A Study to Assess the Effects of 2 Prothrombin Complex Concentrates on the Pharmacodynamics of Apixaban in Healthy Adult Subjects
Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT02074358
Collaborator
(none)
43
3
1.9
Study Details
Study Description
Brief Summary
The purpose of this study is to assess the effect of two 4-Factor PCC formulations on Apixaban pharmacodynamics in healthy adult subjects.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
43 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
A Study to Assess the Effects of 2 Prothrombin Complex Concentrates on the Pharmacodynamics of Apixaban in Healthy Adult Subjects
Study Start Date
:
Feb 1, 2014
Actual Primary Completion Date
:
Apr 1, 2014
Actual Study Completion Date
:
Apr 1, 2014
Arms and Interventions
| 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:
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:
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:
Drug: Beriplex P/N (4-Factor PCC)
|
Outcome Measures
Primary Outcome Measures
- 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 [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)]
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).
- 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 [Day 1 pre-dose apixaban (pre-apixaban Baseline), Day 4 at 30 minutes post infusion (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.
Secondary Outcome Measures
- PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo [Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.]
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.
- PD Parameter: Adjusted Mean Change in TGA Peak Height From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo [Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.]
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).
- PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo [Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.]
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).
- PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo [Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.]
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.
- PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo [Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.]
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.
- 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 [Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.]
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.
- 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 [Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.]
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.
- 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 [Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.]
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.
- 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 [Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.]
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.
- 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 [Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.]
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.
- 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 [Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.]
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
- Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban on Day 4 [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).
- Geometric Mean Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban on Day 4 [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.
- Geometric Mean Area Under the Plasma Concentration-Time Curve in One Dosing Interval [AUC(0-12)] of Apixaban on Day 4 [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)
- Adjusted Geometric Mean AUC (0-12) of Apixaban on Day 4 [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.
- 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 [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.
- Adjusted Geometric Mean AUC (0-24) for Apixaban on Day 4 [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.
- Geometric Mean Trough Observed Plasma Concentration at the End of One Dosing Interval (12h) [Cmin] of Apixaban on Day 4 [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).
- Mean Terminal Elimination Half-Life (T-HALF) of Apixaban on Day 4 [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
- Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population [Day 1 to 30 days Post Last Dose]
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.
- Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population [Day 1 (first dose) to Day of Study Discharge (Day 11 of Treatment Period 3)]
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.
- 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 [Day -1 first treatment period, Days 4 and 7 each treatment period]
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.
- Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 [Screening, Day -1 first treatment period, Days 4 and 7 post treatment]
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.
- Mean Change From Baseline in Heart Rate on Day 4 and Day 7 [Screening, Day -1 first treatment period, Days 4 and 7 post treatment]
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.
- Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 [Screening, Day -1 first treatment period, Days 4 and 7 post treatment]
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.
- Mean Change From Baseline Temperature on Day 4 and Day 7 [Screening, Day -1 first treatment period, Days 4 and 7 post treatment]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 45 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
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
