Anticoagulation
Conditions
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.
Interventions
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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) |
| 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). |
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| All Treated Participants Treated population included all participants who received at least one dose of study medication. Participants received 10 mg apixaban BID on Days 1-3 and on Day 4 received a single dose of 10 mg apixaban followed 3 hours later by an IV infusion of 50 IU/kg prothrombin complex concentrate (PCC) (which was either Cofact or Beriplex P/N) or the participant received an IV infusion of placebo (saline solution). Participants were randomized on Day 1 to one of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB and CBA). There were 3 treatment periods with a total of 3 participants in each of 3 sequences (ABC, ACB, CAB) and 2 participants in each of 3 other sequences (CBA, BAC, BCA) for a total of 15 participants who participated in this open label, randomized, crossover study. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | All Treated Participants |
|---|---|
| Age, Continuous | 33.1 years STANDARD_DEVIATION 7 |
| Body Mass Index (BMI) | 24.5 kg/m^2 STANDARD_DEVIATION 2.5 |
| Race/Ethnicity, Customized Black/African American | 1 participants |
| Race/Ethnicity, Customized White | 14 participants |
| Region of Enrollment Germany | 15 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 13 Participants |
| Weight | 76.5 kilograms STANDARD_DEVIATION 7.96 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 15 | 5 / 15 | 2 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
PD Parameter: Adjusted Mean Change in Endogenous Thrombin Potential (ETP) From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
ETP was evaluated using a Thrombin Generation Assay (TGA), a validated automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids. Thrombin concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample. A dedicated software program (Thrombinoscope, Thrombinoscope B.V., Maastricht, The Netherlands) performed the calculations and derived ETP as area under the curve from the resulting thrombogram curve. Pre-dose Apixaban baseline was Day 1 pre-dose (0 hour). Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period.
Time frame: Day 1 pre-dose apixaban (pre-apixaban Baseline), Day 4 at 30 minutes post infusion (PCC or Placebo)
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Endogenous Thrombin Potential (ETP) From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | -708.0 nM*minute |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | 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 | -276.3 nM*minute |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | 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 | -607.7 nM*minute |
Primary
Pharmacodynamic (PD) Parameter: Adjusted Mean Change in Endogenous Thrombin Potential (ETP) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
ETP was evaluated using a Thrombin Generation Assay (TGA), a validated automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids. Thrombin concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample. Dedicated software (Thrombinoscope, Thrombinoscope B.V., Maastricht, The Netherlands) performed the calculations and derived ETP as area under the curve from the resulting thrombogram curve. Pre-infusion baseline= sample on Day 4, 3 hours post apixaban dose (just prior to IV infusion of PCC or placebo). Samples on Day 4 were obtained at 0 (pre-dose), 0.5, 1, 2, 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. ETP was measured as nanomolar\*minute (nM\*min).
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)
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | Pharmacodynamic (PD) Parameter: Adjusted Mean Change in Endogenous Thrombin Potential (ETP) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | 95.8 nM*min |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | 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 | 521.0 nM*min |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | 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 | 186.3 nM*min |
Comparison: 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.p-value: <0.00195% CI: [219.8, 630.7]Mixed Models Analysis
Comparison: 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.p-value: 0.13195% CI: [-31.3, 212.4]Mixed Models Analysis
Secondary
Adjusted Geometric Mean AUC (0-12) of Apixaban on Day 4
Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability.
Time frame: Day 4
Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | Adjusted Geometric Mean AUC (0-12) of Apixaban on Day 4 | 1972 ng*h/mL |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Adjusted Geometric Mean AUC (0-12) of Apixaban on Day 4 | 2049 ng*h/mL |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Adjusted Geometric Mean AUC (0-12) of Apixaban on Day 4 | 2014 ng*h/mL |
Comparison: 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.90% CI: [0.972, 1.111]
Comparison: 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.90% CI: [0.938, 1.112]
Secondary
Adjusted Geometric Mean AUC (0-24) for Apixaban on Day 4
Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability.
