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

• 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: Portola Pharmaceuticals
• Information provided by (Responsible Party): Portola Pharmaceuticals

Study Description

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 Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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

Contacts and Locations

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015 Dec 17;373(25):2413-24. doi: 10.1056/NEJMoa1510991. Epub 2015 Nov 11.

• Responsible Party: Portola Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02220725
• Other Study ID Numbers: 14-504
• First Posted: August 20, 2014
• 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:

Hemorrhage; Pathologic Processes