Safety, Tolerability and Pharmacokinetics of Single Rising Oral Doses of BI 137882 in Healthy Male Volunteers

Study Overview
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Brief Summary
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Safety, Tolerability and Pharmacokinetics of Single Rising Oral Doses of BI 137882 in Healthy Male Volunteers

Detailed Description
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As a transition from preclinical investigations to clinical development in this first-in-man trial, safety, tolerability, and pharmacokinetics of BI 137882 will be assessed in healthy male volunteers using single rising oral doses in order to provide the basis for a potential ongoing clinical development of BI 137882 in the indication of COPD. Healthy male subjects aged 21 - 50 years will be recruited for this study. They provide a relatively stable physiological, biochemical and hormonal basis (steady state) for studying drug effects, they show no disease-related variation and they are not taking concomitant medication. Within each dose group, all actively treated individuals will receive the same BI 137882 dose. The next higher dose will only be administered if the treatment in the preceding dose group was safe and well tolerated.

Official Title
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Safety, Tolerability and Pharmacokinetics of Single Rising Oral Doses of BI 137882 in Healthy Male Volunteers (A Randomised, Single-blind, Placebo-controlled Phase I Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 137882
* Drug: Placebo


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 electrocardiogram (ECG), clinical laboratory tests Age 21 to 50 years BMI 18.5 to 29.9 kg/m2 (Body Mass Index) Signed and dated written informed consent prior to admission to the study in accordance with GCP 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 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 (more than 10 cigarettes /day) Inability to refrain from smoking on trial days Alcohol abuse (more than 20 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 Torsades de points (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

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: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 137882 Dose 1<br>Powder for oral solution | Drug: BI 137882<br>* Powder for oral solution<br>|
| Experimental: BI 137882 Dose 2<br>Powder for oral solution | Drug: BI 137882<br>* Powder for oral solution<br>|
| Experimental: BI 137882 Dose 3<br>Powder for oral solution | Drug: BI 137882<br>* Powder for oral solution<br>|
| Experimental: BI 137882 Dose 4<br>Powder for oral solution | Drug: BI 137882<br>* Powder for oral solution<br>|
| Experimental: BI 137882 Dose 5<br>Powder for oral solution | Drug: BI 137882<br>* Powder for oral solution<br>|
| Experimental: BI 137882 Dose 6<br>Powder for oral solution | Drug: BI 137882<br>* Powder for oral solution<br>|
| Experimental: BI 137882 Dose 7<br>Powder for oral solution | Drug: BI 137882<br>* Powder for oral solution<br>|
| Experimental: BI 137882 Dose 8<br>Powder for oral solution | Drug: BI 137882<br>* Powder for oral solution<br>|
| Experimental: BI 137882 Dose 9<br>Powder for oral solution | Drug: BI 137882<br>* Powder for oral solution<br>|
| Placebo Comparator: Placebo<br>Powder for oral solution | Drug: Placebo<br>* Powder for oral solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Drug Related Adverse Events | Number of subjects with drug related adverse events (AEs) | From baseline up to 28 days | 
| Blood Pressure | Change from baseline for systolic blood pressure (SBP) and diastolic blood pressure (DBP) | Baseline and 28 days | 
| Pulse Rate (PR) | Change from Baseline to 28 Days in Pulse Rate | Baseline and 28 days | 
| Respiratory Rate (RR) | Change from Baseline to 28 Days in Respiratory rate (RR) | Baseline and 28 days | 
| Body Temperature | Change from baseline to 28 Days in Body temperature | Baseline and 28 days | 
| Assessment of Tolerability by Investigator | The investigator assessed tolerability based on adverse events and the laboratory evaluation according to the categories 'good', 'satisfactory', 'not satisfactory', and 'bad'. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Measured Concentration (Cmax) | Maximum measured concentration of BI 137882 in plasma. | 30 minutes (min) before drug administration and 30min, 1 hour (h), 2h, 4h, 6h, 8h, 12h, 24h, 34h, 48h, 72h, 96h, 144h, 192h, 264h, 336h and 480h after drug administration | 
| Time to Maximum Measured Concentration (Tmax) | Time from dosing to maximum measured concentration of the analyte in plasma. | 30 minutes (min) before drug administration and 30min, 1 hour (h), 2h, 4h, 6h, 8h, 12h, 24h, 34h, 48h, 72h, 96h, 144h, 192h, 264h, 336h and 480h after drug administration | 
| Area Under the Curve 0 to Infinity (AUC0-infinity) | Area under the concentration-time curve of BI 137882 in plasma over the time interval from 0 extrapolated to infinity. | 30 minutes (min) before drug administration and 30min, 1 hour (h), 2h, 4h, 6h, 8h, 12h, 24h, 34h, 48h, 72h, 96h, 144h, 192h, 264h, 336h and 480h after drug administration | 
| Terminal Half-life (t1/2) | Terminal half-life of BI 137882 in plasma. | 30 minutes (min) before drug administration and 30min, 1 hour (h), 2h, 4h, 6h, 8h, 12h, 24h, 34h, 48h, 72h, 96h, 144h, 192h, 264h, 336h and 480h after drug administration | 
| Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point. | 30 minutes (min) before drug administration and 30min, 1 hour (h), 2h, 4h, 6h, 8h, 12h, 24h, 34h, 48h, 72h, 96h, 144h, 192h, 264h, 336h and 480h after drug administration | 
| Terminal Rate Constant (λz) | Terminal rate constant in plasma. | 30 minutes (min) before drug administration and 30min, 1 hour (h), 2h, 4h, 6h, 8h, 12h, 24h, 34h, 48h, 72h, 96h, 144h, 192h, 264h, 336h and 480h after drug administration | 
| Mean Residence Time (MRTpo) | Mean residence time of the analyte in the body after oral administration. | 30 minutes (min) before drug administration and 30min, 1 hour (h), 2h, 4h, 6h, 8h, 12h, 24h, 34h, 48h, 72h, 96h, 144h, 192h, 264h, 336h and 480h after drug administration | 
| Apparent Clearance (CL/F) | Apparent clearance of the analyte in plasma after extravascular administration. | 30 minutes (min) before drug administration and 30min, 1 hour (h), 2h, 4h, 6h, 8h, 12h, 24h, 34h, 48h, 72h, 96h, 144h, 192h, 264h, 336h and 480h after drug administration | 
| Apparent Volume of Distribution (Vz/F) | Apparent volume of distribution of the analyte during the terminal phase. | 30 minutes (min) before drug administration and 30min, 1 hour (h), 2h, 4h, 6h, 8h, 12h, 24h, 34h, 48h, 72h, 96h, 144h, 192h, 264h, 336h and 480h after drug administration | 
| Amount of BI 137882 Eliminated in Urine From the Time Point t1 to Time Point t2 | Amount of BI 137882 eliminated in urine from the time point t1 to time point t2 (Aet1-t2) | 0-4, 4-8, 8-12, and 12-24 hours after drug administration | 
| Fraction of BI 137882 Eliminated in Urine From Time Point t1 to Time Point t2 | Fraction of BI 137882 eliminated in urine from time point t1 to time point t2 (fet1-t2) | 0-4, 4-8, 8-12, and 12-24 hours after drug administration | 
| Renal Clearance of BI 137882 From the Time Point t1 Until the Time Point t2 | Renal clearance of BI 137882 from the time point t1 until the time point t2 (CLR,t1-t2) | 0-4, 4-8, 8-12, and 12-24 hours after drug administration | 
| Concentration of Tumour Necrosis Factor-alpha (TNF-α) Induced by Lipopolysaccharide (LPS) in Whole Blood ex Vivo | Concentrations of TNF-α in plasma were determined by an enzyme-linked immunosorbent assay (ELISA). Concentrations of TNF-α in blood drawn after treatment with BI 137882 were compared with those in pre-dose samples to calculate the percent of inhibition of LPS induction of TNF-α production. Results indicate percent change from baseline of LPS-induced TNF-α production. A positive value indicates inhibition of the production. | 0.5 hours (h) before drug administration and 2h, 6h, 24h and 48h after drug administration | 
| Concentration of Leukotriene B4 (LTB4) Induced by N-formyl-methionine-leucine-phenylalanine (fMLP) in Whole Blood ex Vivo. | Percent of inhibition of fMLP induction of LTB4 production. Concentrations of LTB4 in plasma were determined by an enzyme-linked immunosorbent assay (ELISA). Results indicate percent change from baseline of fMLP induction of LTB4 production. A positive value indicates inhibition of the production. | 0.5 hours (h) before drug administration and 2h, 6h, 24h and 48h after drug administration | 
| Area Under the Effect Curve (AUEC) | Area under the effect curve for TNF-alpha induced by LPS and LTB4 induced by fMLP. Results indicate percent change from baseline of TNF-α/LTB4 production. A positive value indicates inhibition of the production. | 30 minutes (min) before drug administration and 2 hours (h), 6h, 24h and 48h after drug administration | 
| Maximum Effect (Emax) | Maximum effect for TNF-alpha induced by LPS and LTB4 induced by fMLP. Results indicate percent change from baseline of TNF-α/LTB4 production. A positive value indicates inhibition of the production. | 30 minutes (min) before drug administration and 2 hours (h), 6h, 24h and 48h after drug administration | 
| Minimum Effect (Emin) | Minimum effect for TNF-alpha induced by LPS and LTB4 induced by fMLP. Results indicate percent change from baseline of TNF-α/LTB4 production. A positive value indicates inhibition of the production. | 30 minutes (min) before drug administration and 2 hours (h), 6h, 24h and 48h after drug administration |