Bleeding
Conditions
Keywords
Andexanet alpha, Anticoagulation, Antidote, Apixaban, Anti-fXa inhibitor, PRT4445, Eliquis, Reversal agent
Brief summary
The purpose of this stuy is to evaluate the ability of Andexanet Alfa to reverse the anticoagulation effect of Apixaban.
Interventions
BIOLOGICALAndexanet
OTHERPlacebo
Sponsors
Portola Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II) | 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 I, 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 II, 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, 3 hours following the Day 4 dose of apixaban. Anti-fXa activity was measured by a modified chromogenic assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Part II) | 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 |
| Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir | 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) | Occurrence of ≥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 |
| Efficacy -Change From Baseline in Free Apixaban Concentration at the Nadir | 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 apixaban concentration (ng/mL) at the nadir, when nadir was defined as the smaller value for free apixaban 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 apixaban was determined using a validated method that involved analysis of citrated human plasma with high-throughput equilibrium dialysis followed by liquid chromatography mass spectrometry. |
| Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II] | 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. |
| Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population) | 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 |
Countries
United States
Participant flow
Recruitment details
Subject recruitment occurred at investigative site in the US between March 2014 through December 2014
Pre-assignment details
Apixaban was administered orally at 5 mg twice daily for 3.5 days to steady-state and then administered andexanet as a bolus (400 mg; Part I) or as a bolus followed by an infusion (400 mg bolus followed by 4 mg/min infusion for 120 minutes, 880 mg total dose; Part II). Bolus was started 3 hours after the last apixaban dose.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Part I) Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 3 hours after the last apixaban dose (at the approximate steady-state Cmax for apixaban). | 9 |
| Andexanet (Part I) Andexanet was administered IV as a bolus of 400 mg at a target rate of approximately 30 mg/minute (Part 1). The bolus was started 3 hours after the last apixaban dose (at the approximate steady-state Cmax for apixaban) | 24 |
| Placebo (Part II) Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 3 hours after the last apixaban dose (at the approximate steady-state Cmax for apixaban). | 8 |
| Andexanet (Part II) Andexanet was administered IV as a bolus of 400 mg at a target rate of approximately 30 mg/minute, followed by a continuous infusion of 480 mg at 4 mg/minute for 120 minutes (Part II). The bolus was started 3 hours after the last apixaban dose (at the approximate steady-state Cmax for apixaban) | 24 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Did Not Receive Treatment | 0 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo (Part I) | Andexanet (Part I) | Placebo (Part II) | Andexanet (Part II) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.0 years STANDARD_DEVIATION 3.54 | 61.0 years STANDARD_DEVIATION 6.37 | 59.5 years STANDARD_DEVIATION 6.91 | 59.4 years STANDARD_DEVIATION 7.83 | 59.9 years STANDARD_DEVIATION 6.64 |
| Sex: Female, Male Female | 3 Participants | 11 Participants | 3 Participants | 7 Participants | 24 Participants |
| Sex: Female, Male Male | 6 Participants | 13 Participants | 5 Participants | 17 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 9 | 7 / 24 | 2 / 8 | 9 / 24 |
| serious Total, serious adverse events | 0 / 9 | 0 / 24 | 0 / 8 | 0 / 24 |
Outcome results
Primary
Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II)
In Part I, 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 II, 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, 3 hours following the Day 4 dose of apixaban. Anti-fXa activity was measured by a modified chromogenic assay.
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)
Population: 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 = 33); 110 minute during continuous infusion, 2 minute before or 5 minute after the end of continuous infusion (Part II; N = 31).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part I) | Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II) | -20.71 Percent change in anti-fXa activity | Standard Deviation 8.559 |
| Andexanet (Part I) | Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II) | -93.86 Percent change in anti-fXa activity | Standard Deviation 1.65 |
| Placebo (Part II) | Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II) | -32.70 Percent change in anti-fXa activity | Standard Deviation 5.578 |
| Andexanet (Part II) | Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II) | -92.34 Percent change in anti-fXa activity | Standard Deviation 2.809 |
p-value: <0.000195% CI: [-78.39, -66.28]2-sided test exact Wilcoxon rank-sum tes
p-value: <0.000195% CI: [-64.1, -55.17]2-sided test exact Wilcoxon rank-sum tes
Secondary
Efficacy -Change From Baseline in Free Apixaban Concentration at the Nadir
Change from baseline in free apixaban concentration (ng/mL) at the nadir, when nadir was defined as the smaller value for free apixaban 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 apixaban was determined using a validated method that involved analysis of citrated human plasma with high-throughput equilibrium dialysis followed by liquid chromatography mass spectrometry.
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)
Population: 54 subjects who received apixaban were included in the apixaban pharmacokinetics (PK) analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part I) | Efficacy -Change From Baseline in Free Apixaban Concentration at the Nadir | -1.854 ng/mL | Standard Deviation 1.6152 |
| Andexanet (Part I) | Efficacy -Change From Baseline in Free Apixaban Concentration at the Nadir | -9.338 ng/mL | Standard Deviation 3.2043 |
| Placebo (Part II) | Efficacy -Change From Baseline in Free Apixaban Concentration at the Nadir | -2.964 ng/mL | Standard Deviation 1.1567 |
| Andexanet (Part II) | Efficacy -Change From Baseline in Free Apixaban Concentration at the Nadir | -6.480 ng/mL | Standard Deviation 2.7814 |
p-value: <0.000195% CI: [-8.86, -5.42]2-sided test exact Wilcoxon rank-sum tes
p-value: 0.000295% CI: [-5.66, -1.25]2-sided test exact Wilcoxon rank-sum tes
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.
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)
Population: 33 and 31 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively; mITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part I) | Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II] | 88.182 nmol/min | Standard Deviation 125.7621 |
| Andexanet (Part I) | Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II] | 1323.180 nmol/min | Standard Deviation 335.4321 |
| Placebo (Part II) | Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II] | 189.409 nmol/min | Standard Deviation 184.7842 |
| Andexanet (Part II) | Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II] | 1193.060 nmol/min | Standard Deviation 263.3471 |
p-value: <0.000195% CI: [984.01, 1456.38]2-sided test exact Wilcoxon rank-sum tes
p-value: <0.000195% CI: [819.5, 1200.53]2-sided test exact Wilcoxon rank-sum tes
Secondary
Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir
Occurrence of ≥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
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)
Population: mITT; 33 and 31 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis in Part I and II, respectively.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (Part I) | Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir | 0 Participants |
| Andexanet (Part I) | Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir | 24 Participants |
| Placebo (Part II) | Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir | 0 Participants |
| Andexanet (Part II) | Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir | 23 Participants |
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
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)
Population: 33 and 31 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively; mITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (Part I) | Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population) | 1 Participants |
| Andexanet (Part I) | Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population) | 24 Participants |
| Placebo (Part II) | Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population) | 2 Participants |
| Andexanet (Part II) | Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population) | 23 Participants |
Secondary
Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (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
Time frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II)
Population: mITT; 33 and 31 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part I) | Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Part II) | -16.73 Percent change in anti-fXa activity | Standard Deviation 4.104 |
| Andexanet (Part I) | Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Part II) | -93.49 Percent change in anti-fXa activity | Standard Deviation 1.525 |
p-value: <0.000195% CI: [-79.98, -74.04]2-sided test exact Wilcoxon rank-sum tes