Time frame: Day 4
Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | Adjusted Geometric Mean AUC (0-24) for Apixaban on Day 4 | 2546 ng*h/mL |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Adjusted Geometric Mean AUC (0-24) for Apixaban on Day 4 | 2594 ng*h/mL |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Adjusted Geometric Mean AUC (0-24) for Apixaban on Day 4 | 2592 ng*h/mL |
Comparison: 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.90% CI: [0.955, 1.087]
Comparison: 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.90% CI: [0.94, 1.102]
Secondary
Geometric Mean Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours After Dose Administration [AUC(0-24)] of Apixaban on Day 4
Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. AUC(0-24) was measured in ng\*h/mL.
Time frame: Day 4
Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | Geometric Mean Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours After Dose Administration [AUC(0-24)] of Apixaban on Day 4 | 2537 ng*h/mL | Geometric Coefficient of Variation 23 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | 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 | 2583 ng*h/mL | Geometric Coefficient of Variation 27 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | 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 | 2585 ng*h/mL | Geometric Coefficient of Variation 28 |
Secondary
Geometric Mean Area Under the Plasma Concentration-Time Curve in One Dosing Interval [AUC(0-12)] of Apixaban on Day 4
Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. AUC(0-12) was measured in ng\*hours/mL (ng\*h/mL)
Time frame: Day 4
Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | Geometric Mean Area Under the Plasma Concentration-Time Curve in One Dosing Interval [AUC(0-12)] of Apixaban on Day 4 | 1965 ng*h/mL | Geometric Coefficient of Variation 22 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Geometric Mean Area Under the Plasma Concentration-Time Curve in One Dosing Interval [AUC(0-12)] of Apixaban on Day 4 | 2046 ng*h/mL | Geometric Coefficient of Variation 26 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Geometric Mean Area Under the Plasma Concentration-Time Curve in One Dosing Interval [AUC(0-12)] of Apixaban on Day 4 | 2010 ng*h/mL | Geometric Coefficient of Variation 26 |
Secondary
Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban on Day 4
Plasma samples for pharmacokinetic (PK) analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) assay within the period of known analyte stability. Cmax was measured in nanograms per milliliter (ng/mL).
Time frame: Day 4
Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban on Day 4 | 291 ng/mL | Geometric Coefficient of Variation 23 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban on Day 4 | 310 ng/mL | Geometric Coefficient of Variation 29 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban on Day 4 | 290 ng/mL | Geometric Coefficient of Variation 28 |
Secondary
Geometric Mean Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban on Day 4
Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. Tmax was measured in hours.
Time frame: Day 4
Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | Geometric Mean Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban on Day 4 | 2.00 hours |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Geometric Mean Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban on Day 4 | 2.00 hours |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Geometric Mean Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban on Day 4 | 2.00 hours |
Secondary
Geometric Mean Trough Observed Plasma Concentration at the End of One Dosing Interval (12h) [Cmin] of Apixaban on Day 4
Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. Cmin was measured in nanograms per milliliter (ng/mL).
Time frame: Day 4
Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | Geometric Mean Trough Observed Plasma Concentration at the End of One Dosing Interval (12h) [Cmin] of Apixaban on Day 4 | 86.0 ng/mL | Geometric Coefficient of Variation 26 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Geometric Mean Trough Observed Plasma Concentration at the End of One Dosing Interval (12h) [Cmin] of Apixaban on Day 4 | 93.7 ng/mL | Geometric Coefficient of Variation 37 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Geometric Mean Trough Observed Plasma Concentration at the End of One Dosing Interval (12h) [Cmin] of Apixaban on Day 4 | 95.5 ng/mL | Geometric Coefficient of Variation 39 |
Secondary
Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7
Blood pressures were recorded at screening, Day -1 of Period 1, and Days 4 and 7 of each period. Blood pressure was measured after the participant had been seated quietly for at least 5 minutes and was measured in millimeters of mercury (mmHg). Baseline was last non-missing result with a collection date-time less than the date-time of the first active dose.
Time frame: Screening, Day -1 first treatment period, Days 4 and 7 post treatment
Population: Those participants who received any study medication and had blood pressure data at baseline and post baseline were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A: Apixaban + Placebo | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Diastolic BP Day 4 (n=15,15,15) | -2.1 mmHg | Standard Deviation 6.64 |
| Treatment A: Apixaban + Placebo | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Diastolic BP Day 7 (n=15,15,15) | -0.1 mmHg | Standard Deviation 8.34 |
| Treatment A: Apixaban + Placebo | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Systolic BP Day 4 (n=15,15,15) | 0.9 mmHg | Standard Deviation 8.43 |
| Treatment A: Apixaban + Placebo | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Systolic BP Day 7 (n=15,15,15) | 2.1 mmHg | Standard Deviation 8.03 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Diastolic BP Day 4 (n=15,15,15) | -3.3 mmHg | Standard Deviation 6.76 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Systolic BP Day 7 (n=15,15,15) | 3.7 mmHg | Standard Deviation 8.46 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Diastolic BP Day 7 (n=15,15,15) | 0.0 mmHg | Standard Deviation 7.43 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Systolic BP Day 4 (n=15,15,15) | -2.1 mmHg | Standard Deviation 10.67 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Diastolic BP Day 7 (n=15,15,15) | -0.1 mmHg | Standard Deviation 6.58 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Systolic BP Day 4 (n=15,15,15) | -2.9 mmHg | Standard Deviation 10.22 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Systolic BP Day 7 (n=15,15,15) | 1.3 mmHg | Standard Deviation 8.87 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline in Diastolic and Systolic Blood Pressure on Day 4 and Day 7 | Diastolic BP Day 4 (n=15,15,15) | -3.1 mmHg | Standard Deviation 5.7 |
Secondary
Mean Change From Baseline in Heart Rate on Day 4 and Day 7
Heart Rate was recorded at screening, Day -1 of Period 1, and Days 4 and 7 of each period. Heart Rate was measured after the participant had been seated quietly for at least 5 minutes and was measured in beats per minute (bpm). Baseline was last non-missing result with a collection date-time less than the date-time of the first active dose.
Time frame: Screening, Day -1 first treatment period, Days 4 and 7 post treatment
Population: Those participants who received any study medication and had heart rate data at baseline and post baseline were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A: Apixaban + Placebo | Mean Change From Baseline in Heart Rate on Day 4 and Day 7 | Heart Rate Day 4 (n=15,15,15) | -4.3 bpm | Standard Deviation 12.1 |
| Treatment A: Apixaban + Placebo | Mean Change From Baseline in Heart Rate on Day 4 and Day 7 | Heart Rate Day 7 (n=15,15,15) | -1.8 bpm | Standard Deviation 10.09 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline in Heart Rate on Day 4 and Day 7 | Heart Rate Day 4 (n=15,15,15) | -4.9 bpm | Standard Deviation 11.46 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline in Heart Rate on Day 4 and Day 7 | Heart Rate Day 7 (n=15,15,15) | 0.4 bpm | Standard Deviation 10.73 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline in Heart Rate on Day 4 and Day 7 | Heart Rate Day 4 (n=15,15,15) | -5.5 bpm | Standard Deviation 9.91 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline in Heart Rate on Day 4 and Day 7 | Heart Rate Day 7 (n=15,15,15) | -2.1 bpm | Standard Deviation 10.17 |
Secondary
Mean Change From Baseline in Respiration Rate on Day 4 and Day 7
Respiration Rate was recorded at screening, Day -1 of Period 1, and Days 4 and 7 of each period. Respiration Rate was measured after the participant had been seated quietly for at least 5 minutes and was measured in respirations (breaths) per minute. Baseline was last non-missing result with a collection date-time less than the date-time of the first active dose.
