To assess the normalization (reversal) of coagulation assays upon administration of two dosages of Prothrombin Complex Concentratre (PCC, Cofact®) in healthy volunteers treated with either rivaroxaban or apixaban
ID
Source
Brief title
Condition
- Vascular haemorrhagic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome is the reversal (normalisation) of coagulation assays, at
the end of oral f-Xa inhibitor administration and after the infusion of PCC or
placebo.
Secondary outcome
not applicable
Background summary
Novel oral anticoagulants (NOACs) were originally designed as alternatives for
vitamin K antagonists (VKAs) who lack the possibility of being prescribed in a
fixed dose regimen. Rivaroxaban and apixaban are examples of NOACs, both direct
factor (f) Xa inhibitors that come with a stable pharmacologic profile and
therefore do not require regular monitoring for dose adjustments unlike VKAs.
Following several phase III trials, NOACs have been approved for several
clinical indications. Even though these antithrombotic agents are already on
the market, there is no internationally approved method of reversal. As for any
anticoagulant, these drugs can cause potential life threatening bleedings and
need to be reversed in case of an emergency procedure. In the absence of a
specific antidote, the immediate reversal of their anticoagulant effect of a
direct fXa inhibitor could be achieved by administration of a prothrombin
complex concentrate (PCC), as a recent phase I in vitro study has shown.
However, a high dose of PCC was used in this particular study, and a lower
dosage may be more practical, less costly and potentially less harmful.
Although there is ample experience with PCCs to confirm that they have a low
risk of side effects, any prohemostatic agent may increase the risk of
thrombosis. Hence, establishing the lowest possible effective dose of PCC is
highly relevant.
Study objective
To assess the normalization (reversal) of coagulation assays upon
administration of two dosages of Prothrombin Complex Concentratre (PCC,
Cofact®) in healthy volunteers treated with either rivaroxaban or apixaban
Study design
The study will be performed as an investigator initiated, single-centre, double
blind, placebo-controlled, randomized, cross-over trial. Subjects will follow
three sessions, and they will cross over for the reversal method.
Two groups of 6 healthy male subjects will be enrolled (group 1 and group 2)
after a screening phase in which they will be evaluated for eligibility
criteria. Subjects in group 1 will take apixaban (h. 8-20 circa) 10 mg twice
daily from day -3 to day 0. Subjects in group 2 will take rivaroxaban (h. 8-20
circa) 15 mg twice daily from day -2 to day 0. The final dose of either
anticoagulant will be taken on the morning of day 0 without the consumption of
food.
After 3 hours from the final dose of the anticoagulant (on day 0) volunteers
will receive a single bolus of 25 IU/kg PCC (Cofact®), or a single bolus of
37.5 IU/kg PCC (Cofact®), or placebo (saline). The infusion will be
administered intravenously in 30 minutes.
Volunteers will be randomized at the first visit (Day -3 or -2 for apixaban and
rivaroxaban respectively) for the reversal method (PCC Cofact® 25 IU/kg; PCC
Cofact® 37.5 IU/kg; or saline). Volunteers will be randomized in a fixed ratio
of 1:1:1 to placebo (saline), PCC (Cofact®) 25 IU/kg or PCC (Cofact®) 37.5
IU/kg. After a wash out period of 18 days, all subjects will return to the
same anticoagulant (apixaban/rivaroxaban), but they will cross-over for the
method of reversal and receive a method of reversal that they did not get the
previous round (either PCC (Cofact®) 25 IU/ kg or 37.5 IU/kg, or a similar
volume of saline). Following another wash-out period of 18 days, all subjects
will receive the same anticoagulant (apixaban/rivaroxaban), but will again
cross-over for the method of reversal and receive the method of reversal they
have not been given in the previous rounds (PCC (Cofact®) 25 IU/ kg or 37.5
IU/kg, or a similar volume of saline). Each session a different reversal method
will be given, so that each volunteer will receive all reversal methods in the
three different sessions.
The order of treatment will be kept double blind throughout the study. Subjects
will be unblinded to the anticoagulant but blinded to placebo (saline) or PCC
(Cofact®).
Blood samples will be collected at the following times: T = screening visit, T
= day -3 or -2 (before starting apixaban and rivaroxaban, respectively), T =
day 0 (before the administration of PCC Cofact®/ saline), and after the
administration of PCC Cofact®/ saline at T = 15 min, 30 min, 60 min, 120 min,
240 min, 360 min and at 24 hours (Day 1).
Intervention
Intravenous administration of PCC (Cofact) 25 IU/kg or PCC (Cofact) 37.5 IU/kg
or placebo (saline)
Study burden and risks
Subjects will be screened before the randomization and instructed. Subjects
treated with apixaban will start with the anticoagulant at day -3; subjects
treated with rivaroxaban will start at day -2. They will take the last dosage
of anticoagulant without the consumption of food on the morning that they are
admitted to the study centre on day 0. Blood samples are collected at the
following times: T = screening period, T = day of randomisation, day -2 or -3
(for apixaban and rivaroxaban respectively, before starting the oral
anticoagulants), T = day 0: before the administration of PCC (Cofact®) 25 IU/
kg or 37.5 IU/kg, or a similar volume of saline, and after the administration
of PCC Cofact®/saline at T = 15 min, 30 min, 60 min, 120 min, 240 min, 360 min
and at 24 hours. PCC (Cofact®) and saline are administered 3 hours after the
ingestion of the anticoagulant.
After a period of 18 days of wash out, the same procedure will be repeated
using the same anticoagulant, but a method of reversal that was not given the
previous round (PCC (Cofact®) 25 IU/ kg or 37.5 IU/kg , or a similar volume of
saline). After a period of 18 days of wash out, the same procedure will be
repeated using the same anticoagulant, but with the method of reversal that has
not been given in the previous rounds (PCC (Cofact®) 25 IU/ kg or 37.5 IU/kg,
or a similar volume of saline). Each session a different reversal method will
be given, so that each volunteer will receive all reversal methods in the three
different sessions.
An intravenous catheter will be placed to administer PCC (Cofact®) or saline,
and a second intravenous catheter will be inserted for blood withdrawal on the
day of PCC Cofact®/saline administration (day 0). Blood samples at other
timepoints will be obtained by venapunctures.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
* Healthy male subjects as documented by laboratory screen tests (including HIV/HBV/HCV screening), personal medical history and normal physical examination.
* Age *18 years, < 50 years.
* No personal history of thrombotic disease/bleeding disorders.
* No significant family history of thrombotic disease/bleeding disorders, such as recurrent thrombotic/bleeding events or thrombotic/bleeding events in the absence of any risk factors.
* Able to provide written informed consent.
Exclusion criteria
Exclusion criteria are:
* History of allergic reaction to blood products.
* Current participation in any other investigational drug study or within the past 30 days.
* Presence of any condition that, as judged by the investigator, would place the subject at increased risk of harm if he participated in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-003529-35-NL |
| CCMO | NL41621.018.12 |