Clinical trial NCT02463591: Reversal of Dabigatran With Prothrombin Complex Concentrate
Official title: Reversal of Anticoagulant Effect of Dabigatran® by Prothrombin Complex Concentrate (Beriplex®), Assessed With a Novel Method of Blood Loss Measurement
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Drug Action Reversal
Keywords: Direct Thrombin Inhibitor
Prothrombin Complex Concentrate
Dabigatran Etexilate
Beriplex
Shed Blood
Washed Blood
Fibrinopeptide A
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
name: CSL Behring
First posted: 2015-06-04
Enrollment: 12
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Inhibition of the anticoagulant effect of Dabigatran, assessed by the "shed and washed blood" methods
timeFrame: 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.)
Secondary outcomes:
measure: Change in Standard Coagulation Assays before / after Dabigatran and before / after PCC.
timeFrame: 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.
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Centre
Study officials:
affiliation: University Medical Center Groningen
name: Pieter Willem Kamphuisen, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wolzt M, Eder M, Weltermann A, Entlicher J, Eichler HG, Kyrle PA. Comparison of the effects of different low molecular weight heparins on the hemostatic system activation in vivo in man. Thromb Haemost. 1997 Aug;78(2):876-9.