Safety, Tolerance, and Pharmacokinetics of Single Oral Doses of BI 201335 NA and Bioavailability in Healthy Male Subjects

Study Overview
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Brief Summary
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The objective of this study was to investigate the safety, tolerability, and pharmacokinetics of BI 201335 NA following administration of single rising doses from 4 mg to 1200 mg. In addition, the food effect on the bioavailability of BI 201335 NA (480 mg) was investigated.

Official Title
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Safety, Tolerance, and Pharmacokinetics of Single Oral Doses of 4 mg, 16 mg, 48 mg, 120 mg, 240 mg, 480 mg, 800 mg, and 1200 mg BI 201335 NA (PEG 400/TRIS/Meglumine/Water Solution) in Healthy Male Subjects, in a Randomised Single Blind, Placebo Controlled Rising Dose Study, Followed With an Open-label Intra-subject Two-stage Crossover Pilot Bioavailability Comparison of 480 mg BI 201335 NA in a PEG 400/TRIS/Meglumine/Water Solution Coadministered With Food

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 201335 NA
* Drug: Placebo solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males 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 ECG (electrocardiogram), clinical laboratory tests Age ≥18 and Age ≤50 years BMI ≥18.5 and BMI ≤29.9 kg/m2 (Body Mass Index) Signed and dated written informed consent prior to admission to the study in accordance with GCP (Good Clinical Practice) and the local legislation 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 Prior history of jaundice 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 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 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 two months prior to administration or during the trial Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day) Inability to refrain from smoking alcohol and 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 trial site A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms) A history of additional risk factors for TdP (torsade de pointes) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

Ages Eligible for Study
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Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 201335 in single rising doses<br> | Drug: BI 201335 NA<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo solution<br> <br> |
| Experimental: BI 201335 NA fasted or fed<br>two randomized sequences: BI 201335 NA or placebo fasted BI 201335 NA or placebo after high-fat breakfast | Drug: BI 201335 NA<br> <br> Drug: Placebo solution<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with abnormal findings in physical examination |  | up to 12 days | 
| Number of patients with clinically significant changes in vital signs (blood pressure, pulse rate) |  | up to 12 days | 
| Number of patients with abnormal findings in 12-lead ECG (electrocardiogram) |  | up to 12 days | 
| Number of patients with abnormal changes in laboratory tests (haematology, clinical chemistry and urinalysis) |  | up to 12 days | 
| Number of patients with adverse events |  | up to 12 days | 
| Assessment of tolerability by investigator on a 4-point scale |  | within 7 days after last trial procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum concentration of the analyte in plasma) |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96 hours post-dose | 
| tmax (time from dosing to maximum concentration) |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96 hours post-dose | 
| AUC0-infinity (area under the concentration time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96 hours post-dose | 
| AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96 hours post-dose | 
| λz (terminal elimination rate constant in plasma) |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96 hours post-dose | 
| t1/2 (terminal half-life of the analyte in plasma) |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96 hours post-dose | 
| MRTpo (Mean residence time of the analyte in the body after oral administration) |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96 hours post-dose | 
| CL/F (apparent clearance of the analyte in the plasma after oral administration) |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96 hours post-dose | 
| Vz/F (apparent volume of distribution during the terminal phase λz following an oral dose) |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96 hours post-dose | 
| Aet1-t2 (amount of analyte that is eliminated in urine from the time point t1 to time point t2) |  | Pre-dose and 0-4, 4-12, 12-24, 24-48 hours post-dose in the single rising dose phase | 
| fet1-t2 (fraction of analyte eliminated in urine from time point t1 to time point t2) |  | Pre-dose and 0-4, 4-12, 12-24, 24-48 hours post-dose in the single rising dose phase | 
| CLR,t1-t2 (renal clearance of the analyte from the time point t1 until the time point t2) |  | Pre-dose and 0-4, 4-12, 12-24, 24-48 hours post-dose in the single rising dose phase |