Trial Outcomes & Findings for A Study to Assess the Effects of 2 Prothrombin Complex Concentrates on the Pharmacodynamics of Apixaban in Healthy Adult Subjects (NCT NCT02074358)

NCT ID: NCT02074358

Last Updated: 2015-08-13

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 43 participants
• Primary outcome timeframe: 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)
• Results posted on: 2015-08-13

Participant Flow

Study initiated in February 2014 in healthy adult participants and completed in April 2014. Participants were admitted to a clinical facility on the evening prior to dosing and remained in the facility for at least 72 hours after the start of the IV infusion on Day 4.

43 enrolled;15 treated. Reasons not treated: 5 withdrew consent; 19 no longer met study criteria; 4 stand-by participants not needed (cohort full). Crossover: 6 treatment sequences (3 periods) with an 11 day washout from study drug between each treatment period; 3 participants in each sequence: ABC, ACB, CAB and 2 in each sequence: CBA, BAC, BCA.

Participant milestones

Measure	Treatment ABC Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet twice daily (BID) on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours (hrs) later by Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) intravenous infusion (IV) for 30 minutes. Treatment B: Apixaban + Cofact \[4-Factor prothrombin complex concentrate (PCC)\]: Apixaban 10 mg oral Tablet BID on Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Cofact (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes. Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Beriplex P/N (4-Factor PCC) 50 IU/kg IV infusion for 30 min.	Treatment ACB Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet twice daily (BID)Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Saline solution (placebo) 0 IU/kg IV infusion for 30 minutes. Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Beriplex P/N (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes. Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Cofact (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes.	Treatment BAC Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Cofact (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes. Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet twice daily (BID)Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Saline solution (placebo) 0 IU/kg IV infusion for 30 minutes. Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Beriplex P/N (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes.	Treatment BCA Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Cofact (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes. Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Beriplex P/N (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes. Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet twice daily (BID)Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Saline solution (placebo) 0 IU/kg IV infusion for 30 minutes.	Treatment CAB Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Beriplex P/N (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes. Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet twice daily (BID)Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Saline solution (placebo) 0 IU/kg IV infusion for 30 minutes. Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Cofact (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes.	Treatment CBA Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Beriplex P/N (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes. Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Cofact (4-Factor PCC) 50 IU/kg IV infusion for 30 minutes. Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet twice daily (BID)Days 1- 3; Day 4: Single 10 mg Dose Apixaban followed 3hrs later by Saline solution (placebo) 0 IU/kg IV infusion for 30 minutes.
Overall Study STARTED	3	3	2	2	3	2
Overall Study COMPLETED	3	3	2	2	3	2
Overall Study NOT COMPLETED	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	All Treated Participants n=15 Participants Treated population included all participants who received at least one dose of study medication. Participants received 10 mg apixaban BID on Days 1-3 and on Day 4 received a single dose of 10 mg apixaban followed 3 hours later by an IV infusion of 50 IU/kg prothrombin complex concentrate (PCC) (which was either Cofact or Beriplex P/N) or the participant received an IV infusion of placebo (saline solution). Participants were randomized on Day 1 to one of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB and CBA). There were 3 treatment periods with a total of 3 participants in each of 3 sequences (ABC, ACB, CAB) and 2 participants in each of 3 other sequences (CBA, BAC, BCA) for a total of 15 participants who participated in this open label, randomized, crossover study.
Age, Continuous	33.1 years STANDARD_DEVIATION 7.00 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants
Race/Ethnicity, Customized White	14 participants n=5 Participants
Race/Ethnicity, Customized Black/African American	1 participants n=5 Participants
Region of Enrollment Germany	15 participants n=5 Participants
Body Mass Index (BMI)	24.5 kg/m^2 STANDARD_DEVIATION 2.50 • n=5 Participants
Weight	76.5 kilograms STANDARD_DEVIATION 7.96 • n=5 Participants

PRIMARY outcome

Timeframe: 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)

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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).

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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	95.8 nM*min Interval 21.3 to 170.2	521.0 nM*min Interval 314.6 to 727.4	186.3 nM*min Interval 49.7 to 322.9

PRIMARY outcome

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

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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	-708.0 nM*minute Interval -791.1 to -625.0	-276.3 nM*minute Interval -465.8 to -86.9	-607.7 nM*minute Interval -701.2 to -514.2

SECONDARY outcome

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

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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 Lag Time (n=15, 14, 15)	-0.16 minutes Interval -0.59 to 0.26	-0.38 minutes Interval -0.85 to 0.1	-0.32 minutes Interval -0.75 to 0.1
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 Time to Peak (n=15, 14, 15)	-1.29 minutes Interval -3.45 to 0.87	0.06 minutes Interval -1.3 to 1.42	3.32 minutes Interval 1.97 to 4.68

SECONDARY outcome

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

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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).