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Bristol-Myers Squibb
Investigators
- Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT02074358
Other Study ID Numbers:
- CV185-156
- 2013-000646-18
First Posted:
Feb 28, 2014
Last Update Posted:
Aug 13, 2015
Last Verified:
Jul 1, 2015
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | 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. |
|---|---|
| Pre-assignment Detail | 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. |
| Arm/Group Title | Treatment ABC | Treatment ACB | Treatment BAC | Treatment BCA | Treatment CAB | Treatment CBA |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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 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 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 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 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 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. |
| Period Title: Overall Study | ||||||
| STARTED | 3 | 3 | 2 | 2 | 3 | 2 |
| COMPLETED | 3 | 3 | 2 | 2 | 3 | 2 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | All Treated Participants |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 15 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
33.1
(7.00)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
2
13.3%
|
| Male |
13
86.7%
|
| Race/Ethnicity, Customized (participants) [Number] | |
| White |
14
93.3%
|
| Black/African American |
1
6.7%
|
| Region of Enrollment (participants) [Number] | |
| Germany |
15
100%
|
| Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [kg/m^2] |
24.5
(2.50)
|
| Weight (kilograms) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [kilograms] |
76.5
(7.96)
|
Outcome Measures
| Title | 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 |
|---|---|
| Description | 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). |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Mean (95% Confidence Interval) [nM*min] |
95.8
|
521.0
|
186.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | The ETP change from pre-PCC baseline was analyzed using a mixed effect model that included treatment, sequence, and period as main effects. A hierarchical analysis was conducted with comparisons beginning with the primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 425.3 | |
| Confidence Interval |
(2-Sided) 95% 219.8 to 630.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.131 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for any secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 90.6 | |
| Confidence Interval |
(2-Sided) 95% -31.3 to 212.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| TGA Lag Time (n=15, 14, 15) |
-0.16
|
-0.38
|
-0.32
|
| TGA Time to Peak (n=15, 14, 15) |
-1.29
|
0.06
|
3.32
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | TGA Lag Time. ETP change from pre-PCC baseline was analyzed using a mixed effect model that included treatment, sequence, and period as main effects. A hierarchical analysis was conducted with comparisons beginning with the primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.389 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for other secondary endpoints since a non-significant treatment difference was observed for this first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -0.21 | |
| Confidence Interval |
(2-Sided) 95% -0.73 to 0.30 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | Lag Time. ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.142 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -0.16 | |
| Confidence Interval |
(2-Sided) 95% -0.38 to 0.06 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | Time to Peak. ETP change from pre-PCC baseline was analyzed using a mixed effect model that included treatment, sequence, and period as main effects. A hierarchical analysis was conducted with comparisons beginning with the primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.200 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 1.35 | |
| Confidence Interval |
(2-Sided) 95% -0.81 to 3.52 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | Time to Peak. ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 4.62 | |
| Confidence Interval |
(2-Sided) 95% 2.80 to 6.44 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
| Title | 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 |
|---|---|
| Description | 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). |
| Time Frame | Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Mean (95% Confidence Interval) [nM] |
11.1
|
32.1
|
4.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | The ETP change from pre-PCC baseline was analyzed using a mixed effect model that included treatment, sequence, and period as main effects. A hierarchical analysis was conducted with comparisons beginning with the primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.014 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 21.1 | |
| Confidence Interval |
(2-Sided) 95% 4.9 to 37.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.076 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -6.4 | |
| Confidence Interval |
(2-Sided) 95% -13.5 to 0.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
| Title | 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 |
|---|---|
| Description | 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). |
| Time Frame | Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Mean (95% Confidence Interval) [nM/min] |
3.4
|
3.4
|
-3.2
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | The ETP change from pre-PCC baseline was analyzed using a mixed effect model that included treatment, sequence, and period as main effects. A hierarchical analysis was conducted with comparisons beginning with the primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.996 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -5.6 to 5.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -6.5 | |
