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Safety, Tolerability, PK and PD of BI 655075 and Establishment of BI 655075 Dose(s) Effective to Reverse Prolongation of Blood Coagulation Time by Dabigatran

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ClinicalTrials.gov Identifier: NCT01955720
Recruitment Status : Completed
First Posted : October 7, 2013
Results First Posted : February 11, 2016
Last Update Posted : February 11, 2016
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Tracking Information
First Submitted Date  ICMJE September 30, 2013
First Posted Date  ICMJE October 7, 2013
Results First Submitted Date  ICMJE November 13, 2015
Results First Posted Date  ICMJE February 11, 2016
Last Update Posted Date February 11, 2016
Study Start Date  ICMJE September 2013
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 13, 2016)
  • Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time [ Time Frame: End of last infusion and 10 minutes after completion of last infusion of BI 655075 ]
    Percentage of subjects with at least one assay value from diluted thrombin time (dTT) or ecarin clotting time (ECT) reversed within 10min after completion of infusion. Reversal was defined as return to baseline, where the threshold for reversal to baseline was determined using PK/PD correlation between unbound sum dabigatran and the clotting parameters ECT and dTT. Measured at the end of the infusion and 10 min later.
  • The Percentage of Subjects With Drug-related Adverse Events [ Time Frame: From baseline up to the start of follow-up period (from Day 1 to Day 35) ]
    The percentage of subjects with possibly drug-related AEs (as defined by the investigator) during the treatment period.
Original Primary Outcome Measures  ICMJE
 (submitted: September 30, 2013)
  • Reversal of prolongation of blood coagulation time by dabigatran [ Time Frame: 10 minutes after completion of last infusion of BI 655075 ]
  • The endpoint for safety is the number (%) of subjects with BI 655075 related adverse events [ Time Frame: up to the 7 days pos dose ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2016)
  • AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) [ Time Frame: From Day 4 to Day 9 (details in description) ]
    AUC0-infinity. PK/PD sampling time: (p=predose, D=day)
    1. single medium or high dose, healthy subjects(HS) mid-age (45-64 yrs): D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00p, 21:00. D6: 9:00.
    2. single low or high dose, HS elderly or mild renal impaired: D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for renal impaired: D8: 9:00;D9: 9:00.
    3. high 2 doses, moderate renal impaired: D4: 8:55p, 9:00, 9:10,9:30,9:55p, 10:00,10:10,10:30,11:00, 13:00, 15:00, 19:00, 21:00, 01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for renal impaired: D8:9:00; D9:9:00.
  • AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) [ Time Frame: from 2h to12h of post DE dose at steady state (details in description) ]
    PK/PD sampling time:(d=dose,D=Day,p=predose)
    1. single medium or high dose,healthy, mid-age (45-64 yrs): D4: 7:00p,8:55p,9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00, 01:00; D5:9:00p,11:00,21:00p; D6:9:00p, 21:00p; D7:9:00p, 11:00.
    2. single low or high dose,healthy elder or mild renal impaired: D4:7:00p,8:55p,9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00;D5:9:00;D6:9:00;D7:9:00; additional sampling for renal impaired: D8:9:00;D9:9:00.
    3. high 2 doses, moderate renal impaired: D4:7:00p,8:55p,9:00,9:10,9:30,9:55p,10:00,10:10,10:30,11:00,13:00,15:00,19:00,21:00,01:00;D5:9:00;D6:9:00; D7:9:00; additional sampling for renal impaired: D8:9:00;D9:9:00.
  • Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) [ Time Frame: From 0 to 74h post of last DE dose (details in description) ]
    Urinary excretion of sum dabigatran from the time point t1 to t2 at steady state. PK Urine sampling time: Urine sampling relative to first DE administration: Planned times 72:00 - 73:55h, 73:55 - 80:00h, 80:00 - 86:00h, 86:00 - 98:00h, 98:00 - 122:00h, 122:00 - 146:00h; additional sampling for renal impaired: 146:00 - 170:00; 170:00 - 194:00h. Ae0-26,ss was not measured in Period 3 (re-exposure period). Ae0-74,ss was not measured in healthy subjects aged 45 to 64 years.