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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	11.1 nM Interval 5.1 to 17.0	32.1 nM Interval 15.2 to 49.1	4.7 nM Interval -3.3 to 12.7

SECONDARY outcome

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

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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).

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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	3.4 nM/min Interval -0.5 to 7.3	3.4 nM/min Interval -1.5 to 8.2	-3.2 nM/min Interval -5.4 to -0.9

SECONDARY outcome

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

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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 PT (Neoplastin CI+) (n=15, 14, 15)	-0.21 seconds Interval -0.44 to 0.02	-1.85 seconds Interval -2.3 to -1.4	-1.68 seconds Interval -1.99 to -1.38
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 PT (Recombiplastin 2G) (n=15, 14, 15)	0.35 seconds Interval -0.13 to 0.83	-2.24 seconds Interval -2.74 to -1.75	-1.54 seconds Interval -2.16 to -0.92
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 aPTT (n=15, 14, 15)	1.13 seconds Interval 0.38 to 1.87	9.60 seconds Interval 7.69 to 11.51	3.43 seconds Interval 2.66 to 4.2

SECONDARY outcome

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

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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 INR (Neoplastin CI+) (n=15, 14, 15)	-0.015 fraction Interval -0.048 to 0.019	-0.213 fraction Interval -0.274 to -0.152	-0.185 fraction Interval -0.218 to -0.152
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 INR (Recombiplastin 2G) (n=15, 14, 15)	0.032 fraction Interval -0.014 to 0.077	-0.207 fraction Interval -0.254 to -0.161	-0.144 fraction Interval -0.202 to -0.086

SECONDARY outcome

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

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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	-0.368 U/mL Interval -0.588 to -0.148	-0.607 U/mL Interval -0.827 to -0.387	-0.538 U/mL Interval -0.683 to -0.393

SECONDARY outcome

Timeframe: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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 Lag Time (n=15,14,15)	3.56 minutes Interval 3.16 to 3.96	3.36 minutes Interval 2.86 to 3.86	3.40 minutes Interval 3.05 to 3.76
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 Time to Peak (n=15,14,15)	6.42 minutes Interval 3.96 to 8.89	7.90 minutes Interval 6.41 to 9.4	10.81 minutes Interval 9.22 to 12.39

SECONDARY outcome

Timeframe: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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	-196.1 nM Interval -205.6 to -186.6	-174.9 nM Interval -192.3 to -157.5	-202.7 nM Interval -211.7 to -193.7

SECONDARY outcome

Timeframe: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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	-63.7 nM/min Interval -67.1 to -60.3	-63.6 nM/min Interval -68.3 to -58.9	-71.5 nM/min Interval -74.1 to -69.0

SECONDARY outcome

Timeframe: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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 PT (Neoplastin CI+) (n=15,14,15)	2.74 seconds Interval 2.54 to 2.94	1.17 seconds Interval 0.65 to 1.7	1.31 seconds Interval 0.94 to 1.67
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 PT (Recombiplastin 2G) (n=15,14,15)	4.94 seconds Interval 4.57 to 5.33	2.30 seconds Interval 1.74 to 2.86	3.01 seconds Interval 2.43 to 3.59
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 aPTT (n=15, 14, 15)	7.49 seconds Interval 6.75 to 8.23	15.87 seconds Interval 13.91 to 17.82	9.68 seconds Interval 8.84 to 10.52

SECONDARY outcome

Timeframe: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.

Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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 INR (Neoplastin CI+) (n=15,14,15)	0.290 fraction Interval 0.26 to 0.321	0.103 fraction Interval 0.026 to 0.18	0.130 fraction Interval 0.084 to 0.176
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 INR (Recombiplastin 2G) (n=15,14,15)	0.460 fraction Interval 0.424 to 0.497	0.216 fraction Interval 0.164 to 0.269	0.281 fraction Interval 0.227 to 0.335

SECONDARY outcome

Timeframe: Day 4

Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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).

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban on Day 4	291 ng/mL Geometric Coefficient of Variation 23	310 ng/mL Geometric Coefficient of Variation 29	290 ng/mL Geometric Coefficient of Variation 28

SECONDARY outcome

Timeframe: Day 4

Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Geometric Mean Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban on Day 4	2.00 hours Interval 1.02 to 2.98	2.00 hours Interval 0.98 to 2.98	2.00 hours Interval 1.0 to 2.98

SECONDARY outcome

Timeframe: Day 4

Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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)

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Geometric Mean Area Under the Plasma Concentration-Time Curve in One Dosing Interval [AUC(0-12)] of Apixaban on Day 4	1965 ng*h/mL Geometric Coefficient of Variation 22	2046 ng*h/mL Geometric Coefficient of Variation 26	2010 ng*h/mL Geometric Coefficient of Variation 26

SECONDARY outcome

Timeframe: Day 4

Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Adjusted Geometric Mean AUC (0-12) of Apixaban on Day 4	1972 ng*h/mL Interval 1752.0 to 2219.0	2049 ng*h/mL Interval 1818.0 to 2309.0	2014 ng*h/mL Interval 1809.0 to 2241.0

SECONDARY outcome

Timeframe: Day 4

Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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	2537 ng*h/mL Geometric Coefficient of Variation 23	2583 ng*h/mL Geometric Coefficient of Variation 27	2585 ng*h/mL Geometric Coefficient of Variation 28

SECONDARY outcome

Timeframe: Day 4

Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Adjusted Geometric Mean AUC (0-24) for Apixaban on Day 4	2546 ng*h/mL Interval 2258.0 to 2871.0	2594 ng*h/mL Interval 2295.0 to 2932.0	2592 ng*h/mL Interval 2315.0 to 2902.0

SECONDARY outcome

Timeframe: Day 4

Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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).

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Geometric Mean Trough Observed Plasma Concentration at the End of One Dosing Interval (12h) [Cmin] of Apixaban on Day 4	86.0 ng/mL Geometric Coefficient of Variation 26	93.7 ng/mL Geometric Coefficient of Variation 37	95.5 ng/mL Geometric Coefficient of Variation 39

SECONDARY outcome

Timeframe: Day 4

Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.

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

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=14 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Mean Terminal Elimination Half-Life (T-HALF) of Apixaban on Day 4	10.9 hours Standard Deviation 2.49	10.8 hours Standard Deviation 2.95	11.0 hours Standard Deviation 1.87

SECONDARY outcome

Timeframe: Day 1 to 30 days Post Last Dose

Population: Treated population: All participants who received at least one dose of study medication were analyzed.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=15 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population Adverse Events	1 participants	5 participants	2 participants
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population SAEs	0 participants	0 participants	0 participants
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population Discontinuation due to AEs	0 participants	0 participants	0 participants
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population Death	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: Day 1 (first dose) to Day of Study Discharge (Day 11 of Treatment Period 3)

Population: All participants who received any study medication and had available laboratory test data were analyzed. n=number of participants evaluated.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=15 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population Red Blood Cells in Urine (n=5,7,6)	1 participants	0 participants	0 participants
Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population Leukocytes High (n=15,15,15)	0 participants	1 participants	0 participants
Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population ALT High (n=15,15,15)	1 participants	1 participants	0 participants
Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population Bilirubin Direct High (n=4,4,4)	2 participants	2 participants	2 participants
Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population Bilirubin Total High (n=15,15,15)	2 participants	1 participants	2 participants
Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population Blood in Urine (n=15,15,15)	1 participants	1 participants	2 participants
Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population White Blood Cells in Urine (n=5,7,6)	0 participants	2 participants	0 participants

SECONDARY outcome

Timeframe: Day -1 first treatment period, Days 4 and 7 each treatment period

Population: Those participants who received any study medication and had available ECG data at baseline and Days 4 and 7 in each treatment period were analyzed.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=15 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
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 PR >200 msec (n=15,15,15)	0 participants	0 participants	0 participants
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 QRS > 120 msec (n=15,15,15)	0 participants	0 participants	0 participants
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 QT > 500 msec (n=15,15,15)	0 participants	0 participants	0 participants
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 QTcF > 450 msec (n=15,15,15)	0 participants	0 participants	0 participants
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 Change from Baseline >30 msec in QT (n=15,15,15)	3 participants	2 participants	3 participants
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 Change from Baseline >30 msec in QTcF (n=15,15,15)	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: Screening, Day -1 first treatment period, Days 4 and 7 post treatment

