A Healthy Volunteer PK/PD, Safety and Tolerability Study of Andexanet After Betrixaban Dosing
Condition: Bleeding
Intervention: Andexanet alfa (bolus); Betrixaban 80 mg PO QD; Andexanet alfa (infusion IV)
Intervention description: fXa inhibitor antidote; fXa inhibitor; fXa inhibitor antidote
Intervention MeSH terms: Betrixaban
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
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This is a randomized, double-blind, single center study in healthy volunteers dosed to steady
      state with betrixaban, designed to (1) Determine an andexanet dosing regimen required to
      reverse anticoagulant activity of betrixaban in healthy subjects, (2) Assess the safety and
      tolerability of andexanet vs. placebo (3) Determine the PK properties of andexanet and
      betrixaban (4) Determine the PD properties of betrixaban before, during, and after receiving
      andexanet or placebo and (5) Investigate the immunogenicity of andexanet in the presence of
      betrixaban.
    

Eligibility criteria:

        Inclusion Criteria:

          1. The subject is a healthy man or woman between the ages of 18 and 45 years old,
             inclusive, who agrees to comply with the contraception and reproduction restrictions
             of the study:

             Men 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 three months following last study drug administration, and
             refrain from attempting to father a child or donating sperm in the three (3) months
             following the last study drug administration. Periodic abstinence (e.g., calendar,
             ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable
             methods of contraception.

             OR Men who report surgical sterilization (e.g., bilateral vasectomy) must have had the
             procedure at least six (6) months prior to initial dosing. 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., intra-uterine
             device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.), from
             the time of screening and for the duration of the study, through at least three months
             following last study drug administration. NOTE: Oral contraceptive use 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 one
             (1) year prior to initial dosing. Menopause will be confirmed by an elevated plasma
             Follicle-stimulating hormone (FSH) level > 40mIU/mL at screening for women not in
             receipt of hormone replacement therapy (HRT); OR Women who report surgical
             sterilization (i.e., hysterectomy and/or bilateral oophorectomy) must have had the
             procedure at least six (6) months prior to initial dosing. 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 women must have a documented negative pregnancy test result at screening and
             at baseline.

          2. The subject has clinically unremarkable medical history, physical examination, ECG,
             and vital signs, as determined by the Investigator. Laboratory values must also be
             clinically unremarkable as determined by the Investigator, with the exception of the
             following labs which must be strictly within the normal range:

               1. Coagulation labs - PT, aPTT, ACT;

               2. Hematology lab - Hematocrit/Hemoglobin;

               3. Liver function labs - Aspartate aminotransferase (AST)/alanine aminotransferase
                  (ALT) (may be below lower limit of normal [LLN], but not above upper limit of
                  normal [ULN]).

          3. The subject has a body mass index 19 to 30 kg/m2, inclusive, and weighs at least 60
             kg.

          4. The subject agrees to abstain from alcohol consumption for 48 hours prior to dosing
             and for the duration of the in-house study period.

          5. The subject smokes <4 cigarettes/day (or equivalent: ≤0.5 can of chewing tobacco/week,
             1 cigar/day) and agrees to abstain from smoking while domiciled.

          6. The subject is able to read and give written informed consent and has signed a consent
             form approved by the Investigator's Institutional Review Board (IRB) or Ethics
             Committee (EC).

        Exclusion Criteria:

          1. The subject has a known history (including family history) of, symptoms of, or risk
             factors for bleeding (e.g., prior gastrointestinal bleeding, known berry aneurysm/
             vascular malformation) or a stool specimen within 6 months of randomization that is
             positive for occult blood.

          2. The subject has an absolute/relative contraindication to anticoagulation.

          3. The subject has a history (including family history) of or risk factors for a
             hypercoagulable or thrombotic condition (e.g., deep vein thrombosis/pulmonary
             embolism, Factor V Leiden carrier).

          4. The subject has a history of any clinically significant (as determined by the
             Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic,
             urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, or other major
             disease or condition which is known to make the subject susceptible to volume
             overload.

          5. The subject has taken any prescription drugs (including oral contraceptives/HRT) or
             illicit drugs in the 30 days prior to randomization. The subject is also excluded if
             he/she has taken over the counter drugs, including dietary supplements and herbal
             products, in the 2 weeks prior to randomization. Furthermore, the subject agrees not
             to take any such drugs throughout the study (if it becomes medically necessary to do
             so, the Investigator and Portola Medical Monitor must be informed immediately).

          6. The subject has a history of major surgery, severe trauma or bone fracture within 3
             months prior to dosing; or planned surgery within 1 month after dosing.

          7. The subject has a history of blood donation of more than 500 mL within 3 months prior
             to dosing.

          8. The subject has participated in an investigational drug study within 30 days or 5
             half-lives of the investigational compound, whichever is greater, of Day -1.

          9. The subject has a positive screen for drugs of abuse at Day -1.

         10. The subject has a medical or surgical condition which may impair drug absorption.

         11. The subject is allergic to any of the vehicle ingredients: tris, arginine,
             hydrochloric acid, sucrose and polysorbate 80.

         12. Subject is breastfeeding.

         13. The subject has any condition which could interfere with or for which the treatment
             might interfere with the conduct of the study, or which 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.