Time frame: Screening, Day -1 first treatment period, Days 4 and 7 post treatment
Population: Those participants who received any study medication and had respiration rate data at baseline and post baseline were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A: Apixaban + Placebo | Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 | Respirate Rate Day 4 (n=15,15,15) | -0.7 breaths per minute | Standard Deviation 2.58 |
| Treatment A: Apixaban + Placebo | Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 | Respirate Rate Day 7 (n=15,15,15) | -0.4 breaths per minute | Standard Deviation 2.2 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 | Respirate Rate Day 4 (n=15,15,15) | -1.3 breaths per minute | Standard Deviation 1.87 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 | Respirate Rate Day 7 (n=15,15,15) | -0.3 breaths per minute | Standard Deviation 2.41 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 | Respirate Rate Day 4 (n=15,15,15) | -1.4 breaths per minute | Standard Deviation 2.41 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline in Respiration Rate on Day 4 and Day 7 | Respirate Rate Day 7 (n=15,15,15) | -0.5 breaths per minute | Standard Deviation 2.9 |
Secondary
Mean Change From Baseline Temperature on Day 4 and Day 7
Temperature was recorded at screening, Day -1 of Period 1, and Days 4 and 7 of each period and was measured in degrees centigrade (C). Baseline was last non-missing result with a collection date-time less than the date-time of the first active dose.
Time frame: Screening, Day -1 first treatment period, Days 4 and 7 post treatment
Population: Those participants who received any study medication and had temperature data at baseline and post baseline were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A: Apixaban + Placebo | Mean Change From Baseline Temperature on Day 4 and Day 7 | Temperature Day 4 (n=15,15,15) | -0.15 C | Standard Deviation 0.432 |
| Treatment A: Apixaban + Placebo | Mean Change From Baseline Temperature on Day 4 and Day 7 | Temperature Day 7 (n=15,15,15) | -0.20 C | Standard Deviation 0.321 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline Temperature on Day 4 and Day 7 | Temperature Day 4 (n=15,15,15) | -0.14 C | Standard Deviation 0.35 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Change From Baseline Temperature on Day 4 and Day 7 | Temperature Day 7 (n=15,15,15) | -0.08 C | Standard Deviation 0.328 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline Temperature on Day 4 and Day 7 | Temperature Day 4 (n=15,15,15) | -0.22 C | Standard Deviation 0.399 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Change From Baseline Temperature on Day 4 and Day 7 | Temperature Day 7 (n=15,15,15) | -0.17 C | Standard Deviation 0.418 |
Secondary
Mean Terminal Elimination Half-Life (T-HALF) of Apixaban on Day 4
Plasma samples for PK analysis were obtained on Day 4 at 0 hour (pre-dose), 0.5, 1, 2, and 3 hours post apixaban dose, and at 0.5, 1, 2, 4, 6, 9 hours post infusion (PCC or Placebo), and at 21, 45, and 69 hours post infusion (Days 5, 6, and 7) in each treatment period. PK parameters were derived from plasma concentration versus time. Concentration of apixaban was determined using a validated LC/MS/MS assay within the period of known analyte stability. T-HALF was measured in hours
Time frame: Day 4
Population: Those participants who received any study medication and had adequate PK profiles were included; 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | Mean Terminal Elimination Half-Life (T-HALF) of Apixaban on Day 4 | 10.9 hours | Standard Deviation 2.49 |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Mean Terminal Elimination Half-Life (T-HALF) of Apixaban on Day 4 | 10.8 hours | Standard Deviation 2.95 |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Mean Terminal Elimination Half-Life (T-HALF) of Apixaban on Day 4 | 11.0 hours | Standard Deviation 1.87 |
Secondary
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Medical Dictionary for Regulatory Activities (MedDRA) version 17.0 was used.
