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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03330457
Recruitment Status : Terminated (Ended prematurely)
First Posted : November 6, 2017
Results First Posted : August 19, 2020
Last Update Posted : August 19, 2020
Sponsor:
Information provided by (Responsible Party):
Portola Pharmaceuticals

Brief 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.

Condition or disease Intervention/treatment Phase
Bleeding Biological: Andexanet alfa (bolus) Drug: Betrixaban 80 mg PO QD Biological: Andexanet alfa (infusion IV) Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Double Blind
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 6, 2015
Actual Primary Completion Date : February 22, 2016
Actual Study Completion Date : February 22, 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Betrixaban

Arm Intervention/treatment
Experimental: Cohort 1 Bertrixaban/Andexanet
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)
fXa inhibitor antidote

Drug: Betrixaban 80 mg PO QD
fXa inhibitor

Experimental: Cohort 1 Bertrixaban/Placebo
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)
fXa inhibitor antidote

Drug: Betrixaban 80 mg PO QD
fXa inhibitor

Biological: Andexanet alfa (infusion IV)
fXa inhibitor antidote

Experimental: Cohort 2 Bertrixaban/Andexanet
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)
fXa inhibitor antidote

Drug: Betrixaban 80 mg PO QD
fXa inhibitor

Biological: Andexanet alfa (infusion IV)
fXa inhibitor antidote

Experimental: Cohort 2 Bertrixaban/Placebo
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)
fXa inhibitor antidote

Drug: Betrixaban 80 mg PO QD
fXa inhibitor

Biological: Andexanet alfa (infusion IV)
fXa inhibitor antidote




Primary Outcome Measures :
  1. Change in Anti-Fxa Activity From Baseline to End of Bolus [ Time Frame: Baseline to end of bolus, approximately 2.5 hours ]
    Change in Anti-Fxa Activity from baseline to end of bolus


Secondary Outcome Measures :
  1. Change in Thrombin Generation From Baseline to End of Bolus [ Time Frame: Baseline to end of bolus, approximately 2.5 hours ]
    Change in Thrombin Generation from baseline to end of bolus



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03330457


Locations
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United States, California
WCCT Global
Cypress, California, United States, 90630
Sponsors and Collaborators
Portola Pharmaceuticals
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Responsible Party: Portola Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03330457    
Other Study ID Numbers: 15-507
First Posted: November 6, 2017    Key Record Dates
Results First Posted: August 19, 2020
Last Update Posted: August 19, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hemorrhage
Pathologic Processes
Betrixaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants