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Phase 2 Healthy Volunteer Study to Evaluate the Ability of PRT064445 to Reverse the Effects of Several Blood Thinner Drugs on Laboratory Tests (Module 3 of 4)

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ClinicalTrials.gov Identifier: NCT03551730
Recruitment Status : Completed
First Posted : June 11, 2018
Results First Posted : August 13, 2018
Last Update Posted : September 26, 2018
Sponsor:
Information provided by (Responsible Party):
Portola Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Healthy Volunteers
Interventions Combination Product: PRT064445/Enoxaparin
Combination Product: Placebo/Enoxaparin
Drug: Placebo
Enrollment 27
Recruitment Details Subject recruitment occurred at investigative site in the US between August 2013 through November 2013
Pre-assignment Details 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.
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized
Hide Arm/Group Description Placebo administered intravenously (IV) as a bolus. 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) 420 mg andexanet IV bolus over 14 minutes (~30 mg/min) 210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
Period Title: Overall Study
Started 9 6 6 6
Completed 8 6 6 6
Not Completed 1 0 0 0
Reason Not Completed
Adverse Event             1             0             0             0
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized Total
Hide Arm/Group Description Placebo administered intravenously (IV) as a bolus. 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) 420 mg andexanet IV bolus over 14 minutes (~30 mg/min) 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) Total of all reporting groups
Overall Number of Baseline Participants 9 6 6 6 27
Hide Baseline Analysis Population Description
27 subjects were enrolled in Module 3
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9 participants 6 participants 6 participants 6 participants 27 participants
33.7  (5.59) 33.2  (8.30) 32.5  (5.09) 35.7  (8.66) 33.7  (6.60)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 6 participants 6 participants 6 participants 27 participants
Female
5
  55.6%
2
  33.3%
0
   0.0%
3
  50.0%
10
  37.0%
Male
4
  44.4%
4
  66.7%
6
 100.0%
3
  50.0%
17
  63.0%
1.Primary Outcome
Title Efficacy:Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration Activity
Hide Description 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)
Time Frame Baseline to 2 minutes following the end of andexanet/placebo administration
Hide Outcome Measure Data
Hide Analysis Population Description
26 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized
Hide Arm/Group Description:
Placebo administered intravenously (IV) as a bolus.
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
420 mg andexanet IV bolus over 14 minutes (~30 mg/min)
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
Overall Number of Participants Analyzed 8 6 6 6
Mean (Standard Deviation)
Unit of Measure: Percent change in anti-fXa activity
-3.57  (12.80) -70.80  (6.98) -60.83  (8.39) -69.85  (7.46)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Module 3 (210 mg Bolus) Original
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Means (Difference)
Estimated Value -0.23
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Module 3 (420 mg Bolus) Original
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Means (Difference)
Estimated Value -0.20
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Module 3 (210 mg) Lyophilized
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Means (Difference)
Estimated Value -0.23
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Efficacy: Percent Change From Baseline in Thrombin Generation at 2 Mins Following Andexanet/Placebo Administration
Hide Description 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.
Time Frame Baseline to 2 minutes following the end of andexanet/placebo administration
Hide Outcome Measure Data
Hide Analysis Population Description
26 subjects who received andexanet or placebo were included in the PD analysis
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized
Hide Arm/Group Description:
Placebo administered intravenously (IV) as a bolus.
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
420 mg andexanet IV bolus over 14 minutes (~30 mg/min)
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
Overall Number of Participants Analyzed 8 6 6 6
Mean (Standard Deviation)
Unit of Measure: Percent change in thrombin generation
3.48  (15.162) 36.34  (15.127) 107.48  (73.301) 72.7  (74.301)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Module 3 (210 mg Bolus) Original
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1529
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Means (Difference)
Estimated Value 53922.58
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Module 3 (420 mg Bolus) Original
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Means (Difference)
Estimated Value 124993.1
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Module 3 (210 mg) Lyophilized
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0032
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Means (Difference)
Estimated Value 96385.09
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Andexanet Maximum Observed Plasma Concentration (Cmax)
Hide Description 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.
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
18 subjects who received andexanet were included in the andexanet pharmacokinetics (PK) analysis
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized
Hide Arm/Group Description:
Placebo administered intravenously (IV) as a bolus.
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
420 mg andexanet IV bolus over 14 minutes (~30 mg/min)
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
Overall Number of Participants Analyzed 0 6 6 6
Mean (Standard Deviation)
Unit of Measure: ng/mL
32000  (7320) 55800  (6050) 42700  (14400)
4.Secondary Outcome
Title Andexanet Area Under the Drug Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf )
Hide Description 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
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
18 subjects who received andexanet were included in the andexanet PK analysis
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized
Hide Arm/Group Description:
Placebo administered intravenously (IV) as a bolus.
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
420 mg andexanet IV bolus over 14 minutes (~30 mg/min)
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
Overall Number of Participants Analyzed 0 6 6 6
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
33600  (4280) 63900  (8880) 40900  (12300)
5.Secondary Outcome
Title Andexanet Time of Maximum Observed Plasma Concentration (Tmax)
Hide Description 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.
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
18 subjects who received andexanet were included in the andexanet PK analysis
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized
Hide Arm/Group Description:
Placebo administered intravenously (IV) as a bolus.
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
420 mg andexanet IV bolus over 14 minutes (~30 mg/min)
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
Overall Number of Participants Analyzed 0 6 6 6
Median (Full Range)
Unit of Measure: hr
0.18
(0.16 to 0.35)
0.29
(0.27 to 0.54)
0.17
(0.17 to 0.19)
6.Secondary Outcome
Title Andexanet Apparent Terminal Elimination Half-life (t1/2)
Hide Description 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.
