A Study to Assess the Effects of 2 Prothrombin Complex Concentrates on the Pharmacodynamics of Apixaban in Healthy Adult Subjects

NCT02074358 | Completed Phase 1 Results

• 2 other identifiers: CV185-1562013-000646-18
• Study Type: interventional
• Target: 43
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to assess the effect of two 4-Factor PCC formulations on Apixaban pharmacodynamics in healthy adult subjects.

Conditions

Anticoagulation

Outcome Measures

Primary Outcomes (2)

• Pharmacodynamic (PD) Parameter: Adjusted Mean Change in Endogenous Thrombin Potential (ETP) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo

  ETP was evaluated using a Thrombin Generation Assay (TGA), a validated automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids. Thrombin concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample. Dedicated software (Thrombinoscope, Thrombinoscope B.V., Maastricht, The Netherlands) performed the calculations and derived ETP as area under the curve from the resulting "thrombogram" curve. Pre-infusion baseline= sample on Day 4, 3 hours post apixaban dose (just prior to IV infusion of PCC or placebo). Samples on Day 4 were obtained at 0 (pre-dose), 0.5, 1, 2, 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. ETP was measured as nanomolar\*minute (nM\*min).

  Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion (PCC or Placebo)

• PD Parameter: Adjusted Mean Change in Endogenous Thrombin Potential (ETP) From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo

  ETP was evaluated using a Thrombin Generation Assay (TGA), a validated automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids. Thrombin concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample. A dedicated software program (Thrombinoscope, Thrombinoscope B.V., Maastricht, The Netherlands) performed the calculations and derived ETP as area under the curve from the resulting "thrombogram" curve. Pre-dose Apixaban baseline was Day 1 pre-dose (0 hour). Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period.

  Day 1 pre-dose apixaban (pre-apixaban Baseline), Day 4 at 30 minutes post infusion (PCC or Placebo)

Secondary Outcomes (26)

• PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo

  Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.

• PD Parameter: Adjusted Mean Change in TGA Peak Height From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo

  Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.

• PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo

  Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.

• PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo

  Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.

• PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo

  Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.

Study Arms (3)

Treatment A: Apixaban + Placebo (Saline solution)

EXPERIMENTAL

Apixaban 10 mg Tablet orally \[Day 1-Day 3: twice daily (BID), Day 4: Single Dose (SD)\] followed 3hr later by Saline solution (placebo) 0 IU/kg infusion for 30 min Intravenously

Drug: Apixaban; Drug: Placebo (Saline solution)

Treatment B: Apixaban + Cofact (4-Factor PCC)

EXPERIMENTAL

Apixaban 10 mg Tablet orally \[Day 1-Day 3: twice daily (BID), Day 4: Single Dose (SD)\] followed 3hr later by a Cofact (4-Factor PCC) 50 IU/kg infusion for 30 min Intravenously

Drug: Apixaban; Drug: Cofact (4-Factor PCC)

Treatment C: Apixaban + Beriplex P/N (4-Factor PCC)

EXPERIMENTAL

Apixaban 10 mg Tablet orally \[Day 1-Day 3: twice daily (BID), Day 4: Single Dose (SD)\] followed 3hr later by a Beriplex P/N (4-Factor PCC) 50 IU/kg infusion for 30 min Intravenously

Drug: Apixaban; Drug: Beriplex P/N (4-Factor PCC)

Interventions

Apixaban DRUG

Also known as: BMS-562247

Treatment A: Apixaban + Placebo (Saline solution); Treatment B: Apixaban + Cofact (4-Factor PCC); Treatment C: Apixaban + Beriplex P/N (4-Factor PCC)

Cofact (4-Factor PCC) DRUG

Treatment B: Apixaban + Cofact (4-Factor PCC)

Beriplex P/N (4-Factor PCC) DRUG

Treatment C: Apixaban + Beriplex P/N (4-Factor PCC)

Placebo (Saline solution) DRUG

Treatment A: Apixaban + Placebo (Saline solution)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy subjects
• Body Mass Index (BMI) of 18 to 30 kg/m2
• Ages 18 to 45 years, including
• Women of childbearing potential (WOCBP) on acceptable contraception and with negative pregnancy test and not breastfeeding

You may not qualify if:

• History or evidence of coagulopathy
• History or evidence of thrombosis such as deep vein thrombosis or other thromboembolic disease or having a first degree relative under 50 years of age with a history of thromboembolic disease
• Any significant acute or chronic medical illness or relevant trauma
• Any major surgery within 4 weeks of dosing (prior to dosing) or planned within 2 weeks after completion of the study
• History of heavy menstrual bleeding that has produced anemia within the past 1 year
• Current symptomatic or recent gastrointestinal disease or surgery that could impact the absorption of study drug
• History of smoking within 1 month prior to dosing
• Recent history (within 6 months of dosing) of pregnancy
• Use of hormonal contraceptives
• Exposure to any investigational drug or placebo within 4 weeks of study drug administration
• Use of any agent, including but not limited to Aspirin, Nonsteroidal anti-inflammatory drugs (NSAIDs), Anticoagulants, Fish oil capsules, Gingko, etc, that are known to increase the potential for bleeding, within 2 weeks prior to dosing
• History of any severe drug allergy including allergy to Heparin or history of Heparin-induced thrombocytopenia, hypersensitivity to PCCs or Factor Xa inhibitors, or history of allergy to human blood plasma derived products; history of any adverse drug reaction to Anticoagulants or Antiplatelet agents that resulted in excessive bleeding requiring medical intervention

Sponsors & Collaborators

• Bristol-Myers Squibb: lead

MeSH Terms

Interventions

apixaban; prothrombin complex concentrates; factor IX, factor VII, factor X, prothrombin drug combination; Saline Solution

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2014
• First Posted: February 28, 2014
• Study Start: February 1, 2014
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: August 13, 2015
• Results First Posted: August 13, 2015

Record last verified: 2015-07