Population: Those participants who received any study medication and had blood pressure data at baseline and post baseline were analyzed.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=15 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 Systolic BP Day 4 (n=15,15,15)	0.9 mmHg Standard Deviation 8.43	-2.1 mmHg Standard Deviation 10.67	-2.9 mmHg Standard Deviation 10.22
Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 Systolic BP Day 7 (n=15,15,15)	2.1 mmHg Standard Deviation 8.03	3.7 mmHg Standard Deviation 8.46	1.3 mmHg Standard Deviation 8.87
Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 Diastolic BP Day 4 (n=15,15,15)	-2.1 mmHg Standard Deviation 6.64	-3.3 mmHg Standard Deviation 6.76	-3.1 mmHg Standard Deviation 5.70
Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 Diastolic BP Day 7 (n=15,15,15)	-0.1 mmHg Standard Deviation 8.34	0.0 mmHg Standard Deviation 7.43	-0.1 mmHg Standard Deviation 6.58

SECONDARY outcome

Timeframe: Screening, Day -1 first treatment period, Days 4 and 7 post treatment

Population: Those participants who received any study medication and had heart rate data at baseline and post baseline were analyzed.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=15 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Mean Change From Baseline in Heart Rate on Day 4 and Day 7 Heart Rate Day 4 (n=15,15,15)	-4.3 bpm Standard Deviation 12.10	-4.9 bpm Standard Deviation 11.46	-5.5 bpm Standard Deviation 9.91
Mean Change From Baseline in Heart Rate on Day 4 and Day 7 Heart Rate Day 7 (n=15,15,15)	-1.8 bpm Standard Deviation 10.09	0.4 bpm Standard Deviation 10.73	-2.1 bpm Standard Deviation 10.17

SECONDARY outcome

Timeframe: Screening, Day -1 first treatment period, Days 4 and 7 post treatment

Population: Those participants who received any study medication and had respiration rate data at baseline and post baseline were analyzed.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=15 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 Respirate Rate Day 4 (n=15,15,15)	-0.7 breaths per minute Standard Deviation 2.58	-1.3 breaths per minute Standard Deviation 1.87	-1.4 breaths per minute Standard Deviation 2.41
Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 Respirate Rate Day 7 (n=15,15,15)	-0.4 breaths per minute Standard Deviation 2.20	-0.3 breaths per minute Standard Deviation 2.41	-0.5 breaths per minute Standard Deviation 2.90

SECONDARY outcome

Timeframe: Screening, Day -1 first treatment period, Days 4 and 7 post treatment

Population: Those participants who received any study medication and had temperature data at baseline and post baseline were analyzed.

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.

Outcome measures

Measure	Treatment A: Apixaban + Placebo n=15 Participants Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=15 Participants Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 Participants Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Mean Change From Baseline Temperature on Day 4 and Day 7 Temperature Day 4 (n=15,15,15)	-0.15 C Standard Deviation 0.432	-0.14 C Standard Deviation 0.350	-0.22 C Standard Deviation 0.399
Mean Change From Baseline Temperature on Day 4 and Day 7 Temperature Day 7 (n=15,15,15)	-0.20 C Standard Deviation 0.321	-0.08 C Standard Deviation 0.328	-0.17 C Standard Deviation 0.418

Adverse Events

Treatment A: Apixaban + Placebo

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

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

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

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

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Treatment A: Apixaban + Placebo n=15 participants at risk Treatment A: Apixaban + Placebo (Saline solution): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Saline solution (placebo) 0 international units per kilogram of body weight (IU/kg) for 30 minutes.	Treatment B: Apixaban + Cofact (4-Factor PCC) n=15 participants at risk Treatment B: Apixaban + Cofact (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Cofact (4-Factor PCC) 50 IU/kg for 30 minutes.	Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) n=15 participants at risk Treatment C: Apixaban + Beriplex P/N (4-Factor PCC): Apixaban 10 mg oral Tablet BID on Days 1- 3; on Day 4: Single 10 mg Dose Apixaban followed 3hours later by IV infusion of Beriplex P/N (4-Factor PCC) 50 IU/kg for 30 minutes.
Gastrointestinal disorders Abdominal Pain	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	13.3% 2/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014
Gastrointestinal disorders Flatulence	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	6.7% 1/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014
Infections and infestations Nasopharyngitis	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	13.3% 2/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014
Nervous system disorders Dizziness	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	6.7% 1/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014
Nervous system disorders Headache	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	6.7% 1/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014
Injury, poisoning and procedural complications Traumatic Hematoma	6.7% 1/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	6.7% 1/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014
Psychiatric disorders Nightmare	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	6.7% 1/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014	0.00% 0/15 • Day 1 to 30 days post last dose. Study initiated February 2014 and completed April 2014

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: Clinical.Trials@bms.com

Results disclosure agreements

• Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
• Publication restrictions are in place

Restriction type: OTHER