Reversal of Dabigatran With Prothrombin Complex Concentrate

Study Overview
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Brief Summary
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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
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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.

Official Title
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Reversal of Anticoagulant Effect of Dabigatran® by Prothrombin Complex Concentrate (Beriplex®), Assessed With a Novel Method of Blood Loss Measurement

Conditions
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Drug Action Reversal

Intervention / Treatment
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* Drug: Beriplex


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Beriplex 50 IU/Kg<br>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<br>* Beriplex 50 IU/Kg i.v. , single dose.<br>* Other names: B02BD01;|
| Placebo Comparator: Placebo<br>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<br>* Beriplex 50 IU/Kg i.v. , single dose.<br>* Other names: B02BD01;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inhibition of the anticoagulant effect of Dabigatran, assessed by the shed and washed blood methods | 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). | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Standard Coagulation Assays before / after Dabigatran and before / after PCC. | aPTT, PT, Diluted Thrombin Time (Hemoclot), Dabigatran Plasma Levels, Endogenous thrombin generation, pre- and Post coagulation factor II / VII / IX / X | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Washed Blood, Fibrinopeptide A, Shed Blood, Prothrombin Complex Concentrate, Dabigatran Etexilate, Beriplex, Direct Thrombin Inhibitor