Drug Action Reversal Clinical Trial
Official title:
Reversal of Anticoagulant Effect of Dabigatran® by Prothrombin Complex Concentrate (Beriplex®), Assessed With a Novel Method of Blood Loss Measurement
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.
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.
;
Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment