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

• 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: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: September 30, 2013
• First Posted Date: October 7, 2013
• Results First Submitted Date: November 13, 2015
• Results First Posted Date: February 11, 2016
• Last Update Posted Date: February 11, 2016
• Study Start Date: September 2013
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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 ]

Current Secondary Outcome Measures (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 (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: 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: 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: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Hemorrhage

Intervention

• Drug: BI 655075
• Drug: Placebo

Study Arms

• 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 *

• Norris S, Ramael S, Ikushima I, Haazen W, Harada A, Moschetti V, Imazu S, Reilly PA, Lang B, Stangier J, Glund S. Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies. Br J Clin Pharmacol. 2017 Aug;83(8):1815-1825. doi: 10.1111/bcp.13269. Epub 2017 Apr 6.
• Glund S, Stangier J, van Ryn J, Schmohl M, Moschetti V, Haazen W, De Smet M, Gansser D, Norris S, Lang B, Reilly P, Kreuzer J. Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study. Clin Pharmacokinet. 2017 Jan;56(1):41-54. doi: 10.1007/s40262-016-0417-0.
• Glund S, Stangier J, van Ryn J, Schmohl M, Moschetti V, Haazen W, De Smet M, Gansser D, Norris S, Lang B, Reilly P, Kreuzer J. Restarting Dabigatran Etexilate 24 h After Reversal With Idarucizumab and Redosing Idarucizumab in Healthy Volunteers. J Am Coll Cardiol. 2016 Apr 5;67(13):1654-1656. doi: 10.1016/j.jacc.2016.01.043.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 2, 2014): 46
• Original Estimated Enrollment (submitted: September 30, 2013): 40
• Actual Study Completion Date: August 2014
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 45 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium

Administrative Information

• NCT Number: NCT01955720
• Other Study ID Numbers: 1321.2; 2013-003616-52 ( EudraCT Number: EudraCT )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Boehringer Ingelheim
• Study Sponsor: Boehringer Ingelheim
• Collaborators: Not Provided

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

• PRS Account: Boehringer Ingelheim
• Verification Date: January 2016