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The purpose of this study is to evaluate the ability of Andexanet Alfa to reverse the anticoagulation effect of Rivaroxaban.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Andexanet 800mg bolus (Part I) | Experimental | Andexanet (antidote) - 800 mg bolus |
|
| Andexanet 800mg + 960mg (Part II) | Experimental | 800 mg bolus + 960 mg infusion (8 mg/min) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Andexanet | Biological |
|
|
| 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) |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Vandana Mathur, M.D. | Portola Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| West Coast Clinical Trials | Cypress | California | 90630 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26559317 | Derived | 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. |
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Rivaroxaban was administered orally at 20 mg once daily for 4 days followed by andexanet as a bolus (800 mg; Part I) or as a bolus followed by an infusion (800 mg bolus followed by 8 mg/min infusion for 120 minutes, 1760 mg total dose; Part II). Bolus was started 4 hours after the last rivaroxaban dose.
Subject recruitment occurred at investigative site in the US between May 2014 through June 2015
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo (Part I) | Vehicle Control |
| FG001 | Andexanet (Part I) | 800 mg bolus |
| FG002 | Placebo (Part II) | Vehicle Control |
| FG003 | Andexanet (Part II) | 800 mg bolus + 960 mg infusion (8 mg/min) |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
41 and 39 subjects were randomized in Part I and Part II of study, respectively
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo (Part I) | Vehicle Control |
| BG001 | Andexanet (Part I) | 800 mg bolus |
| BG002 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Modified Intent-to-Treat Population included all subjects receiving andexanet/placebo with anti-fXa activity baseline value at ≥1 timepoints: 2 or 5 minute after the end of the bolus (Part I; N = 41); 110 minute during continuous infusion, 2 minute before or 5 minute after the end of continuous infusion (Part II; N = 39). | Posted | Mean | Standard Deviation | Percent change in anti-fXa activity | 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) |
~8 to 12 weeks
The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo (Part I) | Vehicle Control |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infusion Related Reaction | Injury, poisoning and procedural complications | MedDRA 15.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Head of Clinical Development | Portola Pharmaceuticals, Inc. | 650-246-7000 |
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| ID | Term |
|---|---|
| D006470 | Hemorrhage |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C580915 | PRT064445 |
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| Placebo | Other |
|
| 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) |
| Withdrawal by Subject |
|
| Placebo (Part II) |
Vehicle Control |
| BG003 | Andexanet (Part II) | 800 mg bolus + 960 mg infusion (8 mg/min) |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
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|
|
| Secondary | 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 | mITT; 41 and 39 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis in Part I and II, respectively. | Posted | Mean | Standard Deviation | Percent change in anti-fXa activity | Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II) |
|
|
|
|
| Secondary | 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 | mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively. | Posted | Count of Participants | Participants | 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 | 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. | 54 subjects who received rivaroxaban were included in the rivaroxaban pharmacokinetics (PK) analysis | Posted | Mean | Standard Deviation | ng/mL | 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 | 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. | mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively. | Posted | Mean | Standard Deviation | nmol/min | 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) |
|
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| Secondary | 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 | mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively. | Posted | Count of Participants | Participants | 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) |
|
|
|
| 0 |
| 14 |
| 0 |
| 14 |
| EG001 | Andexanet (Part I) | 800 mg bolus | 0 | 27 | 5 | 27 |
| EG002 | Placebo (Part II) | Vehicle Control | 0 | 13 | 2 | 13 |
| EG003 | Andexanet (Part II) | 800 mg bolus + 960 mg infusion (8 mg/min) | 0 | 26 | 5 | 26 |
| Muscle Spasms | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
|
Conducted in healthy volunteers at Clinical Research Organization.
| <0.0001 |
| Hodges-Lehman estimate of shift |
| 1205.05 |
| 2-Sided |
| 95 |
| 1034.17 |
| 1400.79 |
| Superiority |