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

Phase 1

Terminated

• Conditions: Healthy
• Interventions: Drug: BI 137882; Drug: Placebo

• Registration Number: NCT01348165
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study Start: 2011-05
• Study First Submitted: 2011-05-03
• Study First Submitted QC: 2011-05-04
• Study First Posted: 2011-05-05
• Primary Completion: 2011-08
• Results First Submitted: 2014-03-12
• Results First Submitted QC: 2014-05-12
• Results First Posted: 2014-06-04
• Status Verified: 2016-08
• Last Update Submitted: 2016-08-04
• Last Update Posted: 2016-09-16

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Male
• Target Recruitment: 40

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BI 137882 Dose 1	BI 137882	Powder for oral solution
BI 137882 Dose 2	BI 137882	Powder for oral solution
BI 137882 Dose 3	BI 137882	Powder for oral solution
BI 137882 Dose 4	BI 137882	Powder for oral solution
BI 137882 Dose 5	BI 137882	Powder for oral solution
BI 137882 Dose 6	BI 137882	Powder for oral solution
BI 137882 Dose 7	BI 137882	Powder for oral solution
BI 137882 Dose 8	BI 137882	Powder for oral solution
BI 137882 Dose 9	BI 137882	Powder for oral solution
Placebo	Placebo	Powder for oral solution

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Maximum Measured Concentration (Cmax)	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	Maximum measured concentration of BI 137882 in plasma.
Time to Maximum Measured Concentration (Tmax)	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 from dosing to maximum measured concentration of the analyte in plasma.
Area Under the Curve 0 to Infinity (AUC0-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	Area under the concentration-time curve of BI 137882 in plasma over the time interval from 0 extrapolated to infinity.
Terminal Half-life (t1/2)	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 of BI 137882 in plasma.
Renal Clearance of BI 137882 From the Time Point t1 Until the Time Point 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 (CLR,t1-t2)
Concentration of Tumour Necrosis Factor-alpha (TNF-α) Induced by Lipopolysaccharide (LPS) in Whole Blood ex Vivo	0.5 hours (h) before drug administration and 2h, 6h, 24h and 48h after drug administration	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.
Apparent Volume of Distribution (Vz/F)	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 of the analyte during the terminal phase.
Concentration of Leukotriene B4 (LTB4) Induced by N-formyl-methionine-leucine-phenylalanine (fMLP) in Whole Blood ex Vivo.	0.5 hours (h) before drug administration and 2h, 6h, 24h and 48h after drug administration	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.
Area Under the Effect Curve (AUEC)	30 minutes (min) before drug administration and 2 hours (h), 6h, 24h and 48h after drug administration	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.
Maximum Effect (Emax)	30 minutes (min) before drug administration and 2 hours (h), 6h, 24h and 48h after drug administration	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.
Minimum Effect (Emin)	30 minutes (min) before drug administration and 2 hours (h), 6h, 24h and 48h after drug administration	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.
Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)	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 concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point.
Terminal Rate Constant (λz)	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 in plasma.
Mean Residence Time (MRTpo)	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 of the analyte in the body after oral administration.
Apparent Clearance (CL/F)	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 of the analyte in plasma after extravascular administration.
Amount of BI 137882 Eliminated in Urine From the Time Point t1 to Time Point t2	0-4, 4-8, 8-12, and 12-24 hours after drug administration	Amount of BI 137882 eliminated in urine from the time point t1 to time point t2 (Aet1-t2)
Fraction of BI 137882 Eliminated in Urine From Time Point t1 to Time Point 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 (fet1-t2)