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A Study in Older Subject to Evaluate the Safety and Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Rivaroxaban

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ClinicalTrials.gov Identifier: NCT02220725
Recruitment Status : Completed
First Posted : August 20, 2014
Results First Posted : September 25, 2018
Last Update Posted : October 1, 2018
Sponsor:
Information provided by (Responsible Party):
Portola Pharmaceuticals

Brief Summary:
The purpose of this study is to evaluate the ability of Andexanet Alfa to reverse the anticoagulation effect of Rivaroxaban.

Condition or disease Intervention/treatment Phase
Bleeding Biological: Andexanet Other: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3 Randomized, Double-blind, Placebo-controlled Study in Older Subjects to Assess Safety and the Reversal of Rivaroxaban Anticoagulation With Intravenously Administered Andexanet Alpha
Study Start Date : May 2014
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Rivaroxaban

Arm Intervention/treatment
Experimental: Andexanet 800mg bolus (Part I)
Andexanet (antidote) - 800 mg bolus
Biological: Andexanet
Other Names:
  • Andexanet alpha
  • PRT4445

Other: Placebo
Experimental: Andexanet 800mg + 960mg (Part II)
800 mg bolus + 960 mg infusion (8 mg/min)
Biological: Andexanet
Other Names:
  • Andexanet alpha
  • PRT4445

Other: Placebo



Primary Outcome Measures :
  1. Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II) [ Time Frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II) ]
    In Part 1, the primary endpoint was percent change from baseline in anti-fXa activity at the nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minutes or +5 minutes time point following the end of the bolus. In Part 2, the primary endpoint was the percent change from baseline in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion. The baseline for the primary endpoint in both parts was the anti-fXa activity just prior to administration of andexanet, 4 hours following the Day 4 dose of rivaroxaban. Anti-fXa activity was measured by a modified chromogenic assay.


Secondary Outcome Measures :
  1. Efficacy: Percent Change in Anti-fXa Activity (Part II) [ Time Frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II) ]
    The percent change from baseline in anti-fXa activity at the nadir, following the bolus, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part II). Baseline was the last assessment obtained prior to the first dose of andexanet or placebo

  2. Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir [ Time Frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II) ]
    Number of participants with ≥80% reduction in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) {Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo

  3. Efficacy: Change From Baseline in Free Rivaroxaban Concentration at the Nadir [ Time Frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II) ]
    Change from baseline in free rivaroxaban concentration (ng/mL) at the nadir, when nadir was defined as the smaller value for free rivaroxaban at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Free plasma concentrations of rivaroxaban was determined using a validated method that involved analysis of citrated human plasma with high-throughput equilibrium dialysis followed by liquid chromatography mass spectrometry.

  4. Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II] [ Time Frame: Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II) ]
    Change in ETP from baseline to its peak, where peak was defined as the largest value for ETP between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) {Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo. ETP was measured using a tissue factor-initiated thrombin generation assay.

  5. Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population) [ Time Frame: Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II) ]
    Number of participants with ETP above the lower limit of the normal range at its peak, between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) [Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. ETP was measured using a tissue factor-initiated thrombin generation assay



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Reasonably healthy men and women aged 50 to 75

Exclusion Criteria:

  • History of abnormal bleeding, active bleeding or risk factors for bleeding
  • History of thrombosis or risk factors for thrombosis
  • History of adult asthma or use of inhaled medications

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): NCT02220725


Locations
United States, California
West Coast Clinical Trials
Cypress, California, United States, 90630
Sponsors and Collaborators
Portola Pharmaceuticals
Investigators
Study Director: Vandana Mathur, M.D. Portola Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Portola Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02220725     History of Changes
Other Study ID Numbers: 14-504
First Posted: August 20, 2014    Key Record Dates
Results First Posted: September 25, 2018
Last Update Posted: October 1, 2018
Last Verified: September 2015

Keywords provided by Portola Pharmaceuticals:
Andexanet alpha
Anticoagulation
Antidote
Rivaroxaban
Anti-fXa inhibitor
PRT4445
Xarelto
Reversal agent

Additional relevant MeSH terms:
Rivaroxaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants