A Healthy Volunteer PK/PD, Safety and Tolerability Study of Andexanet After Betrixaban Dosing

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double-blind, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenously Administered Andexanet After Dosing to Steady-State With Oral Betrixaban in Healthy Subjects

Conditions
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Bleeding

Intervention / Treatment
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* Biological: Andexanet alfa (bolus)
* Drug: Betrixaban 80 mg PO QD
* Biological: Andexanet alfa (infusion IV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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: Coagulation labs - PT, aPTT, ACT; Hematology lab - Hematocrit/Hemoglobin; 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]). The subject has a body mass index 19 to 30 kg/m2, inclusive, and weighs at least 60 kg. The subject agrees to abstain from alcohol consumption for 48 hours prior to dosing and for the duration of the in-house study period. 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. 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: 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. The subject has an absolute/relative contraindication to anticoagulation. 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). 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. 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). 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. The subject has a history of blood donation of more than 500 mL within 3 months prior to dosing. 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. The subject has a positive screen for drugs of abuse at Day -1. The subject has a medical or surgical condition which may impair drug absorption. The subject is allergic to any of the vehicle ingredients: tris, arginine, hydrochloric acid, sucrose and polysorbate 80. Subject is breastfeeding. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 Bertrixaban/Andexanet<br>Andexanet 800 mg, administered as a slow IV bolus after having been dosed to steady-state with betrixaban 80 mg PO once daily (QD) for 7 days | Biological: Andexanet alfa (bolus)<br>* fXa inhibitor antidote<br>Drug: Betrixaban 80 mg PO QD<br>* fXa inhibitor<br>|
| Experimental: Cohort 1 Bertrixaban/Placebo<br>Placebo, administered as a slow IV bolus after having been dosed to steady-state with betrixaban 80 mg PO once daily (QD) for 7 days | Biological: Andexanet alfa (bolus)<br>* fXa inhibitor antidote<br>Drug: Betrixaban 80 mg PO QD<br>* fXa inhibitor<br>Biological: Andexanet alfa (infusion IV)<br>* fXa inhibitor antidote<br>|
| Experimental: Cohort 2 Bertrixaban/Andexanet<br>andexanet 800 mg administered as a slow IV bolus at a target rate of approximately 30 mg/min followed by a continuous infusion of up to 8 mg/min for 120 min (960 mg) starting 4 h after the last dose of betrixaban | Biological: Andexanet alfa (bolus)<br>* fXa inhibitor antidote<br>Drug: Betrixaban 80 mg PO QD<br>* fXa inhibitor<br>Biological: Andexanet alfa (infusion IV)<br>* fXa inhibitor antidote<br>|
| Experimental: Cohort 2 Bertrixaban/Placebo<br>Placebo administered as a slow IV bolus at a target rate of approximately 30 mg/min followed by a continuous infusion of up to 8 mg/min for 120 min (960 mg) starting 4 h after the last dose of betrixaban | Biological: Andexanet alfa (bolus)<br>* fXa inhibitor antidote<br>Drug: Betrixaban 80 mg PO QD<br>* fXa inhibitor<br>Biological: Andexanet alfa (infusion IV)<br>* fXa inhibitor antidote<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Anti-Fxa Activity From Baseline to End of Bolus | Change in Anti-Fxa Activity from baseline to end of bolus | Baseline to end of bolus, approximately 2.5 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Thrombin Generation From Baseline to End of Bolus | Change in Thrombin Generation from baseline to end of bolus | Baseline to end of bolus, approximately 2.5 hours |