Time frame: Day 1 to 30 days Post Last Dose
Population: Treated population: All participants who received at least one dose of study medication were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | Adverse Events | 1 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | SAEs | 0 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | Discontinuation due to AEs | 0 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | Death | 0 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | Death | 0 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | Adverse Events | 5 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | Discontinuation due to AEs | 0 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | SAEs | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | Death | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | SAEs | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | Discontinuation due to AEs | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuation Due to AEs - Treatment Population | Adverse Events | 2 participants |
Secondary
Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population
Blood, urine samples obtained at screening, Days -1, 4, and 7 of each treatment period, and study discharge (Day 11 of Treatment Period 3). MA: Leukocyte White Blood Cells (WBC) \*10\^3 cells per microliter (c/µL); High (H): \> 1.2\*upper limits normal (ULN) if lower limits normal (LLN) \<= pre-therapy (PreRx) \<= ULN; \> 1.2\*ULN if PreRx = Missing; \> 1.5\*PreRx if PreRx \> ULN; \> ULN if PreRx \< LLN. Alanine Aminotransferase (ALT) units per liter (U/L); H: \> 1.25\*PreRx if PreRx \> ULN; \> 1.25\*ULN if PreRx \<= ULN; \> 1.25\*ULN if PreRx = Missing. Total and Direct Bilirubin in milligrams/deciliter (mg/dL) H: \> 1.1\*ULN if PreRx \<= ULN;\> 1.1\*ULN if PreRx = Missing; \> 1.25\*PreRx if PreRx \> ULN. Blood in Urine H: \>= 2\*PreRx if PreRx \>= 1; \>= 2 if PreRx \< 1; \>= 2 if PreRx = Missing. Urine Red Blood Cells (RBC) and Urine WBC/ high powered field (hpf) H: \>= 2 if PreRx = Missing; \>= 2 if PreRx \< 2; \>= 4 if PreRx \>= 2. Crossover study: same participant with MA could be reported in multiple arms.
Time frame: Day 1 (first dose) to Day of Study Discharge (Day 11 of Treatment Period 3)
Population: All participants who received any study medication and had available laboratory test data were analyzed. n=number of participants evaluated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | ALT High (n=15,15,15) | 1 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Blood in Urine (n=15,15,15) | 1 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Bilirubin Total High (n=15,15,15) | 2 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Leukocytes High (n=15,15,15) | 0 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | White Blood Cells in Urine (n=5,7,6) | 0 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Red Blood Cells in Urine (n=5,7,6) | 1 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Bilirubin Direct High (n=4,4,4) | 2 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Bilirubin Total High (n=15,15,15) | 1 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Leukocytes High (n=15,15,15) | 1 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | ALT High (n=15,15,15) | 1 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Bilirubin Direct High (n=4,4,4) | 2 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Blood in Urine (n=15,15,15) | 1 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Red Blood Cells in Urine (n=5,7,6) | 0 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | White Blood Cells in Urine (n=5,7,6) | 2 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Blood in Urine (n=15,15,15) | 2 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | ALT High (n=15,15,15) | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | White Blood Cells in Urine (n=5,7,6) | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Red Blood Cells in Urine (n=5,7,6) | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Bilirubin Total High (n=15,15,15) | 2 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Bilirubin Direct High (n=4,4,4) | 2 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Marked Abnormalities (MA) in Laboratory Tests - Treated Population | Leukocytes High (n=15,15,15) | 0 participants |
Secondary
Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF
Single 12-lead ECGs were obtained at screening, Day -1 of Period 1, and Days 4 and 7 of each treatment period after the participant had been supine for at least 5 minutes. Pulse Rate (PR), Complex of Q, R, S waves (QRS), and contraction of ventricle between the beginning of the Q wave and end of the T wave (QT) were measured in milliseconds (msec). QT was corrected by the Fridericia method (QTcF) and measured in msec. Baseline was Day -1 of first treatment period. Crossover study: same participant with out of range ECG intervals could be reported in multiple arms.
