A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Andexanet Alfa Administered to Healthy Japanese and Caucasian Subjects
Overview
- Phase
- Phase 2
- Intervention
- Placebo
- Conditions
- Bleeding
- Sponsor
- Portola Pharmaceuticals
- Enrollment
- 108
- Locations
- 1
- Primary Endpoint
- Percent Change in Anti-Fxa Activity From Baseline to the End of Infusion (EOI) Nadir.
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief 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."
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
- •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.
- •Must be between the ages of 18 and 75 years, inclusive, at the time of signing of the Inform Consent Form (ICF).
- •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.
- •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;
Exclusion Criteria
- •Previous use of andexanet or previous participation in the current study (even if the subject received placebo).
- •History of abnormal bleeding, signs or symptoms of active bleeding, or risk factors for bleeding.
- •Has a stool specimen that was positive for occult blood within 6 months of study Screening or during the Screening Period.
- •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.
- •Absolute or relative contraindication to anticoagulation or treatment with apixaban, rivaroxaban, and/or edoxaban.
- •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.
- •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.
- •Family history of or risk factors for a hypercoagulable or thrombotic condition, including one of the following:
- •Factor V Leiden carrier or homozygote.
Arms & Interventions
Cohort 3
Edoxaban + high dose andexanet
Intervention: Placebo
Cohort 7
Edoxaban + low dose andexanet
Intervention: Andexanet alfa
Cohort 7
Edoxaban + low dose andexanet
Intervention: Edoxaban
Cohort 1
Apixaban + low dose andexanet
Intervention: Andexanet alfa
Cohort 1
Apixaban + low dose andexanet
Intervention: Apixaban
Cohort 1
Apixaban + low dose andexanet
Intervention: Placebo
Cohort 2
Rivaroxaban + high dose andexanet
Intervention: Andexanet alfa
Cohort 2
Rivaroxaban + high dose andexanet
Intervention: Rivaroxaban
Cohort 2
Rivaroxaban + high dose andexanet
Intervention: Placebo
Cohort 3
Edoxaban + high dose andexanet
Intervention: Andexanet alfa
Cohort 3
Edoxaban + high dose andexanet
Intervention: Edoxaban
Cohort 4
Edoxaban + high dose andexanet
Intervention: Andexanet alfa
Cohort 4
Edoxaban + high dose andexanet
Intervention: Edoxaban
Cohort 4
Edoxaban + high dose andexanet
Intervention: Placebo
Cohort 5
Apixaban + low dose andexanet
Intervention: Andexanet alfa
Cohort 5
Apixaban + low dose andexanet
Intervention: Apixaban
Cohort 5
Apixaban + low dose andexanet
Intervention: Placebo
Cohort 6
Apixaban + high dose andexanet
Intervention: Andexanet alfa
Cohort 6
Apixaban + high dose andexanet
Intervention: Apixaban
Cohort 6
Apixaban + high dose andexanet
Intervention: Placebo
Cohort 7
Edoxaban + low dose andexanet
Intervention: Placebo
Cohort 8
Apixaban + low dose andexanet
Intervention: Andexanet alfa
Cohort 8
Apixaban + low dose andexanet
Intervention: Apixaban
Cohort 8
Apixaban + low dose andexanet
Intervention: Placebo
Cohort 9
Rivaroxaban + low dose andexanet
Intervention: Andexanet alfa
Cohort 9
Rivaroxaban + low dose andexanet
Intervention: Rivaroxaban
Cohort 9
Rivaroxaban + low dose andexanet
Intervention: Placebo
Cohort 10
Edoxaban + low dose andexanet
Intervention: Andexanet alfa
Cohort 10
Edoxaban + low dose andexanet
Intervention: Edoxaban
Cohort 10
Edoxaban + low dose andexanet
Intervention: Placebo
Outcomes
Primary Outcomes
Percent Change in Anti-Fxa Activity From Baseline to the End of Infusion (EOI) Nadir.
Time Frame: Baseline to the end of infusion (EOI) nadir, approximately 2.5 hours
The primary efficacy endpoint is the percent change in the anti-FXa activity from baseline to the end of infusion (EOI) nadir.
Secondary Outcomes
- Percent Change in Free Fxa Inhibitor Concentration From Baseline to the End of Infusion (EOI) Nadir.(Baseline to the end of infusion (EOI) nadir, approximately 2.5 hours)
- Change in Thrombin Generation From Baseline to the End of Bolus (EOB) Nadir.(Baseline to the end of bolus (EOB) nadir, approximately 2.5 hours)
- Percent Change in Anti-Fxa Activity From Baseline to the End of Bolus (EOB) Nadir.(Baseline to the end of bolus (EOB) nadir, approximately 2.5 hours)
- Change in Thrombin Generation From Baseline to the End of Infusion (EOI) Nadir.(Baseline to the end of infusion (EOI) nadir, approximately 2.5 hours)
- Percent Change in Free Fxa Inhibitor Concentration From Baseline to the End of Bolus (EOB) Nadir.(Baseline to the end of bolus (EOB) nadir, approximately 2.5 hours)