| Confidence Interval |
(2-Sided) 95% -9.5 to -3.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| PT (Neoplastin CI+) (n=15, 14, 15) |
-0.21
|
-1.85
|
-1.68
|
| PT (Recombiplastin 2G) (n=15, 14, 15) |
0.35
|
-2.24
|
-1.54
|
| aPTT (n=15, 14, 15) |
1.13
|
9.60
|
3.43
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | PT (Neoplastin CI+). ETP change from pre-PCC baseline was analyzed using mixed effect model that included treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -1.64 | |
| Confidence Interval |
(2-Sided) 95% -2.16 to -1.12 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | PT (Neoplastin CI+). ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -1.47 | |
| Confidence Interval |
(2-Sided) 95% -1.95 to -0.99 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | PT (Recombiplastin 2G). ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -2.59 | |
| Confidence Interval |
(2-Sided) 95% -3.30 to -1.89 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | PT (Recombiplastin 2G). ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -1.89 | |
| Confidence Interval |
(2-Sided) 95% -2.59 to -1.20 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | aPTT. The ETP change from pre-PCC baseline was analyzed using a mixed effect model and included treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 8.47 | |
| Confidence Interval |
(2-Sided) 95% 6.29 to 10.66 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | aPTT. ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 2.30 | |
| Confidence Interval |
(2-Sided) 95% 1.28 to 3.32 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| INR (Neoplastin CI+) (n=15, 14, 15) |
-0.015
|
-0.213
|
-0.185
|
| INR (Recombiplastin 2G) (n=15, 14, 15) |
0.032
|
-0.207
|
-0.144
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | INR (Neoplastin CI+). ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -0.198 | |
| Confidence Interval |
(2-Sided) 95% -0.266 to -0.130 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | INR (Neoplastin CI+). ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -0.170 | |
| Confidence Interval |
(2-Sided) 95% -0.229 to -0.111 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | INR (Recombiplastin 2G). ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -0.239 | |
| Confidence Interval |
(2-Sided) 95% -0.305 to -0.173 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | INR (Recombiplastin 2G). ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | -0.176 | |
| Confidence Interval |
(2-Sided) 95% -0.242 to -0.110 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Mean (95% Confidence Interval) [U/mL] |
-0.368
|
-0.607
|
-0.538
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | Anti-Xa Activity. ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.204 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the first secondary endpoint (TGA lag time). | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect models |
| Estimated Value | -0.239 | |
| Confidence Interval |
(2-Sided) 95% -0.625 to 0.146 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | Anti-Xa Activity. ETP change from pre-PCC baseline was analyzed using mixed effect model, including treatment, sequence, and period as main effects. Hierarchical analysis was conducted with comparisons beginning with primary endpoint and continuing through secondary endpoints (ETP; TGA lag time; TGA time to peak; TGA peak; TGA velocity index; PT; INR; aPTT; AXA). If resulting p-value was < 0.05, then the next comparison of interest was made until p>0.05 at which point, comparisons ended. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.114 |
| Comments | In the hierarchical analysis, no statistical inferences were drawn from the analysis results for this secondary endpoint since a non-significant treatment difference was observed for the primary endpoint. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect models |
| Estimated Value | -0.170 | |
| Confidence Interval |
(2-Sided) 95% -0.389 to 0.048 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| TGA Lag Time (n=15,14,15) |
3.56
|
3.36
|
3.40
|
| TGA Time to Peak (n=15,14,15) |
6.42
|
7.90
|
10.81
|
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Mean (95% Confidence Interval) [nM] |
-196.1
|
-174.9
|
-202.7
|
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Mean (95% Confidence Interval) [nM/min] |
-63.7
|
-63.6
|
-71.5
|
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 1 pre-dose apixaban (pre-apixaban Baseline), Day 4 at 30 minutes post infusion (PCC or Placebo) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Mean (95% Confidence Interval) [nM*minute] |
-708.0
|
-276.3
|
-607.7
|
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| PT (Neoplastin CI+) (n=15,14,15) |
2.74
|
1.17
|
1.31
|
| PT (Recombiplastin 2G) (n=15,14,15) |
4.94
|
2.30
|
3.01
|
| aPTT (n=15, 14, 15) |
7.49
|
15.87
|
9.68
|
| Title | 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 |
|---|---|
| Description | 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 |
| Time Frame | Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| INR (Neoplastin CI+) (n=15,14,15) |
0.290
|
0.103
|
0.130
|
| INR (Recombiplastin 2G) (n=15,14,15) |
0.460
|
0.216
|
0.281
|
| Title | Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban on Day 4 |
|---|---|
| Description | 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). |
| Time Frame | Day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
291
(23)
|
310
(29)
|
290
(28)
|
| Title | Geometric Mean Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban on Day 4 |
|---|---|