Time frame: Day -1 first treatment period, Days 4 and 7 each treatment period
Population: Those participants who received any study medication and had available ECG data at baseline and Days 4 and 7 in each treatment period were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | PR >200 msec (n=15,15,15) | 0 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | QRS > 120 msec (n=15,15,15) | 0 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | QT > 500 msec (n=15,15,15) | 0 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | QTcF > 450 msec (n=15,15,15) | 0 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | Change from Baseline >30 msec in QT (n=15,15,15) | 3 participants |
| Treatment A: Apixaban + Placebo | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | Change from Baseline >30 msec in QTcF (n=15,15,15) | 0 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | Change from Baseline >30 msec in QTcF (n=15,15,15) | 0 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | PR >200 msec (n=15,15,15) | 0 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | QTcF > 450 msec (n=15,15,15) | 0 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | Change from Baseline >30 msec in QT (n=15,15,15) | 2 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | QRS > 120 msec (n=15,15,15) | 0 participants |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | QT > 500 msec (n=15,15,15) | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | QRS > 120 msec (n=15,15,15) | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | QT > 500 msec (n=15,15,15) | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | Change from Baseline >30 msec in QTcF (n=15,15,15) | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | QTcF > 450 msec (n=15,15,15) | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | PR >200 msec (n=15,15,15) | 0 participants |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | Number of Participants With Out of Range Electrocardiogram (ECG) Intervals and Number of Participants With a Change From Baseline of Greater Than 30 Milliseconds in QT and QTcF | Change from Baseline >30 msec in QT (n=15,15,15) | 3 participants |
Secondary
PD Parameter: Adjusted Mean Change in Coagulation Parameter INR From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
Coagulation parameters were evaluated by Quintiles Laboratories Europe using an ACL TOP analyzer and Instrumentation Laboratory reagents \[HemosIL(Registered) Recombiplastin 2G for PT and Synthasil for aPTT\]. A second PT was also measured at Esoterix using a Diagnostica Stago STA Compact coagulation analyzer and Diagnostica Stago reagents STA-Neoplastin CI Plus (Registered). Baseline was Day 1, 0 hour pre-dose apixaban. Samples on Day 4 were obtained at 0 and 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. INR was measured as a fraction
Time frame: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameter INR From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Neoplastin CI+) (n=15,14,15) | 0.290 fraction |
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameter INR From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Recombiplastin 2G) (n=15,14,15) | 0.460 fraction |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameter INR From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Neoplastin CI+) (n=15,14,15) | 0.103 fraction |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameter INR From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Recombiplastin 2G) (n=15,14,15) | 0.216 fraction |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameter INR From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Neoplastin CI+) (n=15,14,15) | 0.130 fraction |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameter INR From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Recombiplastin 2G) (n=15,14,15) | 0.281 fraction |
Secondary
PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
Coagulation parameters were evaluated by Quintiles Laboratories Europe using an ACL TOP analyzer and Instrumentation Laboratory reagents \[HemosIL(Registered) Recombiplastin 2G for PT and Synthasil for aPTT\]. A second PT was also measured at Esoterix using a Diagnostica Stago STA Compact coagulation analyzer and Diagnostica Stago reagents STA-Neoplastin CI Plus (Registered). Samples on Day 4 were obtained at 0 and 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. INR was measured as a fraction.
Time frame: Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Neoplastin CI+) (n=15, 14, 15) | -0.015 fraction |
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Recombiplastin 2G) (n=15, 14, 15) | 0.032 fraction |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Neoplastin CI+) (n=15, 14, 15) | -0.213 fraction |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Recombiplastin 2G) (n=15, 14, 15) | -0.207 fraction |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Neoplastin CI+) (n=15, 14, 15) | -0.185 fraction |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | INR (Recombiplastin 2G) (n=15, 14, 15) | -0.144 fraction |
Comparison: 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.p-value: <0.00195% CI: [-0.266, -0.13]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [-0.229, -0.111]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [-0.305, -0.173]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [-0.242, -0.11]Mixed Models Analysis
Secondary
PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
Coagulation parameters were evaluated by Quintiles Laboratories Europe using an ACL TOP analyzer and Instrumentation Laboratory reagents \[HemosIL(Registered) Recombiplastin 2G for PT and Synthasil for aPTT\]. A second PT was also measured at Esoterix using a Diagnostica Stago STA Compact coagulation analyzer and Diagnostica Stago reagents STA-Neoplastin CI Plus (Registered). Samples on Day 4 were obtained at 0 and 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. PT (Neoplastin CT+), PT (Recombiplastin 2G) and activated partial thromboplastin time (aPTT) parameters were measured in seconds.
