Reversibility of Apixaban Anticoagulation With the Four Factor Prothrombin Complex Concentrate Kcentra

Oral anticoagulants are effective in the treatment and prevention of venous and arterial
thrombotic events. For more than 50 years the only class of anticoagulant available had been
the vitamin K antagonist (VKA), warfarin, which requires frequent blood work for monitoring.
Apixaban is a new approved anticoagulant that is used to treat patients who have blood clots
or are at risk for developing blood clots. Unlike warfarin, the use of apixaban does not
require frequent blood work for monitoring and is associated with lower bleeding risk. All
anticoagulation therapies are associated with spontaneous or provoked bleeding risk and
reversal of their blood thinning effects might be needed. Reversal of anticoagulation may
also be needed in cases where emergent or urgent surgery is indicated. There is currently no
available reversal agent for apixaban. Prothrombin complex concentrate (PCC) contain
clotting factors and can replace factors inhibited by anticoagulants. In a recent study in
the Netherlands a four factor prothrombin complex concentrate, Cofact (not available in the
USA) was shown to be able to reverse the anticoagulation effects of another factor Xa
inhibitor, rivaroxaban. Kcentra is a four factor prothrombin complex concentrate that was
FDA approved in 2013 and is used as an antidote to treat people with bleeding associated
with taking warfarin. It contains clotting factors II, VII, IX and X derived from donated
blood and could be effective in reversing the anticoagulation effects of the factor Xa
inhibitor, apixaban. No effective reversal agent for apixaban exists. Physicians struggle
with bleeding in patients who are on apixaban. Indeed, this is not an uncommon problem for
patients who suffer brain bleeds or trauma. This study could potentially identify Kcentra as
reversal agent for patients taking apixaban. This study will test the hypothesis that
Kcentra has the potential to significantly reduce the anticoagulation effect of apixaban as
measured by thrombin generation assay at 30 minutes post infusion of Kcentra as compared to
placebo infusion in subjects dosed to steady state with apixaban.

Inclusion Criteria:

- In order to be eligible for participation in this trial, the subject must:

1. Be a healthy male or female between ages 18-55 (inclusive) at the screening
visit

2. Have a body mass index (BMI) >19 and <33 (inclusive)

3. If a female, subject

1. Can be of childbearing potential and must demonstrate a urine β-hCG level
consistent with the nongravid state at the pretrial (screening) visit and
agree to use (and/or have their partner use) an acceptable method of birth
control beginning at the pretrial visit throughout the trial (including
washout intervals between treatment periods) and until 2 weeks after the
last dose of trial drug in the last treatment period.

2. Can be of non-childbearing potential which is defined as: a female who is
postmenopausal without menses for at least 1 year and an Follicle
stimulating hormone value in the postmenopausal range upon pretrial
(screening) evaluation and/or a female who is status post hysterectomy,
oophorectomy or tubal ligation

3. Must be off hormonal oral or transdermal contraceptives for at least 4
weeks prior to initial dose of trial drug

4. Be a nonsmoker for at least approximately 6 months

5. Have serum creatinine level < 1.5 mg/dL

6. Have a prothrombin time (PT) and activated partial thromboplastin time (PTT)
level below the upper limit of normal

7. Have platelet count within normal limits

8. Be willing to refrain from the use of anticoagulants and antiplatelet
medications including aspirin and non-steroidal anti-inflammatory drugs (NSAIDs)
during the entire period of study participation

9. Be willing to provide written informed consent for the trial

10. Be willing to comply with trial restrictions

Exclusion Criteria:

1. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular,
hematological, hepatic, immunological, renal, respiratory, genitourinary or major
neurological (including stroke and chronic seizures) abnormalities or diseases

2. Has history of cancer (excluding treated cutaneous squamous or basal cell carcinoma
of >3 years previous)

3. Has history of venous or arterial thromboembolic disease

4. Has a history of clinically significant bleeding risks including prior serious head
trauma

5. Has had major surgery within 6 months prior to screening visit

6. Is unable to refrain from or anticipates the use of any medication, including
prescription and non-prescription drugs or herbal remedies for 2 weeks prior to trial
start date until the post-trial visit

7. Is unable to refrain from using any drugs or substance known to be inhibitors or
inducers of cytochrome P450 (CYP) enzymes including grapefruit products for 2 weeks
prior to dosing and throughout the study, until the post-trial visit

8. Has a history of illicit drug abuse within six months prior to screening visit

9. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits
[29.5 mL/1 ounce]) per day and cannot refrain from alcohol for the duration of the
trial

10. Has a history of significant multiple and/or severe allergies (e.g. food, drug), or
has had an anaphylactic reaction or significant intolerability to prescription or
non-prescription drugs or food

11. Has known anaphylactic or severe systemic reactions to any components of study drugs
(including heparin induced thrombocytopenia) or contraindication to the
administration of PCC or any other related blood products.

12. Has moderate or severe hepatic disease or other clinically relevant bleeding risk

13. Has positive history for hepatitis B surface antigen, hepatitis C or HIV

14. Has first degree relatives with history of bleeding disorder or hypercoagulable
disease

15. Use of any drugs or products which at the discretion of the investigator would
increase bleeding risk

16. Is considered inappropriate for participation by the investigator for any reason