| Eligibility |
Inclusion Criteria:
1. Must be in reasonably good health as determined by the Investigator based on medical
history, full physical examination (including blood pressure and pulse rate
measurement), 12-lead ECG, and clinical laboratory tests. Subjects with
well-controlled, chronic, stable conditions (e.g., controlled hypertension,
non-insulin dependent diabetes, osteoarthritis, hypothyroidism) may be enrolled based
on the clinical judgment of the Investigator and if approved by the Medical Monitor.
2. Must be between the ages of 18 and 75 years, inclusive, at the time of signing of the
informed consent form (ICF).
3. Agrees to have any dietary or nutritional supplements reviewed by the Investigator and
potentially be withheld during the study if advised by the Investigator. Standard
multivitamin and mineral supplementation will be permitted.
4. Agrees to comply with the contraception and reproduction restrictions of the study:
- Men whose sexual partner is of childbearing potential and/or who are not
monogamous must be using two acceptable methods of contraception, at least one of
which must be a barrier method (e.g., spermicidal gel plus condom), for the
entire duration of the study and for at least 1 month following study-drug
administration; and men must refrain from attempting to father a child or
donating sperm in the 1 month following the study-drug administration. Periodic
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods)
and withdrawal are not acceptable methods of contraception;
- Men who report surgical sterilization (e.g., bilateral vasectomy) must have had
the procedure at least 6 months before study drug administration.
- Surgical sterilization procedures should be supported with clinical documentation
and noted in the Relevant Medical History/Current Medical Conditions section of
the case report forms (CRFs).
- Women of childbearing potential must be using two medically acceptable methods of
contraception, at least one of which must be a barrier method (e.g., non-hormone
containing intra-uterine device plus condom, spermicidal gel plus condom,
diaphragm plus condom), from the time of Screening and for the duration of the
study, through at least 1 month following study drug administration. NOTE: Oral
and topical hormonal contraceptive use, as well as the use of hormone-containing
intra-uterine devices, is not permitted due to their increased risk of
thromboembolism. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception; OR
- Postmenopausal women must have had no regular menstrual bleeding for at least 1
year before initial dosing and either be over the age of 60 years or have an
elevated plasma follicle-stimulating hormone (FSH) level (i.e., > 40 mIU/mL) at
Screening; OR
- Women who report surgical sterilization (i.e., hysterectomy, tubal ligation,
and/or bilateral oophorectomy) must have had the procedure at least 6 months
before study drug administration. Surgical sterilization procedures should be
supported with clinical documentation and noted in the Relevant Medical
History/Current Medical Conditions section of the CRF; AND
- All female subjects must have a documented negative pregnancy test result at
Screening and on Study Day 1.
5. Systolic blood pressure < 160 mmHg and diastolic blood pressure < 90 mmHg at Screening
and Day 1.
6. The following laboratory values must be within the normal laboratory reference range
within 28 days of Day 1: prothrombin time (PT), activated partial thromboplastin time
(aPTT), and activated clotting time (ACT); hemoglobin, hematocrit, and platelet count.
7. The following laboratory values must be equal to or below 2 times the upper limit of
normal (ULN) range within 28 days of Day 1: Aspartate aminotransferase (AST)/alanine
aminotransferase (ALT) and total bilirubin.
8. The Screening serum creatinine must be below 1.5 mg/dL within 28 days of Day 1.
9. Body mass index between 19-30 kg/m2, inclusive, and body weight at least 50 kg.
10. Agrees to abstain from alcohol consumption for the duration of the domicile period,
and from the use of drugs of abuse for the duration of the study.
11. Able to read and give written informed consent and has signed a consent form approved
by the Investigator's Institutional Review Board (IRB) or Independent Ethics Committee
(IEC).
Exclusion Criteria:
1. Previous use of andexanet or previous participation in the current study.
2. History of abnormal bleeding, signs or symptoms of active bleeding, or risk factors
for bleeding.
3. Has a stool specimen that was positive for occult blood within 6 months of study
Screening or during the Screening Period.
4. Past or current medical history of thrombosis, any sign or symptom that suggests an
increased risk of a systemic thrombotic condition or thrombotic event, or recent
events that may increase risk of thrombosis.
a. For example, subjects with a known or suspected hypercoagulable state, history of
VTE, DVT, stroke, myocardial infarction [MI], cancer [other than non-melanoma skin
cancer], atrial fibrillation, heart failure, cardiomyopathy, phlebitis, lower
extremity edema, major surgery or trauma within 2 months of Study Day 1, airplane
travel = 2 hours during the 4 weeks prior to Study Day 1, or general immobility are
excluded.
5. Absolute or relative contraindication to anticoagulation or treatment with apixaban,
rivaroxaban, enoxaparin, or edoxaban.
6. Prior consumption of (by any route) one or more doses of aspirin (including baby
aspirin), salicylate or subsalicylate, other antiplatelet drugs (e.g., ticlopidine,
clopidogrel), non-steroidal anti-inflammatory drugs, fibrinolytic, or any
anticoagulant within 7 days prior to Day 1 or is anticipated to require such drugs
during the study.
7. Receipt of (by any route) hormonal contraception, post-menopausal hormone replacement
therapy (HRT) (including over-the-counter products), or testosterone during the 4
weeks prior to Study Day 1 or is anticipated to require such drugs during the study.
8. Family history of or risk factors for a hypercoagulable or thrombotic condition,
including one of the following:
1. Factor V Leiden carrier or homozygote.
2. Protein C, S, or ATIII activity below the normal range.
9. History of adult asthma or chronic obstructive pulmonary disease or current regular or
as-needed use of inhaled medications.
10. Active HBV, HCV, or HIV-1/2 infection
11. Use of any drugs that are strong dual inhibitors or inducers of CYP3A4 and P-gp within
7 days prior to Study Day 1 or anticipated need for such drugs during the study.
12. Participation in an investigational drug study within 28 days of Day 1 or Day 1 is
within 5 half-lives of the investigational compound.
13. Positive screen for drugs of abuse at Day 1 that is not explained by a prescription
medication that the subject is known to be taking.
14. A medical or surgical condition that may impair drug (fXa inhibitor or andexanet)
metabolism.
15. Allergy to any of the vehicle ingredients: tris, arginine, sucrose, hydrochloric acid,
mannitol, and polysorbate 80.
16. Current breastfeeding or a positive pregnancy test at Screening or Day 1.
17. Any condition that could interfere with, or for which the treatment might interfere
with, the conduct of the study or interpretation of the study results, or that would
in the opinion of the Investigator increase the risk of the subject's participation in
the study. This would include but is not limited to alcoholism, drug dependency or
abuse, psychiatric disease, epilepsy, or any unexplained blackouts.
18. The subject is not judged by the study staff to have adequate bilateral venous access.
19. Unwillingness to adhere to the activity requirements of the study.
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