Time frame: Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Recombiplastin 2G) (n=15, 14, 15) | 0.35 seconds |
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Neoplastin CI+) (n=15, 14, 15) | -0.21 seconds |
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | aPTT (n=15, 14, 15) | 1.13 seconds |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Recombiplastin 2G) (n=15, 14, 15) | -2.24 seconds |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Neoplastin CI+) (n=15, 14, 15) | -1.85 seconds |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | aPTT (n=15, 14, 15) | 9.60 seconds |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Neoplastin CI+) (n=15, 14, 15) | -1.68 seconds |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | aPTT (n=15, 14, 15) | 3.43 seconds |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Recombiplastin 2G) (n=15, 14, 15) | -1.54 seconds |
Comparison: 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.p-value: <0.00195% CI: [-2.16, -1.12]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [-1.95, -0.99]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [-3.3, -1.89]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [-2.59, -1.2]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [6.29, 10.66]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [1.28, 3.32]Mixed Models Analysis
Secondary
PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
Coagulation parameters were evaluated by Quintiles Laboratories Europe using an ACL TOP analyzer and Instrumentation Laboratory reagents \[HemosIL(Registered) Recombiplastin 2G for PT and Synthasil for aPTT\]. A second PT was also measured at Esoterix using a Diagnostica Stago STA Compact coagulation analyzer and Diagnostica Stago reagents STA-Neoplastin CI Plus (Registered). Baseline was Day 1, pre-apixaban dose. Samples on Day 4 were obtained at 0 and 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period.
Time frame: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Recombiplastin 2G) (n=15,14,15) | 4.94 seconds |
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Neoplastin CI+) (n=15,14,15) | 2.74 seconds |
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | aPTT (n=15, 14, 15) | 7.49 seconds |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Recombiplastin 2G) (n=15,14,15) | 2.30 seconds |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Neoplastin CI+) (n=15,14,15) | 1.17 seconds |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | aPTT (n=15, 14, 15) | 15.87 seconds |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Neoplastin CI+) (n=15,14,15) | 1.31 seconds |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | aPTT (n=15, 14, 15) | 9.68 seconds |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Coagulation Parameters PT and aPTT From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | PT (Recombiplastin 2G) (n=15,14,15) | 3.01 seconds |
Secondary
PD Parameter: Adjusted Mean Change in Plasma Anti-Xa Activity From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
Anti-FXa activity was measured using a validated method at Esoterix Coagulation Laboratory (Englewood, CO) using the Diagnostica Stago Rotachrom (Registered) Heparin assay on a STA-Compact (Registered) analyzer. Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. The results of this chromogenic assay were reported in low molecular weight heparin (LMWH) activity units per milliliter (U/mL), which are equivalent to international units per milliliter (IU/mL) with assay reportable range: 0.1 to 18.4 IU/mL.
Time frame: Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in Plasma Anti-Xa Activity From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | -0.368 U/mL |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Plasma Anti-Xa Activity From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | -0.607 U/mL |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in Plasma Anti-Xa Activity From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | -0.538 U/mL |
Comparison: 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.p-value: 0.20495% CI: [-0.625, 0.146]Mixed Models Analysis
Comparison: 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.p-value: 0.11495% CI: [-0.389, 0.048]Mixed Models Analysis
Secondary
PD Parameter: Adjusted Mean Change in TGA Lag Time and TGA Time to Peak From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
TGA is a validated, automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids and the concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample; dedicated software program was Thrombinoscope, B.V., Maastricht, The Netherlands. Baseline was Day 1, 0 hour pre-dose apixaban. Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. TGA Lag Time and Time to Peak parameters were measured in minutes.
Time frame: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in TGA Lag Time and TGA Time to Peak From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Lag Time (n=15,14,15) | 3.56 minutes |
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in TGA Lag Time and TGA Time to Peak From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Time to Peak (n=15,14,15) | 6.42 minutes |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in TGA Lag Time and TGA Time to Peak From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Lag Time (n=15,14,15) | 3.36 minutes |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in TGA Lag Time and TGA Time to Peak From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Time to Peak (n=15,14,15) | 7.90 minutes |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in TGA Lag Time and TGA Time to Peak From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Lag Time (n=15,14,15) | 3.40 minutes |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in TGA Lag Time and TGA Time to Peak From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Time to Peak (n=15,14,15) | 10.81 minutes |
Secondary
PD Parameter: Adjusted Mean Change in TGA Peak Height From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
TGA is a validated, automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids and the concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample; dedicated software program was Thrombinoscope, B.V., Maastricht, The Netherlands. Baseline was Day 1, 0 hour pre-dose apixaban. Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. TGA Lag Time and Time to Peak parameters were measured in minutes.
