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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 3 (210 mg bolus) original | Experimental | 210 mg PRT064445 given as a single IV bolus |
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| Module 3 (420 mg bolus) original | Experimental | 420 mg PRT064445 given as a single IV bolus |
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| Module 3 (210 mg) lyophilized | Experimental | 210 mg PRT064445 (lyophilized formulation) given as a single IV bolus |
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| Module 3 Placebo | Placebo Comparator | Placebo administered intravenously (IV) as a bolus. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PRT064445/Enoxaparin | 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 Activity | 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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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Tempe | Arizona | 85283 | United States |
Enoxaparin was administered subcutaneously at 40 mg once daily for 6 days to steady-state in an open label fashion. Subjects were then randomized to receive study treatment intravenously on Day 6; such that they ended at 3 hours after the last dose of enoxaparin.
Subject recruitment occurred at investigative site in the US between August 2013 through November 2013
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Placebo administered intravenously (IV) as a bolus. |
| FG001 | Module 3 (210 mg Bolus) Original | 210 mg andexanet IV bolus over 7 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/Enoxaparin | Combination Product |
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| Placebo | Drug |
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| 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. Cmax 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 3 (420 mg Bolus) Original | 420 mg andexanet IV bolus over 14 minutes (~30 mg/min) |
| FG003 | Module 3 (210 mg) Lyophilized | 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) |
| COMPLETED |
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| NOT COMPLETED |
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27 subjects were enrolled in Module 3
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Placebo administered intravenously (IV) as a bolus. |
| BG001 | Module 3 (210 mg Bolus) Original | 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) |
| BG002 | Module 3 (420 mg Bolus) Original | 420 mg andexanet IV bolus over 14 minutes (~30 mg/min) |
| BG003 | Module 3 (210 mg) Lyophilized | 210 mg andexanet IV bolus over 7 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 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Efficacy:Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration Activity | 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 | 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. Cmax was taken directly from the raw data. | 18 subjects who received andexanet were included in the andexanet pharmacokinetics (PK) analysis | 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 were included in the andexanet PK analysis | 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 were included in the andexanet PK analysis | 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 were included in the andexanet PK analysis | 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 were included in the andexanet PK analysis | 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. | 18 subjects who received andexanet were included in the andexanet PK analysis | 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 | Placebo | Placebo was administered intravenously (IV) as a bolus | 0 | 8 | 5 | 8 | ||
| EG001 | Module 3 (210 mg Andexanet) Original Formulation | 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) | 0 | 6 | 4 | 6 | ||
| EG002 | Module 3 (420 mg Andexanet) Original Forumulation | 420 mg andexanet IV bolus over 14 minutes (~30 mg/min) 420 mg andexanet IV bolus over 14 minutes (~30 mg/min) | 0 | 6 | 4 | 6 | ||
| EG003 | Module 3 (210 mg Andexanet ) Lyophilized | 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) | 0 | 6 | 5 | 6 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal distension | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Abdominal tenderness | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Dry mouth | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Toothache | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Influenza like illness | General disorders | MedDRA 15.0 | Systematic Assessment |
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| Thirst | General disorders | 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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| Excoriation | Injury, poisoning and procedural complications | 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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| Ligament sprain | Injury, poisoning and procedural complications | MedDRA 15.0 | Systematic Assessment |
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| Post procedural hematoma | Injury, poisoning and procedural complications | MedDRA 15.0 | Systematic Assessment |
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| Procedural pain | Injury, poisoning and procedural complications | MedDRA 15.0 | Systematic Assessment |
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| Procedural site reaction | Injury, poisoning and procedural complications | MedDRA 15.0 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Muscle spasms | 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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| Paresthesia | Nervous system disorders | MedDRA 15.0 | Systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA 15.0 | Systematic Assessment |
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| Metrorrhagia | Reproductive system and breast disorders | MedDRA 15.0 | Systematic Assessment |
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| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Productive cough | Respiratory, thoracic and mediastinal 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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| Pruritus generalized | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Rash erythematous | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Post procedural haemorrhage | Injury, poisoning and procedural complications | 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 |
| D017984 | Enoxaparin |
| ID | Term |
|---|---|
| D006495 | Heparin, Low-Molecular-Weight |
| D006493 | Heparin |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |
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| Male |
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| Least Squares Means (Difference) |
| -0.20 |
| 2-Sided |
| Superiority |
| ANCOVA | <0.0001 | Least Squares Means (Difference) | -0.23 | 2-Sided | Superiority |
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