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Trial record 51 of 332 for:    DABIGATRAN

Reversal of Dabigatran With Prothrombin Complex Concentrate

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ClinicalTrials.gov Identifier: NCT02463591
Recruitment Status : Unknown
Verified May 2016 by Pieter W. Kamphuisen, MD PhD, University Medical Center Groningen.
Recruitment status was:  Recruiting
First Posted : June 4, 2015
Last Update Posted : May 12, 2016
Sponsor:
Collaborators:
Boehringer Ingelheim
CSL Behring
Information provided by (Responsible Party):
Pieter W. Kamphuisen, MD PhD, University Medical Center Groningen

Brief Summary:
The purpose of this study is to investigate whether Prothrombin Complex Concentrate (PCC) is effective in reversing the anticoagulant effect of Dabigatran, as assessed by two modified skin-bleeding tests.

Condition or disease Intervention/treatment Phase
Drug Action Reversal Drug: Beriplex Phase 2

Detailed Description:

There is currently no treatment widely available for immediate reversal of Dabigatran anticoagulant effects, e.g. in case of major bleeding or when emergency surgery or invasive procedures are indicated.

Treatment with prothrombin complex concentrate (PCC) seems effective in reducing blood loss in animal models, but previous studies in humans have failed to show an effect on blood coagulation parameters. Recently, two novel methods of skin blood loss, one called "shed blood" and another "washed blood" were able to measure effects of anticoagulation, either as the inhibition of fibrin formation at the wound site by measuring Fibrinopeptide A (FPA) or as elevated blood loss, respectively, after oral administration of Dabigatran in healthy volunteers.

The investigators hypothesise that the shed/washed blood methods are able to measure Dabigatran reversal following administration of PCC (Beriplex).

The study will be performed as a randomised double blind cross-over study and 12 healthy human male subjects will be enrolled. Subjects will take Dabigatran 300 mg b.i.d. on day -2, -1 and 0. After the fifth dose (on day 0), subjects will be randomised to receive Beriplex (50 IU/kg) or a similar volume of saline as a single bolus dose i.v. over 20 minutes. After a 10 day minimum wash-out period this procedure will be repeated, and the alternative treatment (Saline or Beriplex) is administered.

The Shed / Washed Blood measurements will be performed at different time points before and after starting oral anticoagulants and before and after administration of Beriplex/Saline.

In addition to the Shed / Washed blood tests, several ex vivo standard coagulation tests will be performed. These include: activated partial thromboplastin time (aPTT), prothrombin time (PT), diluted thrombin time (DTT/Hemoclot), Dabigatran plasma levels (using liquid chromatography-tandem mass spectrometry (LC-MS/MS)), endogenous thrombin generation (ETG) and pre and post factor II, VII, IX and X.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Reversal of Anticoagulant Effect of Dabigatran® by Prothrombin Complex Concentrate (Beriplex®), Assessed With a Novel Method of Blood Loss Measurement
Study Start Date : January 2015
Estimated Primary Completion Date : July 2016
Estimated Study Completion Date : December 2016


Arm Intervention/treatment
Experimental: Beriplex 50 IU/Kg
Cross over design: After therapy with Dabigatran Etexilate 300mg BID for 2.5 days, subjects will receive a single dose of Beriplex 50 IU/Kg. After a 10 day minimum wash-out period subjects will receive the alternative treatment (Placebo).
Drug: Beriplex
Beriplex 50 IU/Kg i.v. , single dose.
Other Names:
  • Prothrombin Complex Concentrate
  • RVG 101094
  • B02BD01

Placebo Comparator: Placebo
Cross over design: After therapy with Dabigatran Etexilate 300mg BID for 2.5 days, subjects will receive a single dose of Placebo identically in appearance to Beriplex 50 IU/Kg. After a 10 day minimum wash-out period subjects will receive the alternative treatment (Beriplex).
Drug: Beriplex
Beriplex 50 IU/Kg i.v. , single dose.
Other Names:
  • Prothrombin Complex Concentrate
  • RVG 101094
  • B02BD01




Primary Outcome Measures :
  1. Inhibition of the anticoagulant effect of Dabigatran, assessed by the "shed and washed blood" methods [ Time Frame: Before Dabigatran (Baseline, T= day-2), After Dabigatran / Before PCC (T= day 0), After Dabigatran / After PCC (T=40 min.), After Dabigatran / After PCC (T=360 min.) ]

    The Shed blood test allows assessment of thrombin activity and subsequent fibrinogen conversion to fibrin in vivo by measuring fibrinopeptide A (FPA) generation. A standardized wound, using a disposable device (Surgicutt® Adult) is made on the volar surface of the forearm, from which blood is collected during 4 minutes. The total amount of shed blood is measured in addition to Fibrinopeptide A levels. FPA levels are compared to FPA levels in systemic venous samples collected at corresponding timepoints.

    The washed blood test measures both the time until bleeding stops and sensitively measures small volumes of blood loss as area under the curve (AUC).



Secondary Outcome Measures :
  1. Change in Standard Coagulation Assays before / after Dabigatran and before / after PCC. [ Time Frame: Before Dabigatran (Baseline, T= day-2), After Dabigatran / Before PCC (T= day 0), After Dabigatran / After PCC (T=20 min., T=40 min., T=60 min., T=120 min., T=240 min., T=360 min. ]
    aPTT, PT, Diluted Thrombin Time (Hemoclot), Dabigatran Plasma Levels, Endogenous thrombin generation, pre- and Post coagulation factor II / VII / IX / X



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy males
  • Age between 18 and 50 years
  • Weight <100 kg
  • Signed informed consent
  • eGFR ≥ 80ml/min*1.73m2

Exclusion Criteria:

  • History of allergic reaction to blood products
  • Current participation in any other investigational drug study or within the past 30 days
  • Increased bleeding tendency or history of thrombosis
  • Anticoagulant medication, platelet aggregation inhibitors or NSAIDs
  • Use of any medication 14 days before start of dabigatran intake

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02463591


Contacts
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Contact: Alexander C Stehouwer, MD 0031503610116 a.c.stehouwer@umcg.nl
Contact: Hilde Hop, MD 0031503610116 h.hop@umcg.nl

Locations
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Netherlands
University Medical Centre Recruiting
Groningen, Netherlands, 9713 GZ
Contact: A C Stehouwer, MD    0031503610116    a.c.stehouwer@umcg.nl   
Contact: H Hop, MD    0031503610116    h.hop@umcg.nl   
Principal Investigator: Pieter Willem Kamphuisen, Prof. Dr.         
Sponsors and Collaborators
University Medical Center Groningen
Boehringer Ingelheim
CSL Behring
Investigators
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Principal Investigator: Pieter Willem Kamphuisen, Prof. Dr. University Medical Center Groningen

Publications:
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Responsible Party: Pieter W. Kamphuisen, MD PhD, Prof. dr., University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT02463591     History of Changes
Other Study ID Numbers: BI 1160.203
2014-002204-24 ( EudraCT Number )
First Posted: June 4, 2015    Key Record Dates
Last Update Posted: May 12, 2016
Last Verified: May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Pieter W. Kamphuisen, MD PhD, University Medical Center Groningen:
Direct Thrombin Inhibitor
Prothrombin Complex Concentrate
Dabigatran Etexilate
Beriplex
Shed Blood
Washed Blood
Fibrinopeptide A
Additional relevant MeSH terms:
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Dabigatran
Thrombin
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants
Hemostatics
Coagulants