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The purpose of this study is to evaluate the ability of PRT064445 to reverse the effects of several blood thinner drugs on laboratory tests. The study also is evaluating the blood levels of PRT064445 given at different doses.
A randomized, double-blind, vehicle-controlled study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenously administered PRT064445 after dosing to steady state with one of four direct/indirect factor Xa (fXa) inhibitors in healthy volunteers.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Module 4 (600 mg bolus) | Experimental | 600 mg PRT064445 given as a single IV bolus |
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| Module 4 (800 mg bolus + 480 mg infusion) 8mg/min | Experimental | 1280 mg PRT064445: 800 mg IV at ~30 mg/min, followed by a continuous infusion of 480 mg (4 mg /min over 60 minutes) |
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| Module 4 (800 mg bolus) | Experimental | 800 mg PRT064445 as a single IV bolus |
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| Module 4 Placebo | Placebo Comparator | Placebo administered intravenously (IV) as a bolus or a bolus followed by continuous infusion. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PRT064445/Edoxaban | Combination Product |
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| Measure | Description | Time Frame |
|---|---|---|
| Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration | Anti-fXa activity was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Anti-fXa activity was measured using a commercial kit (Coamatic Heparin-82 33 9363, DiaPharma) | Baseline to 2 minutes following the end of andexanet/placebo administration |
| Measure | Description | Time Frame |
|---|---|---|
| Efficacy: Percent Change From Baseline in Thrombin Generation at 2 Mins Following Andexanet/Placebo Administration | Thrombin generation was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Thrombin generation was measured using a TF-initiated thrombin generation assay. | Baseline to 2 minutes following the end of andexanet/placebo administration |
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Inclusion Criteria:
Exclusion Criteria:
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32092140 | Derived | Lu G, Conley PB, Leeds JM, Karbarz MJ, Levy GG, Mathur VS, Castillo J, Crowther M, Curnutte JT. A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers. Blood Adv. 2020 Feb 25;4(4):728-739. doi: 10.1182/bloodadvances.2019000885. |
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28 subjects were enrolled in Module 4. Edoxaban was administered 60 mg orally once daily for 6 days in an open label fashion. Andexanet/placebo was administered intravenously (IV) on Day 6 such that they ended at 3 hours (Cohorts 1 and 2) or 5 hours (Cohort 3) after the last dose of edoxaban.
Subject recruitment occurred at investigative site in the US between March 2014 through August 2015
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| ID | Title | Description |
|---|---|---|
| FG000 | Module 4 Placebo | Placebo administered intravenously (IV) as a bolus or a bolus followed by continuous infusion. |
| FG001 | Module 4 (600mg) | 600 mg andexanet IV bolus administered over ~20 minutes (~30 mg/min) |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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This study has four modules with a total of 21 cohorts, each module was reported and submitted separately.
Module 1, NCT01758432 (54 subjects with 7 cohorts including placebo); Module 2, NCT03578146 (48 subjects with 6 cohorts including placebo); Module 3, NCT03551730 (27 subjects with 4 cohorts including placebo); Module 4, NCT03551743 (28 subjects with 4 cohorts including placebo)
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| Placebo/Edoxaban | Combination Product |
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| Placebo | Drug |
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| Efficacy: Percent Change From Baseline in Unbound Edoxaban Plasma Concentration at 2 Mins Following Andexanet/Placebo Administration | Unbound edoxaban concentrations was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Unbound plasma concentrations for edoxaban was determined by a rapid equilibrium dialysis method followed by Liquid chromatography- Mass Spectrometry. | Baseline to 2 minutes following the end of andexanet/placebo administration |
| Andexanet Maximum Observed Plasma Concentration (Cmax) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. Maximum observed plasma concentration was taken directly from the raw data. | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
| Andexanet Area Under the Drug Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf ) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. AUC0-inf was calculated using a non-compartmental approach | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
| Andexanet Time of Maximum Observed Plasma Concentration (Tmax) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. Tmax was taken directly from the raw data. | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
| Andexanet Apparent Terminal Elimination Half-life (t1/2) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. t1/2 was determined by linear regression of the log concentration on the terminal portion of the plasma concentration-time curve. | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
| Andexanet Total Systemic Clearance (CL) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. CL was calculated using a non-compartmental approach. | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
| Andexanet Total Volume of Distribution (Vss) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. Vss was calculated using a non-compartmental approach. | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
| FG002 | Module 4 (800 mg Bolus + 480 mg Infusion) | 800 mg andexanet IV bolus over ~27 minutes (~30 mg/min) followed immediately by a continuous infusion of 480 mg (8 mg/min over 60 min) [total 1280 mg] |
| FG003 | Module 4 (800 mg) | 800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min) |
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| NOT COMPLETED |
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28 subjects were enrolled in Module 4 and 26 subjects completed the study follow-up
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| ID | Title | Description |
|---|---|---|
| BG000 | Module 4 Placebo | Placebo administered intravenously (IV) as a bolus or a bolus followed by continuous infusion. |
| BG001 | Module 4 (600mg) | 600 mg andexanet IV bolus administered over ~20 minutes (~30 mg/min) |
| BG002 | Module 4 (800 mg Bolus + 480 mg Infusion) | 800 mg andexanet IV bolus over ~27 minutes (~30 mg/min) followed immediately by a continuous infusion of 480 mg (8 mg/min over 60 min) [total 1280 mg] |
| BG003 | Module 4 (800 mg) | 800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min) |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration | Anti-fXa activity was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Anti-fXa activity was measured using a commercial kit (Coamatic Heparin-82 33 9363, DiaPharma) | 26 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis | Posted | Mean | Standard Deviation | Percent change in anti-fXa activity | Baseline to 2 minutes following the end of andexanet/placebo administration |
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| Secondary | Efficacy: Percent Change From Baseline in Thrombin Generation at 2 Mins Following Andexanet/Placebo Administration | Thrombin generation was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Thrombin generation was measured using a TF-initiated thrombin generation assay. | 26 subjects who received andexanet or placebo were included in the PD analysis | Posted | Mean | Standard Deviation | Percent change in thrombin generation | Baseline to 2 minutes following the end of andexanet/placebo administration |
