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

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

Official Title
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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

Conditions
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Bleeding

Intervention / Treatment
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* Biological: Andexanet
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Andexanet 800mg bolus (Part I)<br>Andexanet (antidote) - 800 mg bolus | Biological: Andexanet<br> <br> * Other names: PRT4445;Other: Placebo<br> <br> |
| Experimental: Andexanet 800mg + 960mg (Part II)<br>800 mg bolus + 960 mg infusion (8 mg/min) | Biological: Andexanet<br> <br> * Other names: PRT4445;Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Percent Change in Anti-fXa Activity (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 | Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II) | 
| Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir | 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 | 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) | 
| Efficacy: Change From Baseline in Free Rivaroxaban Concentration at the Nadir | 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. | 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) | 
| Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and 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. | 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) | 
| Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population) | 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 | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Andexanet alpha, Anticoagulation, Antidote, Rivaroxaban, Anti-fXa inhibitor, PRT4445, Xarelto, Reversal agent