Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BI 655075 (Idarucizumab) Administered Alone or With Dabigatran Etexilate in Japanese Healthy Subjects

Randomised, Double-blind Within Dose Groups, Placebo-controlled Phase I Trial in Healthy Japanese Male Volunteers to Investigate Safety, Tolerability and Pharmacokinetics of Different Doses of BI 655075 (Part 1) and to Explore the Effective Dose of BI 655075 to Reverse Dabigatran Anticoagulant Activity (Part 2).

The primary objective is to investigate the safety, tolerability and pharmacokinetics of BI 655075 following intravenous administration of single rising doses of BI 655075 when administered alone and after administration of dabigatran.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo to dose; Drug: Idarucizumab; Drug: Placebo to Idarucizumab; Drug: dabigatran

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Sumida-ku, Tokyo, Japan
    • 1321.5.00001 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion criteria:

1. Healthy Japanese male subjects

Exclusion criteria:

1. Any relevant deviation from healthy conditions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Idarucizumab single doses; different infusion durations	Drug: Placebo to dose; placebo; Drug: Idarucizumab; short infusion
Experimental: Idarucizumab with dabigatran; short infusion with 2 capsules dabigatran	Drug: Idarucizumab; short infusion; Drug: Placebo to Idarucizumab; Placebo to Idarucizumab; Drug: dabigatran; 2 capsules dabigatran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2	Percentage of subjects with drug-related adverse events in Part 1 and Part 2.	From first drug administration until 13 weeks after the last drug administration, upto 98 days (Part-I) & upto 108 days (Part-II)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II)	Amount of analyte eliminated in urine at steady state from the time point 0 hours to time point 74 hours.	0-2 h, 2-6 h, 6-10 h, 10-12 h,12-14h, 14-26 h, 26-50 h, 50-74 h after drug administration of dabigatran etexilate on Day 4 and Day 11.
AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II).	Area under the concentration-time curve of the dabigatran in plasma at steady state over the time interval 2 hours-12 hours. Time Frame: For dose group 5 to 7 (Day 1 to 3-Part-I):74hours (h), 74.5h, 75h, 76h, 78h, 80h, 82h, 84h, For dose group 8 (Day 1 to 3-Part-I): 74h, 74.5h, 75h, 76h, 78h, 80h, 82h, 84h and For dose group 5-7 (Day11 to Day13-Part II):242h, 242.167h, 242.5h, 243h, 244h,246h, 248h, 250h, 252h. For dose group 8 (Day11 to Day13-Part II):242h, 242.083h, 242.25h, 242.333h, 243.333h, 244h, 246h, 248h, 252h.	Day 4 (Part I) and Day 11 (Part II). Time frame are provided in detail in the Description section
Cmax for Idarucizumab in the Part I & Part II.	Maximum measured concentration of the analyte in plasma for idarucizumab Time frame: For dose group 1 to 3 (Day 1 to 3-Part-I): predose, 0 (end of infusion), 0.033h, 0.083h, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h. For dose group 4 (Day 1 to 3-Part-I): predose, -0.5h, 0 (end of infusion), 0.033h, 0.083h, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 48h. For dose group 5-7 (Day11 to Day13-Part II): predose, 242h (end of infusion), 242.033h, 242.083h, 242.167h, 242.25h, 242.5h, 242.75h, 243h, 243.5h, 244h, 244.5h, 245h, 246h, 248h, 250h, 252h, 254h, 258h, 266h, 290h.For dose group 8 (day11 to Day13-Part II): predose, 242h (end of infusion), 242.083h, 242.25h, 242.333h, 242.367h, 242.5h, 242.833h, 243.333h, 244h, 245h, 246h, 248h, 252h, 254h, 266h, 290h, 314h.	Day 1 to 3 (Part I) and Day 11 to 13 (Part II); Time frame are provided in detail in the Description section
AUC0-inf for Idarucizumab in the Part I & Part II.	Area under the concentration-time curve of the analyte in plasma for idarucizumab over the time interval from 0 extrapolated to infinity. Time frame: For dose group 1 to 3 (Day 1 to 3-Part-I): predose, 0 (end of infusion), 0.033h, 0.083, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h. For dose group 4 (Day 1 to 3-Part-I): predose, -0.5h, 0 (end of infusion), 0.033h, 0.083h, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 48h. For dose group 5-7 (Day11 to Day13-Part II): predose, 242h (end of infusion), 242.033h, 242.083h, 242.167h, 242.25h, 242.5h, 242.75h, 243h, 243.5h, 244h, 244.5h, 245h, 246h, 248h, 250h, 252h, 254h, 258h, 266h, 290h.For dose group 8 (day11 to Day13-Part II): predose, 242h (end of infusion), 242.083h, 242.25h, 242.333h, 242.367h, 242.5h, 242.833h, 243.333h, 244h, 245h, 246h, 248h, 252h, 254h, 266h, 290h, 314h.	Day 1 to 3 (Part I) and Day 11 to 13 (Part II); Time frame are provided in detail in the Description section
Ae0-72 for Idarucizumab in the Part I & Part II.	Amount of idarucizumab eliminated in urine over the time interval 0-72. Time frame: For dose groups 1 to 3 (day1 to day4-Part-1):0-4 h, 4-8 h, 8-12 h, 12-24 h, 24-48 h, 48-72 h. For dose groups 5 to 7 (day 11 to day14-Part-II): 0-4 h, 4-8 h, 8-10 h, 10-12 h,12-24 h, 24-48 h, and 48-72 h. For dose groups 8 (day11 to day14-Part-II): 0-4h, 4-8 h, 8-10 h, 10-24 h, 24-48 h, 48-72 h.	Day 1 to 4 (Part I) and Day 11 to 14 (Part II); Time frame are provided in detail in the Description section
Ae0-73 for the Dose Group 4 in the Part I	Amount of the analyte excreted in urine over the time interval 0-73	For dose group 4 (day1 to day4-Part-1): 0-7h, 7-13h, 13-25h, 25-49h, 49-73h
AUEC2-12	Area under the effect curve over the time interval from 2 to 12h, AUEC2-12 on Days 4 and 11 for diluted thrombin time (dTT). For dose groups 5 to 7(day4-Part-II): 74h, 74.5h, 75h, 76h, 78h, 80h, 82h, 84h on day 4. For dose groups 5 to 7(day11-Part-II): 242h, 242.083h, 242.167h, 242.5h, 243h, 244h, 246h, 248h, 250h, 252h. For dose groups 8(day4-Part-II): 74.5 h, 78 h, 84 h on day 4. For dose groups 8(day11-Part-II): 242h, 242.083h,242.25h, 242.333h, 243.333h, 244h, 246h, 248h, 252h on day 11. AUEC is calculated by multiplying the ratio (Value at each time point/Ebase, unit of Vaue is [s] and Ebase is value [s] at baseline) by time. Therefore, Unit for AUEC2-12 is [h].	Day 4 and Day 11 (Part II); Time frame are provided in detail in the Description section

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General 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.
• Yasaka M, Ikushima I, Harada A, Imazu S, Taniguchi A, Norris S, Gansser D, Stangier J, Schmohl M, Reilly PA. Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study. Res Pract Thromb Haemost. 2017 Aug 5;1(2):202-215. doi: 10.1002/rth2.12029. eCollection 2017 Oct.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: January 6, 2014
• First Submitted That Met QC Criteria: January 6, 2014
• First Posted (Estimate): January 7, 2014

Study Record Updates

• Last Update Posted (Estimate): February 11, 2016
• Last Update Submitted That Met QC Criteria: January 13, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Dabigatran
• Other Study ID Numbers: 1321.5