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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01348165
First received: May 3, 2011
Last updated: June 18, 2014
Last verified: May 2014
  Purpose

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


Condition Intervention Phase
Healthy
Drug: BI 137882
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Single Blind
Primary Purpose: Treatment
Official Title: 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)

Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Number of Subjects With Drug Related Adverse Events [ Time Frame: From baseline up to 28 days ] [ Designated as safety issue: No ]
    Number of subjects with drug related adverse events (AEs)

  • Blood Pressure [ Time Frame: Baseline and 28 days ] [ Designated as safety issue: No ]
    Change from baseline for systolic blood pressure (SBP) and diastolic blood pressure (DBP)

  • Pulse Rate (PR) [ Time Frame: Baseline and 28 days ] [ Designated as safety issue: No ]
    Change from Baseline to 28 Days in Pulse Rate

  • Respiratory Rate (RR) [ Time Frame: Baseline and 28 days ] [ Designated as safety issue: No ]
    Change from Baseline to 28 Days in Respiratory rate (RR)

  • Body Temperature [ Time Frame: Baseline and 28 days ] [ Designated as safety issue: No ]
    Change from baseline to 28 Days in Body temperature

  • Assessment of Tolerability by Investigator [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    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:
  • Maximum Measured Concentration (Cmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Maximum measured concentration of BI 137882 in plasma.

  • Time to Maximum Measured Concentration (Tmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Time from dosing to maximum measured concentration of the analyte in plasma.

  • Area Under the Curve 0 to Infinity (AUC0-infinity) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Terminal half-life of BI 137882 in plasma.

  • Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Terminal rate constant in plasma.

  • Mean Residence Time (MRTpo) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Mean residence time of the analyte in the body after oral administration.

  • Apparent Clearance (CL/F) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Apparent clearance of the analyte in plasma after extravascular administration.

  • Apparent Volume of Distribution (Vz/F) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Apparent volume of distribution of the analyte during the terminal phase.

  • Amount of BI 137882 Eliminated in Urine From the Time Point t1 to Time Point t2 [ Time Frame: 0-4, 4-8, 8-12, and 12-24 hours after drug administration ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0-4, 4-8, 8-12, and 12-24 hours after drug administration ] [ Designated as safety issue: No ]
    Fraction of BI 137882 eliminated in urine from time point t1 to time point t2 (fet1-t2)

  • Renal Clearance of BI 137882 From the Time Point t1 Until the Time Point t2 [ Time Frame: 0-4, 4-8, 8-12, and 12-24 hours after drug administration ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0.5 hours (h) before drug administration and 2h, 6h, 24h and 48h after drug administration ] [ Designated as safety issue: No ]
    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.

  • Concentration of Leukotriene B4 (LTB4) Induced by N-formyl-methionine-leucine-phenylalanine (fMLP) in Whole Blood ex Vivo. [ Time Frame: 0.5 hours (h) before drug administration and 2h, 6h, 24h and 48h after drug administration ] [ Designated as safety issue: No ]
    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) [ Time Frame: 30 minutes (min) before drug administration and 2 hours (h), 6h, 24h and 48h after drug administration ] [ Designated as safety issue: No ]
    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) [ Time Frame: 30 minutes (min) before drug administration and 2 hours (h), 6h, 24h and 48h after drug administration ] [ Designated as safety issue: No ]
    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) [ Time Frame: 30 minutes (min) before drug administration and 2 hours (h), 6h, 24h and 48h after drug administration ] [ Designated as safety issue: No ]
    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.


Enrollment: 40
Study Start Date: May 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BI 137882 low dose
Powder for oral solution
Drug: BI 137882
Low dose powder for oral solution
Experimental: BI 137882 low dose
Powder for oral solution
Drug: BI 137882
Low dose powder for oral solution
Experimental: BI 137882 low dose
Powder for oral solution
Drug: BI 137882
Low dose powder for oral solution
Experimental: BI 137882 medium dose
Powder for oral solution
Drug: BI 137882
Medium dose powder for oral solution
Experimental: BI 137882 medium dose
Powder for oral solution
Drug: BI 137882
Medium dose powder for oral solution
Experimental: BI 137882 medium dose
Powder for oral solution
Drug: BI 137882
Medium dose powder for oral solution
Experimental: BI 137882 high dose
Powder for oral solution
Drug: BI 137882
High dose powder for oral solution
Experimental: BI 137882 high dose
Powder for oral solution
Drug: BI 137882
High dose powder for oral solution
Experimental: BI 137882 high dose
Powder for oral solution
Drug: BI 137882
High dose powder for oral solution
Placebo Comparator: Placebo
Powder for oral solution
Drug: Placebo
Powder for oral solution

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.

  Eligibility

Ages Eligible for Study:   21 Years to 50 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria:

  1. 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
  2. Age 21 to 50 years
  3. BMI 18.5 to 29.9 kg/m2 (Body Mass Index)
  4. Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation.

Exclusion criteria:

  1. Any finding of the medical examination (including BP, PR and ECG) deviating from normal and of clinical relevance
  2. Any evidence of a clinically relevant concomitant disease
  3. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
  4. Surgery of the gastrointestinal tract (except appendectomy)
  5. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
  6. History of relevant orthostatic hypotension, fainting spells or blackouts.
  7. Chronic or relevant acute infections
  8. History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
  9. 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
  10. 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
  11. Participation in another trial with an investigational drug within two months prior to administration or during the trial
  12. Smoker (more than 10 cigarettes /day)
  13. Inability to refrain from smoking on trial days
  14. Alcohol abuse (more than 20 g/day)
  15. Drug abuse
  16. Blood donation (more than 100 mL within four weeks prior to administration or during the trial)
  17. Excessive physical activities (within one week prior to administration or during the trial)
  18. Any laboratory value outside the reference range that is of clinical relevance
  19. Inability to comply with dietary regimen of trial site
  20. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms);
  21. A history of additional risk factors for Torsades de points (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01348165

Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01348165     History of Changes
Other Study ID Numbers: 1306.1, 2010-023462-52
Study First Received: May 3, 2011
Results First Received: March 12, 2014
Last Updated: June 18, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

ClinicalTrials.gov processed this record on September 18, 2014