A Healthy Volunteer Pharmacokinetics (PK)/Pharmacodynamics (PD), Safety and Tolerability Study of Andexanet in Healthy Japanese and Caucasian Subjects
Condition: Bleeding
Intervention: Andexanet alfa; Apixaban; Rivaroxaban; Edoxaban; Placebo
Intervention description: fXa inhibitor antidote; factor Xa inhibitor; factor Xa inhibitor; factor Xa inhibitor; Placebo
Intervention MeSH terms: Rivaroxaban; Apixaban; Edoxaban
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: Double Blind (Participant, Care Provider, Investigator, Sponsor)
Enrollment: 108.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      "This is a single-center, randomized, double-blind, and placebo-controlled trial designed to:
      1) demonstrate the degree to which administered andexanet doses can reverse Factor Ten A
      (FXa)-inhibitor induced anticoagulation; and 2) evaluate the safety and PK/PD of andexanet in
      healthy Japanese subjects taking direct FXa inhibitors at therapeutic doses."
    

Eligibility criteria:

        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.

          2. For all cohorts except Cohort 5, subjects must be of Japanese ethnicity, defined as
             having four ethnic Japanese grandparents. Subjects may not have lived outside of Japan
             for more than 10 years. For Cohort 5, subjects must be of Caucasian race.

          3. Must be between the ages of 18 and 75 years, inclusive, at the time of signing of the
             Inform Consent Form (ICF).

          4. Agrees to have any dietary or nutritional supplements reviewed by the Investigator and
             potentially held during the study if advised by the Investigator. Standard
             multivitamin and mineral supplementation will be permitted.

          5. 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, symptothermal, postovulation 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, symptothermal,
                  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
                  milli-international units (mIU)/mL) at Screening;

               -  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.

          6. Systolic blood pressure < 160 mmHg and diastolic blood pressure < 90 mmHg at Screening
             and Day -1.

          7. The following laboratory values must be within the normal laboratory reference range
             within 45 days of Day -1: Prothrombin Time (PT), Activated Partial Thromboplastin Time
             (aPTT), and Activated Clotting Time (ACT); hemoglobin, hematocrit, and platelet count.

          8. The following laboratory values must be equal to or below 2 times the upper limit of
             normal (ULN) range within 45 days of Day -1: Aspartate aminotransferase (AST)/alanine
             aminotransferase (ALT) and total bilirubin.

          9. The Screening serum creatinine must be below 1.5 mg/dL within 45 days of Day -1.

         10. Body mass index of less than 30 kg/m2, inclusive, and body weight between 50 kg and 80
             kg, inclusive. In addition, subjects must be greater than 60 kg for Cohorts 3, 4, and
             10.

         11. 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.

         12. 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 (even if the
             subject received placebo).

          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
             Venous Thromboembolism(VTE), Deep Venous Thrombosis (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 with a planned flight time for
             any single flight segment ≥ 6 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, and/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 Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or HIV-1/2 infection.

         11. Use of any drugs that are strong dual inhibitors or inducers of CYP3A4 (apixaban and
             rivaroxaban cohorts only) and P-gp (all cohorts) 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 45 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 (anticoagulant or andexanet)
             metabolism.

         15. Allergy to any of the vehicle ingredients: Tris, arginine, sucrose, hydrochloric acid,
             mannitol, and polysorbate 80.

         16. Allergy to soy or soy products.

         17. Current breastfeeding or a positive pregnancy test at Screening or Day -1.

         18. 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.

         19. The subject is not judged by the study staff to have adequate bilateral venous access.

         20. Unwillingness to adhere to the activity requirements of the study."