  • Cmax (Maximum Measured Concentration of the Ida in Plasma) [ Time Frame: From Ida administration to 4 days post dose (details in description) ]
    Cmax. PK/PD sampling time: (p=predose, D=day)
    1. single medium or high dose, HS mid-age (45-64 yrs): D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00p, 21:00. D6: 9:00.
    2. single low or high dose, healthy elderly or mild RI: D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for RI: D8: 9:00;D9: 9:00.
    3. high 2 doses, moderate RI: D4: 8:55p, 9:00, 9:10,9:30,9:55p, 10:00,10:10,10:30,11:00, 13:00, 15:00, 19:00, 21:00, 01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for RI: D8:9:00; D9:9:00.
  • Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h) [ Time Frame: from 0 to 6 hours of post Ida dose (details in description) ]
    Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time point 6 h). PK Urine sampling time: Urine sampling relative to DE administration: Planned times 72:00 - 73:55h, 73:55 - 80:00h, 80:00 - 86:00h, 86:00 - 98:00h, 98:00 - 122:00h, 122:00 - 146:00h; additional sampling for renal impaired: 146:00 - 170:00; 170:00 - 194:00h.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 30, 2013)
  • AUC0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) [ Time Frame: up to 3 days post dose ]
  • Aet1-t2 (amount of analyte eliminated in urine from the time point t1 to time point t2) [ Time Frame: up to 3 days post dose ]
  • Cmax (maximum measured concentration of the analyte in plasma) [ Time Frame: up to 1 hour post dose ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, PK and PD of BI 655075 and Establishment of BI 655075 Dose(s) Effective to Reverse Prolongation of Blood Coagulation Time by Dabigatran
Official Title  ICMJE Randomised, Double-blind, Placebo-controlled, Two-way Cross-over Phase Ib Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BI 655075 and to Establish the Efficacy of BI 655075 in Reversal of Dabigatran Anticoagulant Activity in Volunteers
Brief Summary To investigate safety, tolerability, PK and PD of BI 655075 and to establish the BI 655075 dose(s) effective to reverse prolongation of blood coagulation time by dabigatran
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double
Primary Purpose: Treatment
Condition  ICMJE Hemorrhage
Intervention  ICMJE
  • Drug: BI 655075
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: healthy subjects aged 45-64
    Sequential Crossover to Placebo or BI 655075
    Interventions:
    • Drug: BI 655075
    • Drug: Placebo
  • Experimental: healthy elderly subjects aged 65-80 year
    Sequential Crossover to Placebo or BI 655075
    Interventions:
    • Drug: BI 655075
    • Drug: Placebo
  • Experimental: mild renal impairment aged 45-80 years
    Sequential Crossover to Placebo or BI 655075
    Interventions:
    • Drug: BI 655075
    • Drug: Placebo
  • Experimental: mod renal impairment aged 45-80 years
    Sequential Crossover to Placebo or BI 655075
    Interventions:
    • Drug: Placebo
    • Drug: BI 655075
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 2, 2014)
46
Original Estimated Enrollment  ICMJE
 (submitted: September 30, 2013)
40
Actual Study Completion Date  ICMJE August 2014
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • Healthy midage male and female volunteers, age =45 and =64 years, BMI range: =18.5 and =29.9 kg/m2
  • Healthy elderly male and female volunteers, age =65 and =80 years, BMI range: =18.5 and = 32 kg/m2
  • Male and female volunteers with mild renal impairment (CLcrd 60-90 (mL/min)) in relatively good health, age =45 and =80 years, BMI range: =18.5 and =32 kg/m2 Moderate renal impaired (CLcrd =30 to <60 mL/min according Cockcroft&Gault formula in relatively good health, age =45 and =80 years, BMI range: =18.5 and =32 kg/m2

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 (other than mild renal impairment in the respective group) A significant disease is defined as a disease which in the opinion of the investigator
  • put the volunteer at risk because of participation in the study
  • may influence the results of the study
  • may influence the volunteer¿s ability to participate in the study
  • is not in a stable condition Diabetic, hypercholesterolemia or hypertensive subjects can be entered in this trial if the disease is not significant according to these criteria
  • 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 45 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01955720
Other Study ID Numbers  ICMJE 1321.2
2013-003616-52 ( EudraCT Number: EudraCT )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Boehringer Ingelheim
Study Sponsor  ICMJE Boehringer Ingelheim
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
PRS Account Boehringer Ingelheim
Verification Date January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP