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

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

Study Overview

• Status: Completed
• Conditions: Anticoagulation
• Intervention / Treatment: Drug: Apixaban; Drug: Placebo (Saline solution); Drug: Cofact (4-Factor PCC); Drug: Beriplex P/N (4-Factor PCC)

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment A: Apixaban + Placebo (Saline solution); 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; Other Names: BMS-562247; Drug: Placebo (Saline solution)
Experimental: Treatment B: Apixaban + Cofact (4-Factor PCC); 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; Other Names: BMS-562247; Drug: Cofact (4-Factor PCC)
Experimental: Treatment C: Apixaban + Beriplex P/N (4-Factor PCC); 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; Other Names: BMS-562247; Drug: Beriplex P/N (4-Factor PCC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	TGA is 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 and the 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 program was Thrombinoscope, B.V., Maastricht, The Netherlands. 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. Lag Time and Time to Peak parameters were measured in minutes.	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	TGA is 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 and the 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 program was Thrombinoscope, B.V., Maastricht, The Netherlands. 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. Peak height parameter was measured in nanomolar (nM).	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	TGA is 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 and the 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 program was Thrombinoscope, B.V., Maastricht, The Netherlands. 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. TGA Velocity Index parameter was measured in nM per 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.
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	Coagulation parameters were evaluated by Quintiles Laboratories Europe using an ACL TOP analyzer and Instrumentation Laboratory reagents [HemosIL(Registered) Recombiplastin 2G for PT and Synthasil for aPTT]. A second PT was also measured at Esoterix using a Diagnostica Stago STA Compact coagulation analyzer and Diagnostica Stago reagents STA-Neoplastin CI Plus (Registered). Samples on Day 4 were obtained at 0 and 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. PT (Neoplastin CT+), PT (Recombiplastin 2G) and activated partial thromboplastin time (aPTT) parameters were measured in seconds.	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	Coagulation parameters were evaluated by Quintiles Laboratories Europe using an ACL TOP analyzer and Instrumentation Laboratory reagents [HemosIL(Registered) Recombiplastin 2G for PT and Synthasil for aPTT]. A second PT was also measured at Esoterix using a Diagnostica Stago STA Compact coagulation analyzer and Diagnostica Stago reagents STA-Neoplastin CI Plus (Registered). Samples on Day 4 were obtained at 0 and 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. INR was measured as a fraction.	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 Plasma Anti-Xa Activity From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo	Anti-FXa activity was measured using a validated method at Esoterix Coagulation Laboratory (Englewood, CO) using the Diagnostica Stago Rotachrom (Registered) Heparin assay on a STA-Compact (Registered) analyzer. 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. The results of this chromogenic assay were reported in low molecular weight heparin (LMWH) activity units per milliliter (U/mL), which are equivalent to international units per milliliter (IU/mL) with assay reportable range: 0.1 to 18.4 IU/mL.	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 Lag Time and TGA Time to Peak From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo	TGA is 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 and the 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 program was Thrombinoscope, B.V., Maastricht, The Netherlands. Baseline was Day 1, 0 hour pre-dose apixaban. Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. TGA Lag Time and Time to Peak parameters were measured in minutes.	Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.
PD Parameter: Adjusted Mean Change in TGA Peak Height From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo	TGA is 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 and the 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 program was Thrombinoscope, B.V., Maastricht, The Netherlands. Baseline was Day 1, 0 hour pre-dose apixaban. Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. TGA Lag Time and Time to Peak parameters were measured in minutes.	Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.
PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo	TGA is 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 and the 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 program was Thrombinoscope, B.V., Maastricht, The Netherlands. Baseline was Day 1, 0 hour (pre-dose apixaban). 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. TGA velocity index was measured in nM/min.	Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.
PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo	Coagulation parameters were evaluated by Quintiles Laboratories Europe using an ACL TOP analyzer and Instrumentation Laboratory reagents [HemosIL(Registered) Recombiplastin 2G for PT and Synthasil for aPTT]. A second PT was also measured at Esoterix using a Diagnostica Stago STA Compact coagulation analyzer and Diagnostica Stago reagents STA-Neoplastin CI Plus (Registered). Baseline was Day 1, pre-apixaban dose. Samples on Day 4 were obtained at 0 and 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 (Baseline), Day 4, 30 minutes post infusion.
PD Parameter: Adjusted Mean Change in Coagulation Parameter INR From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo	Coagulation parameters were evaluated by Quintiles Laboratories Europe using an ACL TOP analyzer and Instrumentation Laboratory reagents [HemosIL(Registered) Recombiplastin 2G for PT and Synthasil for aPTT]. A second PT was also measured at Esoterix using a Diagnostica Stago STA Compact coagulation analyzer and Diagnostica Stago reagents STA-Neoplastin CI Plus (Registered). Baseline was Day 1, 0 hour pre-dose apixaban. Samples on Day 4 were obtained at 0 and 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. INR was measured as a fraction	Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.
Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban on Day 4	Plasma samples for pharmacokinetic (PK) analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) assay within the period of known analyte stability. Cmax was measured in nanograms per milliliter (ng/mL).	Day 4
Geometric Mean Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban on Day 4	Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. Tmax was measured in hours.	Day 4
Geometric Mean Area Under the Plasma Concentration-Time Curve in One Dosing Interval [AUC(0-12)] of Apixaban on Day 4	Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. AUC(0-12) was measured in ng*hours/mL (ng*h/mL)	Day 4
Adjusted Geometric Mean AUC (0-12) of Apixaban on Day 4	Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability.	Day 4
Geometric Mean Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours After Dose Administration [AUC(0-24)] of Apixaban on Day 4	Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. AUC(0-24) was measured in ng*h/mL.	Day 4
Adjusted Geometric Mean AUC (0-24) for Apixaban on Day 4	Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability.	Day 4
Geometric Mean Trough Observed Plasma Concentration at the End of One Dosing Interval (12h) [Cmin] of Apixaban on Day 4	Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. Cmin was measured in nanograms per milliliter (ng/mL).	Day 4
Mean Terminal Elimination Half-Life (T-HALF) of Apixaban on Day 4	Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. T-HALF was measured in hours	Day 4
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Medical Dictionary for Regulatory Activities (MedDRA) version 17.0 was used.	Day 1 to 30 days Post Last Dose
Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population	Blood, urine samples obtained at screening, Days -1, 4, and 7 of each treatment period, and study discharge (Day 11 of Treatment Period 3). MA: Leukocyte White Blood Cells (WBC) *10^3 cells per microliter (c/µL); High (H): > 1.2*upper limits normal (ULN) if lower limits normal (LLN) <= pre-therapy (PreRx) <= ULN; > 1.2*ULN if PreRx = Missing; > 1.5*PreRx if PreRx > ULN; > ULN if PreRx < LLN. Alanine Aminotransferase (ALT) units per liter (U/L); H: > 1.25*PreRx if PreRx > ULN; > 1.25*ULN if PreRx <= ULN; > 1.25*ULN if PreRx = Missing. Total and Direct Bilirubin in milligrams/deciliter (mg/dL) H: > 1.1*ULN if PreRx <= ULN;> 1.1*ULN if PreRx = Missing; > 1.25*PreRx if PreRx > ULN. Blood in Urine H: >= 2*PreRx if PreRx >= 1; >= 2 if PreRx < 1; >= 2 if PreRx = Missing. Urine Red Blood Cells (RBC) and Urine WBC/ high powered field (hpf) H: >= 2 if PreRx = Missing; >= 2 if PreRx < 2; >= 4 if PreRx >= 2. Crossover study: same participant with MA could be reported in multiple arms.	Day 1 (first dose) to Day of Study Discharge (Day 11 of Treatment Period 3)
Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF	Single 12-lead ECGs were obtained at screening, Day -1 of Period 1, and Days 4 and 7 of each treatment period after the participant had been supine for at least 5 minutes. Pulse Rate (PR), Complex of Q, R, S waves (QRS), and contraction of ventricle between the beginning of the Q wave and end of the T wave (QT) were measured in milliseconds (msec). QT was corrected by the Fridericia method (QTcF) and measured in msec. Baseline was Day -1 of first treatment period. Crossover study: same participant with out of range ECG intervals could be reported in multiple arms.	Day -1 first treatment period, Days 4 and 7 each treatment period
Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7	Blood pressures were recorded at screening, Day -1 of Period 1, and Days 4 and 7 of each period. Blood pressure was measured after the participant had been seated quietly for at least 5 minutes and was measured in millimeters of mercury (mmHg). Baseline was last non-missing result with a collection date-time less than the date-time of the first active dose.	Screening, Day -1 first treatment period, Days 4 and 7 post treatment
Mean Change From Baseline in Heart Rate on Day 4 and Day 7	Heart Rate was recorded at screening, Day -1 of Period 1, and Days 4 and 7 of each period. Heart Rate was measured after the participant had been seated quietly for at least 5 minutes and was measured in beats per minute (bpm). Baseline was last non-missing result with a collection date-time less than the date-time of the first active dose.	Screening, Day -1 first treatment period, Days 4 and 7 post treatment
Mean Change From Baseline in Respiration Rate on Day 4 and Day 7	Respiration Rate was recorded at screening, Day -1 of Period 1, and Days 4 and 7 of each period. Respiration Rate was measured after the participant had been seated quietly for at least 5 minutes and was measured in respirations (breaths) per minute. Baseline was last non-missing result with a collection date-time less than the date-time of the first active dose.	Screening, Day -1 first treatment period, Days 4 and 7 post treatment
Mean Change From Baseline Temperature on Day 4 and Day 7	Temperature was recorded at screening, Day -1 of Period 1, and Days 4 and 7 of each period and was measured in degrees centigrade (C). Baseline was last non-missing result with a collection date-time less than the date-time of the first active dose.	Screening, Day -1 first treatment period, Days 4 and 7 post treatment

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: February 26, 2014
• First Submitted That Met QC Criteria: February 26, 2014
• First Posted (Estimate): February 28, 2014

Study Record Updates

• Last Update Posted (Estimate): August 13, 2015
• Last Update Submitted That Met QC Criteria: July 15, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: CV185-156; 2013-000646-18 (EudraCT Number)