A Study to Assess the Effects of 2 Prothrombin Complex Concentrates on the Pharmacodynamics of Apixaban in Healthy Adult Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 43
- 主要终点
- 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
研究概览
简要总结
The purpose of this study is to assess the effect of two 4-Factor PCC formulations on Apixaban pharmacodynamics in healthy adult subjects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Treatment A: Apixaban + Placebo (Saline solution)
Apixaban 10 mg Tablet orally [Day 1-Day 3: twice daily (BID), Day 4: Single Dose (SD)] followed 3hr later by Saline solution (placebo) 0 IU/kg infusion for 30 min Intravenously
干预措施: Placebo (Saline solution) (Drug)
Treatment B: Apixaban + Cofact (4-Factor PCC)
Apixaban 10 mg Tablet orally [Day 1-Day 3: twice daily (BID), Day 4: Single Dose (SD)] followed 3hr later by a Cofact (4-Factor PCC) 50 IU/kg infusion for 30 min Intravenously
干预措施: Cofact (4-Factor PCC) (Drug)
Treatment C: Apixaban + Beriplex P/N (4-Factor PCC)
Apixaban 10 mg Tablet orally [Day 1-Day 3: twice daily (BID), Day 4: Single Dose (SD)] followed 3hr later by a Beriplex P/N (4-Factor PCC) 50 IU/kg infusion for 30 min Intravenously
干预措施: Beriplex P/N (4-Factor PCC) (Drug)
Treatment A: Apixaban + Placebo (Saline solution)
Apixaban 10 mg Tablet orally [Day 1-Day 3: twice daily (BID), Day 4: Single Dose (SD)] followed 3hr later by Saline solution (placebo) 0 IU/kg infusion for 30 min Intravenously
干预措施: Apixaban (Drug)
Treatment C: Apixaban + Beriplex P/N (4-Factor PCC)
Apixaban 10 mg Tablet orally [Day 1-Day 3: twice daily (BID), Day 4: Single Dose (SD)] followed 3hr later by a Beriplex P/N (4-Factor PCC) 50 IU/kg infusion for 30 min Intravenously
干预措施: Apixaban (Drug)
Treatment B: Apixaban + Cofact (4-Factor PCC)
Apixaban 10 mg Tablet orally [Day 1-Day 3: twice daily (BID), Day 4: Single Dose (SD)] followed 3hr later by a Cofact (4-Factor PCC) 50 IU/kg infusion for 30 min Intravenously
干预措施: Apixaban (Drug)
结局指标
主要结局
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
时间窗: 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
时间窗: 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.
次要结局
- PD Parameters: Adjusted Mean Change in TGA Lag Time and Adjusted Mean Change in TGA Time to Peak From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo(Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.)
- PD Parameter: Adjusted Mean Change in TGA Peak Height From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo(Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.)
- PD Parameter: Adjusted Mean Change in TGA Velocity Index From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo(Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.)
- PD Parameter: Adjusted Mean Change in Coagulation Parameters Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo(Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.)
- PD Parameter: Adjusted Mean Change in Coagulation Parameter International Normalized Ratio (INR) From Day 4 Pre-Infusion (PCC or Placebo) Baseline at Day 4, 30 Minutes Post Infusion of PCC or Placebo(Day 4 at 3 hours post apixaban dose and prior to infusion (Pre-infusion Baseline), Day 4 at 30 minutes post infusion.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban on Day 4(Day 4)
- Geometric Mean Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban on Day 4(Day 4)
- Adjusted Geometric Mean AUC (0-12) of Apixaban on Day 4(Day 4)
- Geometric Mean Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours After Dose Administration [AUC(0-24)] of Apixaban on Day 4(Day 4)
- Adjusted Geometric Mean AUC (0-24) for Apixaban on Day 4(Day 4)
- Geometric Mean Area Under the Plasma Concentration-Time Curve in One Dosing Interval [AUC(0-12)] of Apixaban on Day 4(Day 4)
- Geometric Mean Trough Observed Plasma Concentration at the End of One Dosing Interval (12h) [Cmin] of Apixaban on Day 4(Day 4)
- Mean Terminal Elimination Half-Life (T-HALF) of Apixaban on Day 4(Day 4)
- 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)
- 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))
- 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)
- 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)
- 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)
- 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)
- Mean Change From Baseline Temperature on Day 4 and Day 7(Screening, Day -1 first treatment period, Days 4 and 7 post treatment)