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

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

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.

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