosis Allergic rhinitis in need of treatment Clinically relevant cardiac arrhythmia Bacterial and viral infections of the lung including tuberculosis

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 1744 CL/BI 54903 XX FDC<br> | Drug: BI 1744 CL/BI 54903 XX FDC<br> <br> |
| Active Comparator: BI 54903 XX<br> | Drug: BI 54903 XX<br> <br> |
| Active Comparator: BI 1744 CL<br> | Drug: BI 1744 CL<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t,ss (area under the concentration time curve of the analyte in plasma from 0 to time t at steady state) | for BI 1744 BS and CD 1857 XX | up to 24 hours after drug administration | 
| Cmax,ss (maximum measured concentration of the analyte in plasma at steady state) | for BI 1744 BS and CD 1857 XX | up to 24 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t (area under the concentration time curve of the analyte in plasma from 0 to time t) |  | up to 24 hours after drug administration | 
| Cmax (maximum measured concentration of the analyte in plasma) | for BI 54903 XX | up to 24 hours after drug administration | 
| Cpre (pre-dose concentration of the analyte in plasma (at steady state) |  | up to 24 hours after drug administration | 
| AUCt1-t2 (area under the concentration time curve of the analyte in plasma over the time interval t1 to t2) |  | up to 24 hours after drug administration | 
| AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point) |  | up to 24 hours after drug administration | 
| AUCτ (area under the plasma concentration-time curve over a uniform dosing interval τ) |  | up to 24 hours after drug administration | 
| AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |  | up to 24 hours after drug administration | 
| %AUCtz-∞ (the percentage of the AUC0-∞ that is obtained by extrapolation) |  | up to 24 hours after drug administration | 
| tmax (time from dosing to the maximum concentration of the analyte in plasma) |  | up to 24 hours after drug administration | 
| λz (terminal rate constant of the analyte in plasma) |  | up to 24 hours after drug administration | 
| t½ (terminal half-life of the analyte in plasma) |  | up to 24 hours after drug administration | 
| MRTih (mean residence time of the analyte in the body after inhaled administration) |  | up to 24 hours after drug administration | 
| Aet1-t2 (amount of the analyte that is eliminated in urine from the time point t1 to time point t2) |  | up to 24 hours after drug administration | 
| fet1-t2 (fraction of the analyte eliminated in urine from time point t1 to time point t2) |  | up to 24 hours after drug administration | 
| CLR,t1-t2 (renal clearance of the analyte from the time point t1 until the time point t2) |  | up to 24 hours after drug administration | 
| CL/F (apparent clearance of the analyte in the plasma after extravascular administration) | For BI 1744 BS and BI 54903 XX only | up to 24 hours after drug administration | 
| Vz/F (apparent volume of distribution of the analyte during the terminal phase following an extravascular dose) | For BI 1744 BS and BI 54903 XX only | up to 24 hours after drug administration | 
| Number of patients with adverse events |  | up to 16 weeks | 
| Assessment of tolerability by investigator on 4-point scale |  | 28 days after each treatment period |