Safety, Tolerability and Pharmacokinetics of BIBW 2948 BS for HandiHaler® in Healthy Male Volunteers

Study Overview
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Brief Summary
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To investigate safety, tolerability, and pharmacokinetics of BIBW 2948 BS after repeated dosing

Official Title
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Safety, Tolerability and Pharmacokinetics of Multiple Rising Inhaled Doses (7.5 to 60 mg Daily for 12 Days) of BIBW 2948 BS Inhalation Powder, Hard Capsule for HandiHaler® in Healthy Male Volunteers (Randomised, Double-blind Placebo-controlled Within Dose Groups)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Low dose of BIBW 2948 BS for oral inhalation
* Drug: Medium dose of BIBW 2948 BS for oral inhalation
* Drug: High dose of BIBW 2948 BS for oral inhalation
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males based on a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests Age ≥21 and Age ≤ 50 years BMI (Body Mass Index) ≥18.5 and BMI ≤ 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 Subjects must be current smokers (<10 cigarettes or <3 cigars <3 pipes/day) with a smoking history >1 year Exclusion Criteria: Any finding of the medical examination (including BP, PR and 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 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) Intake of drugs with a long half-life (>24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial Use of drugs which may have reasonably influenced the results of the trial 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 two 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 60 g/day) Drug abuse Blood donation (more than 100 mL within four weeks prior to administration or during the trial) Excessive physical activities (within one week prior to administration or during the trial) Any laboratory value outside the reference range that is of clinical relevance Inability to comply with dietary regimen of study centre

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 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: Low dose of BIBW 2948 BS<br> | Drug: Low dose of BIBW 2948 BS for oral inhalation<br> <br> |
| Experimental: Medium dose of BIBW 2948 BS<br> | Drug: Medium dose of BIBW 2948 BS for oral inhalation<br> <br> |
| Experimental: High dose of BIBW 2948 BS<br> | Drug: High dose of BIBW 2948 BS 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 patients with clinically significant findings in vital signs |  | Up to day 20 after start of treatment | 
| Number of patients with clinically significant findings in 12-lead electrocardiogram (ECG) |  | Up to day 20 after start of treatment | 
| Number of patients with clinically significant findings in clinical laboratory tests |  | Up to day 20 after start of treatment | 
| Number of patients with adverse events |  | Up to day 41 | 
| Assessment of tolerability by investigator on a 4-point scale |  | Up to day 20 after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration of the analyte BIBW in plasma at different time points (Cmax) |  | Pre-dose, up to 336 hours after start of treatment | 
| Time from dosing to maximum measured concentration of the analyte in plasma at different time points (tmax) |  | Pre-dose, up to 336 hours after start of treatment | 
| area under the concentration-time curve of the analyte in plasma over a uniform dosing interval τ (AUCτ,1) |  | Pre-dose, up to 336 hours after start of treatment | 
| The percentage of the area under the concentration-time curve of the analyte in plasma over the time interval from 0 to infinity (AUC0-∞) that is obtained by extrapolation (%AUCtz-∞) |  | Pre-dose, up to 336 hours after start of treatment | 
| Terminal rate constant of the analyte in plasma at different time points (λz) |  | Pre-dose, up to 336 hours after start of treatment | 
| Terminal half-life of the analyte in plasma at different time points (t1/2) |  | Pre-dose, up to 336 hours after start of treatment | 
| Mean residence time of the analyte in the body after one administration at different time points (MRTih) |  | Pre-dose, up to 336 hours after start of treatment | 
| Apparent clearance of the analyte in plasma following extravascular administration at different time points (CL/F) |  | Pre-dose, up to 336 hours after start of treatment | 
| Apparent volume of distribution during the terminal phase λz following an extravascular administration at different time points (Vz/F) |  | Pre-dose, up to 336 hours after start of treatment | 
| Amount of analyte that is eliminated in urine from at different time points (Ae) |  | Pre-dose, up to 336 hours after start of treatment | 
| Fraction of analyte eliminated in urine at different time points (fe) |  | Pre-dose, up to 336 hours after start of treatment | 
| Renal clearance of the analyte at different time points (CLR) |  | Pre-dose, up to 336 hours after start of treatment | 
| Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval τ (Cmin,ss) |  | Pre-dose, up to 336 hours after start of treatment | 
| Accumulation ratio of the analyte in plasma after multiple dose administration over a uniform dosing interval τ based on Cmax (RA,Cmax,10) |  | Pre-dose, up to 336 hours after start of treatment | 
| Accumulation ratio of the analyte in plasma after multiple dose administration over a uniform dosing interval τ based on AUC0-τ (RA,AUC,10) |  | Pre-dose, up to 336 hours after start of treatment | 
| Linearity index (AUCτ,ss / AUC0-∞) |  | Pre-dose, up to 336 hours after start of treatment | 
| Changes from baseline in induced sputum analysis (amount of cells, mucin) |  | Pre-dose, 268 hours after start of treatment | 
| area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) |  | Pre-dose, up to 336 hours after start of treatment | 
| area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable concentration at tz (AUC0-tz) |  | Pre-dose, up to 336 hours after start of treatment |