| Description | 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. |
| Time Frame | Day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Median (Full Range) [hours] |
2.00
|
2.00
|
2.00
|
| Title | Geometric Mean Area Under the Plasma Concentration-Time Curve in One Dosing Interval [AUC(0-12)] of Apixaban on Day 4 |
|---|---|
| Description | 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) |
| Time Frame | Day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
1965
(22)
|
2046
(26)
|
2010
(26)
|
| Title | Adjusted Geometric Mean AUC (0-12) of Apixaban on Day 4 |
|---|---|
| Description | 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. |
| Time Frame | Day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Geometric Mean (90% Confidence Interval) [ng*h/mL] |
1972
|
2049
|
2014
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | Analysis used a linear mixed effect model including treatment, period, and sequence as fixed effects and within-participant measurements as repeated measures. Point estimates and 90% confidence intervals (CIs) for differences on the log scale were exponentiated to obtain estimates for ratios of geometric means on the original scale between each PCC treatment and placebo (ie, Treatment B versus Treatment A, and Treatment C versus Treatment A). No adjustment was made for multiplicity. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 1.039 | |
| Confidence Interval |
(2-Sided) 90% 0.972 to 1.111 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | Analysis used a linear mixed effect model including treatment, period, and sequence as fixed effects and within-participant measurements as repeated measures. Point estimates and 90% confidence intervals (CIs) for differences on the log scale were exponentiated to obtain estimates for ratios of geometric means on the original scale between each PCC treatment and placebo (ie, Treatment C versus Treatment A). No adjustment was made for multiplicity. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 1.021 | |
| Confidence Interval |
(2-Sided) 90% 0.938 to 1.112 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
2537
(23)
|
2583
(27)
|
2585
(28)
|
| Title | Adjusted Geometric Mean AUC (0-24) for Apixaban on Day 4 |
|---|---|
| Description | 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. |
| Time Frame | Day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Geometric Mean (90% Confidence Interval) [ng*h/mL] |
2546
|
2594
|
2592
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment B: Apixaban + Cofact (4-Factor PCC) |
|---|---|---|
| Comments | Analysis used a linear mixed effect model including treatment, period, and sequence as fixed effects and within-participant measurements as repeated measures. Point estimates and 90% confidence intervals (CIs) for differences on the log scale were exponentiated to obtain estimates for ratios of geometric means on the original scale between each PCC treatment and placebo (ie, Treatment B versus Treatment A). No adjustment was made for multiplicity. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 1.019 | |
| Confidence Interval |
(2-Sided) 90% 0.955 to 1.087 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment B versus Treatment A | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Treatment A: Apixaban + Placebo, Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|
| Comments | Analysis used a linear mixed effect model including treatment, period, and sequence as fixed effects and within-participant measurements as repeated measures. Point estimates and 90% confidence intervals (CIs) for differences on the log scale were exponentiated to obtain estimates for ratios of geometric means on the original scale between each PCC treatment and placebo (ie, Treatment C versus Treatment A). No adjustment was made for multiplicity. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | mixed effect model |
| Estimated Value | 1.018 | |
| Confidence Interval |
(2-Sided) 90% 0.940 to 1.102 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Treatment C versus Treatment A | |
| Title | Geometric Mean Trough Observed Plasma Concentration at the End of One Dosing Interval (12h) [Cmin] of Apixaban on Day 4 |
|---|---|
| Description | 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). |
| Time Frame | Day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
86.0
(26)
|
93.7
(37)
|
95.5
(39)
|
| Title | Mean Terminal Elimination Half-Life (T-HALF) of Apixaban on Day 4 |
|---|---|
| Description | 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 |
| Time Frame | Day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 14 | 15 |
| Mean (Standard Deviation) [hours] |
10.9
(2.49)
|
10.8
(2.95)
|
11.0
(1.87)
|
| Title | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population |
|---|---|
| Description | 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. |
| Time Frame | Day 1 to 30 days Post Last Dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Treated population: All participants who received at least one dose of study medication were analyzed. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 15 | 15 |
| Adverse Events |
1
6.7%
|
5
NaN
|
2
NaN
|
| SAEs |
0
0%
|
0
NaN
|
0
NaN
|
| Discontinuation due to AEs |
0
0%
|
0
NaN
|
0
NaN
|
| Death |
0
0%
|
0
NaN
|
0
NaN
|
| Title | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population |
|---|---|
| Description | 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. |
| Time Frame | Day 1 (first dose) to Day of Study Discharge (Day 11 of Treatment Period 3) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants who received any study medication and had available laboratory test data were analyzed. n=number of participants evaluated. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 15 | 15 |
| Leukocytes High (n=15,15,15) |
0
0%
|
1
NaN
|
0
