Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Inhalative Doses of BI 1744 CL in Fixed Dose Combination With Tiotropium Bromide in Healthy Male Volunteers

Study Overview
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Brief Summary
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To investigate safety, tolerability, pharmacokinetics and pharmacodynamics of BI 1744 CL and Tiotropium Bromide when given as fixed dose combination

Official Title
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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Inhalative Doses (2 μg/5 μg, 10 μg/5 μg, and 40 μg/10 μg) of BI 1744 CL in Fixed Dose Combination With Tiotropium Bromide for 14 Days in Healthy Male Volunteers (Double-blind, Randomised, Placebo Controlled [at Each Dose Level] Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Single rising doses of BI 1744 CL, solution for oral inhalation
* Drug: Tiotropium, fixed dose, solution for oral inhalation
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male based upon a complete medical history, including physical examination, regarding vital signs (BP, PR), 12-lead ECG measurement, and clinical laboratory tests. There is no finding deviating from normal and of clinical relevance. There is no evidence of a clinically relevant concomitant disease Age ≥21 and ≤45 years BMI ≥18.5 and <30 kg/m2 (Body Mass Index) 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 BP, PR, and ECG measurements) deviating from normal and of clinical relevance Evidence of a clinically relevant concomitant disease Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders 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 the drug or its excipients) as judged clinically relevant by the investigator Intake of drugs with a long half-life (>24 hours) within at least 1 month or less than 10 half-lives of the respective drug prior to randomization Use of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation within 10 days prior to randomisation Participation in another trial with an investigational drug within 2 months prior to randomisation Smoker (>10 cigarettes or >3 cigars or >3 pipes/day) Inability to refrain from smoking on trial days as judged by the investigator Alcohol abuse (more than 40 g alcohol a day) Drug abuse Blood donation (more than 100 mL blood within 4 weeks prior to randomisation or during the trial) Excessive physical activities within 1 week prior to randomisation or during the trial Any laboratory value outside the reference range that is of clinical relevance Inability to comply with dietary regimen of the study centre The following exclusion criteria are specific for this study due to the known class side effect profile of ß2-mimetics: Asthma or history of pulmonary hyperreactivity Hyperthyrosis Allergic rhinitis in need of treatment Clinically relevant cardiac arrhythmia Paroxysmal tachycardia (>100 beats per minute) The following exclusion criteria are specific for this study due to the known class side effect profile of Tiotropium: Hypersensitivity to tiotropium and/or related drugs of these classes History of narrow-angle glaucoma History of prostatic hyperplasia History of bladder-neck obstruction

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 1744 CL in combination with Tiotropium<br> | Drug: Single rising doses of BI 1744 CL, solution for oral inhalation<br> <br> Drug: Tiotropium, fixed dose, solution for oral inhalation<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with clinically relevant findings in physical examination |  | Up to day 32 | 
| Number of subjects with clinically relevant findings in vital signs | blood pressure, pulse rate | Up to day 32 | 
| Number of subjects with clinically relevant findings in 12-lead ECG |  | Up to day 32 | 
| Number of subjects with clinically relevant findings in laboratory tests |  | Up to day 32 | 
| Number of subjects witch clinically relevant changes in additional safety laboratory test parameters | Systemic metabolic parameters: cyclic adenosine mono phosphate (cAMP) and potassium | up to 318 hours after start of treatment | 
| Number of subjects with clinically relevant changes in airway resistance (Raw) measured by body plethysmography |  | Pre-dose, up to 408 hours after start of treatment | 
| Number of subjects with adverse events |  | Up to day 32 | 
| Global assessment of tolerability by investigator on a 4-point scale |  | Up to day 32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration in plasma (Cmax) |  | up to 504 hours after start of treatment | 
| Time from dosing to maximum concentration in plasma (tmax) |  | up to 504 hours after start of treatment | 
| Area under the concentration-time curve in plasma (AUC) |  | up to 504 hours after start of treatment | 
| Area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) |  | up to 504 hours after start of treatment | 
| Percentage of AUC 0-∞ that is obtained by extrapolation (%AUCtz-∞) |  | up to 504 hours after start of treatment | 
| Terminal rate constant in plasma (λz) |  | up to 504 hours after start of treatment | 
| Terminal half-life in plasma (t½) |  | up to 504 hours after start of treatment | 
| Mean residence time in the body after inhalation (MRTih) |  | up to 504 hours after start of treatment | 
| Apparent clearance after extravascular administration (CL/F) |  | up to 504 hours after start of treatment | 
| Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F) |  | up to 504 hours after start of treatment | 
| Amount eliminated in urine from the time point t1 to t2 (Aet1-t2) |  | up to 336 hours after start of treatment | 
| Fraction excreted in urine from time point t1 to t2 (fet1-t2) |  | up to 336 hours after start of treatment | 
| Renal clearance from the time point t1 until the time point t2 (CLR,t1-t2) |  | up to 504 hours after start of treatment | 
| Minimum measured concentration in plasma at steady state over a uniform dosing interval τ (Cmin,ss) |  | up to 504 hours after start of treatment | 
| Predose concentration of the analytes in plasma at steady state immediately before administration of the next dose (Cpre,ss) |  | Pre-dose every 24 hours | 
| Time of last measurable concentration in plasma (tz) |  | up to 504 hours after start of treatment | 
| Linearity index (LI) |  | up to 504 hours after start of treatment | 
| Accumulation ratio based on Cmax (RA,Cmax) |  | up to 504 hours after start of treatment | 
| Accumulation ratio based on AUCτ (RA,AUC) |  | up to 504 hours after start of treatment |