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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

Primary Purpose

Hemorrhage

Status
Completed
Phase
Phase 1
Locations
Belgium
Study Type
Interventional
Intervention
BI 655075
BI 655075
Placebo
BI 655075
Placebo
Placebo
Placebo
BI 655075
Sponsored by
Boehringer Ingelheim
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemorrhage

Eligibility Criteria

45 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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)

Sites / Locations

  • 1321.2.1 Boehringer Ingelheim Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

healthy subjects aged 45-64

healthy elderly subjects aged 65-80 year

mild renal impairment aged 45-80 years

mod renal impairment aged 45-80 years

Arm Description

Sequential Crossover to Placebo or BI 655075

Sequential Crossover to Placebo or BI 655075

Sequential Crossover to Placebo or BI 655075

Sequential Crossover to Placebo or BI 655075

Outcomes

Primary Outcome Measures

Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time
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
The percentage of subjects with possibly drug-related AEs (as defined by the investigator) during the treatment period.

Secondary Outcome Measures

AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
AUC0-infinity. PK/PD sampling time: (p=predose, D=day) 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. 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. 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)
PK/PD sampling time:(d=dose,D=Day,p=predose) 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. 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. 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)
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)
Cmax. PK/PD sampling time: (p=predose, D=day) 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. 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. 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)
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.

Full Information

First Posted
September 30, 2013
Last Updated
January 13, 2016
Sponsor
Boehringer Ingelheim
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1. Study Identification

Unique Protocol Identification Number
NCT01955720
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2016
Overall Recruitment Status
Completed
Study Start Date
September 2013 (undefined)
Primary Completion Date
May 2014 (Actual)
Study Completion Date
August 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim

4. Oversight

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemorrhage

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
Double
Allocation
Randomized
Enrollment
46 (Actual)

8. Arms, Groups, and Interventions

Arm Title
healthy subjects aged 45-64
Arm Type
Experimental
Arm Description
Sequential Crossover to Placebo or BI 655075
Arm Title
healthy elderly subjects aged 65-80 year
Arm Type
Experimental
Arm Description
Sequential Crossover to Placebo or BI 655075
Arm Title
mild renal impairment aged 45-80 years
Arm Type
Experimental
Arm Description
Sequential Crossover to Placebo or BI 655075
Arm Title
mod renal impairment aged 45-80 years
Arm Type
Experimental
Arm Description
Sequential Crossover to Placebo or BI 655075
Intervention Type
Drug
Intervention Name(s)
BI 655075
Intervention Type
Drug
Intervention Name(s)
BI 655075
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Type
Drug
Intervention Name(s)
BI 655075
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Type
Drug
Intervention Name(s)
BI 655075
Primary Outcome Measure Information:
Title
Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time
Description
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.
Time Frame
End of last infusion and 10 minutes after completion of last infusion of BI 655075
Title
The Percentage of Subjects With Drug-related Adverse Events
Description
The percentage of subjects with possibly drug-related AEs (as defined by the investigator) during the treatment period.
Time Frame
From baseline up to the start of follow-up period (from Day 1 to Day 35)
Secondary Outcome Measure Information:
Title
AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
Description
AUC0-infinity. PK/PD sampling time: (p=predose, D=day) 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. 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. 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.
Time Frame
From Day 4 to Day 9 (details in description)
Title
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)
Description
PK/PD sampling time:(d=dose,D=Day,p=predose) 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. 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. 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.
Time Frame
from 2h to12h of post DE dose at steady state (details in description)
Title
Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2)
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.
Time Frame
From 0 to 74h post of last DE dose (details in description)
Title
Cmax (Maximum Measured Concentration of the Ida in Plasma)
Description
Cmax. PK/PD sampling time: (p=predose, D=day) 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. 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. 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.
Time Frame
From Ida administration to 4 days post dose (details in description)
Title
Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h)
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.
Time Frame
from 0 to 6 hours of post Ida dose (details in description)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boehringer Ingelheim
Organizational Affiliation
Boehringer Ingelheim
Official's Role
Study Chair
Facility Information:
Facility Name
1321.2.1 Boehringer Ingelheim Investigational Site
City
Antwerpen
Country
Belgium

12. IPD Sharing Statement

Citations:
PubMed Identifier
28230262
Citation
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.
Results Reference
derived
PubMed Identifier
27317414
Citation
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.
Results Reference
derived
PubMed Identifier
27150693
Citation
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. No abstract available.
Results Reference
derived

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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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