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
18 subjects who received andexanet were included in the andexanet PK analysis
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized
Hide Arm/Group Description:
Placebo administered intravenously (IV) as a bolus.
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
420 mg andexanet IV bolus over 14 minutes (~30 mg/min)
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
Overall Number of Participants Analyzed 0 6 6 6
Mean (Standard Deviation)
Unit of Measure: hr
5.28  (1.99) 6.11  (2.34) 8.36  (7.46)
7.Secondary Outcome
Title Andexanet Total Systemic Clearance (CL)
Hide Description 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.
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
18 subjects who received andexanet were included in the andexanet PK analysis
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized
Hide Arm/Group Description:
Placebo administered intravenously (IV) as a bolus.
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
420 mg andexanet IV bolus over 14 minutes (~30 mg/min)
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
Overall Number of Participants Analyzed 0 6 6 6
Mean (Standard Deviation)
Unit of Measure: L/hr
6.34  (0.870) 6.69  (0.991) 5.56  (1.76)
8.Secondary Outcome
Title Andexanet Total Volume of Distribution (Vss)
Hide Description 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.
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
18 subjects who received andexanet were included in the andexanet PK analysis
Arm/Group Title Placebo Module 3 (210 mg Bolus) Original Module 3 (420 mg Bolus) Original Module 3 (210 mg) Lyophilized
Hide Arm/Group Description:
Placebo administered intravenously (IV) as a bolus.
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
420 mg andexanet IV bolus over 14 minutes (~30 mg/min)
210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
Overall Number of Participants Analyzed 0 6 6 6
Mean (Standard Deviation)
Unit of Measure: L
9.86  (2.61) 9.62  (1.13) 9.69  (4.16)
Time Frame ~7 weeks
Adverse Event Reporting Description Only subjects who received at least one dose of study drug were included in the safety analysis.
 
Arm/Group Title Placebo Module 3 (210 mg Andexanet) Original Formulation Module 3 (420 mg Andexanet) Original Forumulation Module 3 (210 mg Andexanet ) Lyophilized
Hide Arm/Group Description Placebo was administered intravenously (IV) as a bolus 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) 420 mg andexanet IV bolus over 14 minutes (~30 mg/min) 420 mg andexanet IV bolus over 14 minutes (~30 mg/min) 210 mg andexanet IV bolus over 7 minutes (~30 mg/min) 210 mg andexanet IV bolus over 7 minutes (~30 mg/min)
All-Cause Mortality
Placebo Module 3 (210 mg Andexanet) Original Formulation Module 3 (420 mg Andexanet) Original Forumulation Module 3 (210 mg Andexanet ) Lyophilized
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Module 3 (210 mg Andexanet) Original Formulation Module 3 (420 mg Andexanet) Original Forumulation Module 3 (210 mg Andexanet ) Lyophilized
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/8 (0.00%)   0/6 (0.00%)   0/6 (0.00%)   0/6 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Placebo Module 3 (210 mg Andexanet) Original Formulation Module 3 (420 mg Andexanet) Original Forumulation Module 3 (210 mg Andexanet ) Lyophilized
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/8 (62.50%)   4/6 (66.67%)   4/6 (66.67%)   5/6 (83.33%) 
Gastrointestinal disorders         
Abdominal distension  1  1/8 (12.50%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Abdominal pain  1  0/8 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Abdominal tenderness  1  3/8 (37.50%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Dry mouth  1  0/8 (0.00%)  0/6 (0.00%)  2/6 (33.33%)  0/6 (0.00%) 
Dyspepsia  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Nausea  1  1/8 (12.50%)  0/6 (0.00%)  1/6 (16.67%)  1/6 (16.67%) 
Toothache  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Vomiting  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
General disorders         
Influenza like illness  1  1/8 (12.50%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Thirst  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Infections and infestations         
Upper respiratory tract infection  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Injury, poisoning and procedural complications         
Excoriation  1  0/8 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Infusion related reaction  1  0/8 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  2/6 (33.33%) 
Ligament sprain  1  1/8 (12.50%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Post procedural hematoma  1  0/8 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  0/6 (0.00%) 
Procedural pain  1  2/8 (25.00%)  1/6 (16.67%)  1/6 (16.67%)  0/6 (0.00%) 
Procedural site reaction  1  2/8 (25.00%)  1/6 (16.67%)  2/6 (33.33%)  1/6 (16.67%) 
Post procedural haemorrhage  1  1/8 (12.50%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  1/8 (12.50%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Muscle spasms  1  0/8 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Pain in extremity  1  0/8 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Nervous system disorders         
Dizziness  1  0/8 (0.00%)  0/6 (0.00%)  2/6 (33.33%)  0/6 (0.00%) 
Headache  1  0/8 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Paresthesia  1  1/8 (12.50%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Psychiatric disorders         
Anxiety  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Reproductive system and breast disorders         
Metrorrhagia  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Epistaxis  1  0/8 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Productive cough  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Skin and subcutaneous tissue disorders         
Pruritus  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Pruritus generalized  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Rash erythematous  1  0/8 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Conducted in healthy volunteers at Clinical Research Organization
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Head of Clinical Development
Organization: Portola Pharmaceuticals, Inc.
Phone: 650-246-7000
Layout table for additonal information
Responsible Party: Portola Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03551730     History of Changes
Other Study ID Numbers: 12-502 Module 3
First Submitted: May 15, 2018
First Posted: June 11, 2018
Results First Submitted: June 8, 2018
Results First Posted: August 13, 2018
Last Update Posted: September 26, 2018