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| Secondary | Efficacy: Percent Change From Baseline in Unbound Edoxaban Plasma Concentration at 2 Mins Following Andexanet/Placebo Administration | Unbound edoxaban concentrations was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Unbound plasma concentrations for edoxaban was determined by a rapid equilibrium dialysis method followed by Liquid chromatography- Mass Spectrometry. | 26 subjects who received edoxaban were included in the edoxaban pharmacokinetics (PK) analysis | Posted | Mean | Standard Deviation | Percent change in unbound edoxaban conce | Baseline to 2 minutes following the end of andexanet/placebo administration |
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| Secondary | Andexanet Maximum Observed Plasma Concentration (Cmax) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. Maximum observed plasma concentration was taken directly from the raw data. | 18 subjects who received andexanet are included in the PK analysis for andexanet | Posted | Mean | Standard Deviation | ng/mL | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
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| Secondary | Andexanet Area Under the Drug Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf ) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. AUC0-inf was calculated using a non-compartmental approach | 18 subjects who received andexanet are included in the PK analysis for andexanet | Posted | Mean | Standard Deviation | ng*hr/mL | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
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| Secondary | Andexanet Time of Maximum Observed Plasma Concentration (Tmax) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. Tmax was taken directly from the raw data. | 18 subjects who received andexanet are included in the PK analysis for andexanet | Posted | Median | Full Range | hr | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
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| Secondary | Andexanet Apparent Terminal Elimination Half-life (t1/2) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. t1/2 was determined by linear regression of the log concentration on the terminal portion of the plasma concentration-time curve. | 18 subjects who received andexanet are included in the PK analysis for andexanet | Posted | Mean | Standard Deviation | hr | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
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| Secondary | Andexanet Total Systemic Clearance (CL) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. CL was calculated using a non-compartmental approach. | 18 subjects who received andexanet are included in the PK analysis for andexanet | Posted | Mean | Standard Deviation | L/hr | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
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| Secondary | Andexanet Total Volume of Distribution (Vss) | Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. Vss was calculated using a non-compartmental approach. | Posted | Mean | Standard Deviation | L | Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. |
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~7 weeks
Only subjects who received at least one dose of study drug were included in the safety analysis.
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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 | Module 4 Placebo | Placebo administered IV as a bolus or a bolus followed by continuous infusion. | 0 | 8 | 3 | 8 | ||
| EG001 | Module 4 (600mg) | 600 mg andexanet IV bolus administered over ~20 minutes (~30 mg/min) | 0 | 6 | 5 | 6 | ||
| EG002 | Module 4 (800 mg Bolus + 480 mg Infusion) | 800 mg andexanet IV bolus over ~27 minutes (~30 mg/min) followed immediately by a continuous infusion of 480 mg (8 mg/min over 60 min) [total 1280 mg] | 0 | 6 | 3 | 6 | ||
| EG003 | Module 4 (800 mg) | 800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min) | 0 | 6 | 3 | 6 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | MedDRA 15.0 | Systematic Assessment |
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| Gingival pain | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Gingival swelling | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Hematochezia | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Chest discomfort | General disorders | MedDRA 15.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 15.0 | Systematic Assessment |
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| Thirst | General disorders | MedDRA 15.0 | Systematic Assessment |
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| Vessel puncture site hematoma | General disorders | MedDRA 15.0 | Systematic Assessment |
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| Vessel puncture site pain | General disorders | MedDRA 15.0 | Systematic Assessment |
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| Respiratory tract infection | Infections and infestations | MedDRA 15.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 15.0 | Systematic Assessment |
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| Infusion related reaction | Injury, poisoning and procedural complications | MedDRA 15.0 | Systematic Assessment |
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| White blood cells urine positive | Investigations | MedDRA 15.0 | Systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA 15.0 | Systematic Assessment |
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| Joint swelling | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 15.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 15.0 | Systematic Assessment |
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| Presyncope | Nervous system disorders | MedDRA 15.0 | Systematic Assessment |
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| Ecchymosis | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Rash papular | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Pallor | Vascular disorders | MedDRA 15.0 | Systematic Assessment |
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Conducted in healthy volunteers at Clinical Research Organization.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Head of Clinical Development | Portola Pharmaceuticals, Inc. | 650-246-7000 |
| ID | Term |
|---|---|
| C580915 | PRT064445 |
| C552171 | edoxaban |
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| Male |
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| Least Squares Means (Difference) |
| -92.38 |
| 2-Sided |
| Superiority |
| ANCOVA | 0.0002 | Least Squares Means (Difference) | -46.26 | 2-Sided | Superiority |
800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min) |
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| OG003 |
| Module 4 (800 mg) |
800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min) |
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800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min) |
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800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min) |
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800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min)
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800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min) |
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800 mg andexanet IV bolus administered over ~27 minutes (~30 mg/min)
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