NaN
|
| ALT High (n=15,15,15) |
1
6.7%
|
1
NaN
|
0
NaN
|
| Bilirubin Direct High (n=4,4,4) |
2
13.3%
|
2
NaN
|
2
NaN
|
| Bilirubin Total High (n=15,15,15) |
2
13.3%
|
1
NaN
|
2
NaN
|
| Blood in Urine (n=15,15,15) |
1
6.7%
|
1
NaN
|
2
NaN
|
| Red Blood Cells in Urine (n=5,7,6) |
1
6.7%
|
0
NaN
|
0
NaN
|
| White Blood Cells in Urine (n=5,7,6) |
0
0%
|
2
NaN
|
0
NaN
|
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Day -1 first treatment period, Days 4 and 7 each treatment period |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 15 | 15 |
| PR >200 msec (n=15,15,15) |
0
0%
|
0
NaN
|
0
NaN
|
| QRS > 120 msec (n=15,15,15) |
0
0%
|
0
NaN
|
0
NaN
|
| QT > 500 msec (n=15,15,15) |
0
0%
|
0
NaN
|
0
NaN
|
| QTcF > 450 msec (n=15,15,15) |
0
0%
|
0
NaN
|
0
NaN
|
| Change from Baseline >30 msec in QT (n=15,15,15) |
3
20%
|
2
NaN
|
3
NaN
|
| Change from Baseline >30 msec in QTcF (n=15,15,15) |
0
0%
|
0
NaN
|
0
NaN
|
| Title | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 |
|---|---|
| Description | 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. |
| Time Frame | Screening, Day -1 first treatment period, Days 4 and 7 post treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| Those participants who received any study medication and had blood pressure data at baseline and post baseline were analyzed. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 15 | 15 |
| Systolic BP Day 4 (n=15,15,15) |
0.9
(8.43)
|
-2.1
(10.67)
|
-2.9
(10.22)
|
| Systolic BP Day 7 (n=15,15,15) |
2.1
(8.03)
|
3.7
(8.46)
|
1.3
(8.87)
|
| Diastolic BP Day 4 (n=15,15,15) |
-2.1
(6.64)
|
-3.3
(6.76)
|
-3.1
(5.70)
|
| Diastolic BP Day 7 (n=15,15,15) |
-0.1
(8.34)
|
0.0
(7.43)
|
-0.1
(6.58)
|
| Title | Mean Change From Baseline in Heart Rate on Day 4 and Day 7 |
|---|---|
| Description | 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. |
| Time Frame | Screening, Day -1 first treatment period, Days 4 and 7 post treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| Those participants who received any study medication and had heart rate data at baseline and post baseline were analyzed. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 15 | 15 |
| Heart Rate Day 4 (n=15,15,15) |
-4.3
(12.10)
|
-4.9
(11.46)
|
-5.5
(9.91)
|
| Heart Rate Day 7 (n=15,15,15) |
-1.8
(10.09)
|
0.4
(10.73)
|
-2.1
(10.17)
|
| Title | Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 |
|---|---|
| Description | 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. |
| Time Frame | Screening, Day -1 first treatment period, Days 4 and 7 post treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| Those participants who received any study medication and had respiration rate data at baseline and post baseline were analyzed. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 15 | 15 |
| Respirate Rate Day 4 (n=15,15,15) |
-0.7
(2.58)
|
-1.3
(1.87)
|
-1.4
(2.41)
|
| Respirate Rate Day 7 (n=15,15,15) |
-0.4
(2.20)
|
-0.3
(2.41)
|
-0.5
(2.90)
|
| Title | Mean Change From Baseline Temperature on Day 4 and Day 7 |
|---|---|
| Description | 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. |
| Time Frame | Screening, Day -1 first treatment period, Days 4 and 7 post treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| Those participants who received any study medication and had temperature data at baseline and post baseline were analyzed. |
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) |
|---|---|---|---|
| Arm/Group Description | 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): 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): 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. |
| Measure Participants | 15 | 15 | 15 |
| Temperature Day 4 (n=15,15,15) |
-0.15
(0.432)
|
-0.14
(0.350)
|
-0.22
(0.399)
|
| Temperature Day 7 (n=15,15,15) |
-0.20
(0.321)
|
-0.08
(0.328)
|
-0.17
(0.418)
|
Adverse Events
| Time Frame | Day 1 to 30 days post last dose. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Study initiated February 2014 and completed April 2014 | |||||
| Arm/Group Title | Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | |||
| Arm/Group Description | 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): 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): 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. | |||
All Cause Mortality |
||||||
| Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/15 (0%) | 0/15 (0%) | 0/15 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Treatment A: Apixaban + Placebo | Treatment B: Apixaban + Cofact (4-Factor PCC) | Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/15 (6.7%) | 5/15 (33.3%) | 2/15 (13.3%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal Pain | 0/15 (0%) | 0/15 (0%) | 2/15 (13.3%) | |||
| Flatulence | 0/15 (0%) | 1/15 (6.7%) | 0/15 (0%) | |||
| Infections and infestations | ||||||
| Nasopharyngitis | 0/15 (0%) | 2/15 (13.3%) | 0/15 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Traumatic Hematoma | 1/15 (6.7%) | 0/15 (0%) | 0/15 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Myalgia | 0/15 (0%) | 1/15 (6.7%) | 0/15 (0%) | |||
| Nervous system disorders | ||||||
| Dizziness | 0/15 (0%) | 1/15 (6.7%) | 0/15 (0%) | |||
| Headache | 0/15 (0%) | 1/15 (6.7%) | 0/15 (0%) | |||
| Psychiatric disorders | ||||||
| Nightmare | 0/15 (0%) | 1/15 (6.7%) | 0/15 (0%) | |||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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.
Results Point of Contact
| Name/Title | Bristol-Myers Squibb Study Director |
|---|---|
| Organization | Bristol-Myers Squibb |
| Phone | |
| Clinical.Trials@bms.com |
Responsible Party:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT02074358
Other Study ID Numbers:
- CV185-156
- 2013-000646-18
First Posted:
Feb 28, 2014
Last Update Posted:
Aug 13, 2015
Last Verified:
Jul 1, 2015