A Healthy Volunteer Pharmacokinetics (PK)/Pharmacodynamics (PD), Safety and Tolerability Study of Andexanet in Healthy Japanese and Caucasian Subjects

NCT03310021 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 16-508
• Study Type: interventional
• Target: 108
• Locations: 1 country
• Sites: 1

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."

Conditions

Bleeding

Outcome Measures

Primary Outcomes (1)

• Percent Change in Anti-Fxa Activity From Baseline to the End of Infusion (EOI) Nadir.

  The primary efficacy endpoint is the percent change in the anti-FXa activity from baseline to the end of infusion (EOI) nadir.

  Baseline to the end of infusion (EOI) nadir, approximately 2.5 hours

Secondary Outcomes (5)

• 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

• 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

• 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

• 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

Study Arms (10)

Cohort 1

EXPERIMENTAL

Apixaban + low dose andexanet

Biological: Andexanet alfa; Drug: Apixaban; Drug: Placebo

Cohort 2

EXPERIMENTAL

Rivaroxaban + high dose andexanet

Biological: Andexanet alfa; Drug: Rivaroxaban; Drug: Placebo

Cohort 3

EXPERIMENTAL

Edoxaban + high dose andexanet

Biological: Andexanet alfa; Drug: Edoxaban; Drug: Placebo

Cohort 4

EXPERIMENTAL

Edoxaban + high dose andexanet

Biological: Andexanet alfa; Drug: Edoxaban; Drug: Placebo

Cohort 5

EXPERIMENTAL

Apixaban + low dose andexanet

Biological: Andexanet alfa; Drug: Apixaban; Drug: Placebo

Cohort 6

EXPERIMENTAL

Apixaban + high dose andexanet

Biological: Andexanet alfa; Drug: Apixaban; Drug: Placebo

Cohort 7

EXPERIMENTAL

Edoxaban + low dose andexanet

Biological: Andexanet alfa; Drug: Edoxaban; Drug: Placebo

Cohort 8

EXPERIMENTAL

Apixaban + low dose andexanet

Biological: Andexanet alfa; Drug: Apixaban; Drug: Placebo

Cohort 9

EXPERIMENTAL

Rivaroxaban + low dose andexanet

Biological: Andexanet alfa; Drug: Rivaroxaban; Drug: Placebo

Cohort 10

EXPERIMENTAL

Edoxaban + low dose andexanet

Biological: Andexanet alfa; Drug: Edoxaban; Drug: Placebo

Interventions

Andexanet alfa BIOLOGICAL

fXa inhibitor antidote

Also known as: 200 mg/vial for IV injection

Cohort 1; Cohort 10; Cohort 2; Cohort 3; Cohort 4; Cohort 5; Cohort 6; Cohort 7; Cohort 8; Cohort 9

Apixaban DRUG

factor Xa inhibitor

Also known as: Eliquis

Cohort 1; Cohort 5; Cohort 6; Cohort 8

Rivaroxaban DRUG

factor Xa inhibitor

Also known as: Xarelto

Cohort 2; Cohort 9

Edoxaban DRUG

factor Xa inhibitor

Also known as: Savaysa, Lixiana

Cohort 10; Cohort 3; Cohort 4; Cohort 7

Placebo DRUG

Placebo

Cohort 1; Cohort 10; Cohort 2; Cohort 3; Cohort 4; Cohort 5; Cohort 6; Cohort 7; Cohort 8; Cohort 9

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;
• 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.
• Systolic blood pressure \< 160 mmHg and diastolic blood pressure \< 90 mmHg at Screening and Day -1.
• 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.
• 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.
• The Screening serum creatinine must be below 1.5 mg/dL within 45 days of Day -1.

You may not qualify if:

• 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.
• Protein C, S, or ATIII activity below the normal range.
• History of adult asthma or chronic obstructive pulmonary disease or current regular or as needed use of inhaled medications.
• Active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or HIV-1/2 infection.
• 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.
• Participation in an investigational drug study within 45 days of Day -1 or Day -1 is within 5 half-lives of the investigational compound.

Sponsors & Collaborators

• Portola Pharmaceuticals: lead

Study Sites (1)

WCCT Global

Cypress, California, 90630, United States

Location

MeSH Terms

Conditions

Hemorrhage

Interventions

PRT064445; Injections, Intravenous; apixaban; Rivaroxaban; edoxaban

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Administration, Intravenous; Drug Administration Routes; Drug Therapy; Therapeutics; Injections; Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Head of Clinical Development
• Organization: Portola Pharmaceuticals

ClinicalTrials@Portola.com

6502767153

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Double Blind (Participant, Care Provider, Investigator, Sponsor)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 7, 2017
• First Posted: October 16, 2017
• Study Start: August 28, 2017
• Primary Completion: August 13, 2019
• Study Completion: August 13, 2019
• Last Updated: February 24, 2023
• Results First Posted: August 14, 2020

Record last verified: 2023-02

Locations

US (1)