Time frame: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in TGA Peak Height From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | -196.1 nM |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | 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 | -174.9 nM |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | 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 | -202.7 nM |
Secondary
PD Parameter: Adjusted Mean Change in TGA Peak Height From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
TGA is a validated automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids and the concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample; dedicated software program was Thrombinoscope, B.V., Maastricht, The Netherlands. Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. Peak height parameter was measured in nanomolar (nM).
Time frame: Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in TGA Peak Height From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | 11.1 nM |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | 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 | 32.1 nM |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | 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 | 4.7 nM |
Comparison: 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.p-value: 0.01495% CI: [4.9, 37.2]Mixed Models Analysis
Comparison: 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.p-value: 0.07695% CI: [-13.5, 0.8]Mixed Models Analysis
Secondary
PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
TGA is a validated, automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids and the concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample; dedicated software program was Thrombinoscope, B.V., Maastricht, The Netherlands. Baseline was Day 1, 0 hour (pre-dose apixaban). Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. TGA velocity index was measured in nM/min.
Time frame: Day 1, pre-dose apixaban (Baseline), Day 4, 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | -63.7 nM/min |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 1 Pre-Dose Apixaban Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | -63.6 nM/min |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | 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 | -71.5 nM/min |
Secondary
PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
TGA is a validated automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids and the concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample; dedicated software program was Thrombinoscope, B.V., Maastricht, The Netherlands. Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. TGA Velocity Index parameter was measured in nM per minute (nM/min).
Time frame: Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | 3.4 nM/min |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | 3.4 nM/min |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | -3.2 nM/min |
Comparison: 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.p-value: 0.99695% CI: [-5.6, 5.6]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [-9.5, -3.6]Mixed Models Analysis
Secondary
PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo
TGA is a validated automated ex vivo assay performed on platelet-poor plasma samples and based on the automated, calibrated thrombin generation method: thrombin formation was triggered with recombinant tissue factor and phospholipids and the concentration in each sample was calculated over time by measuring the cleavage of a fluorogenic substrate in the context of a paired calibration sample; dedicated software program was Thrombinoscope, B.V., Maastricht, The Netherlands. Samples on Day 4 were obtained at 0, 0.5, 1, 2, 3 hours post apixaban dose and at 0.5, 1, 2, 4, 6, 9, 21, 45, and 69 hours post infusion (PCC or Placebo) in each treatment period. Lag Time and Time to Peak parameters were measured in minutes.
Time frame: Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.
Population: PD Population included all participants who received any study medication and had PD data available for at least the analysis-specified baseline and 30 minutes after the start of the study drug infusion. 1 participant who received a partial PCC dose (approximately 2 IU/kg) was excluded from this summary analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A: Apixaban + Placebo | PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Lag Time (n=15, 14, 15) | -0.16 minutes |
| Treatment A: Apixaban + Placebo | PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Time to Peak (n=15, 14, 15) | -1.29 minutes |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Lag Time (n=15, 14, 15) | -0.38 minutes |
| Treatment B: Apixaban + Cofact (4-Factor PCC) | PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Time to Peak (n=15, 14, 15) | 0.06 minutes |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Lag Time (n=15, 14, 15) | -0.32 minutes |
| Treatment C: Apixaban + Beriplex P/N (4-Factor PCC) | PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo | TGA Time to Peak (n=15, 14, 15) | 3.32 minutes |
Comparison: 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.p-value: 0.38995% CI: [-0.73, 0.3]Mixed Models Analysis
Comparison: 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.p-value: 0.14295% CI: [-0.38, 0.06]Mixed Models Analysis
Comparison: 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.p-value: 0.295% CI: [-0.81, 3.52]Mixed Models Analysis
Comparison: 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.p-value: <0.00195% CI: [2.8, 6.44]Mixed Models Analysis