A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of 3K3A-APC, a Recombinant Variant of Human Activated Protein C (APC), in Healthy Adult Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 64
- 试验地点
- 1
- 主要终点
- Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in Protocol.
研究概览
简要总结
The purpose of this study is to evaluate the safety and pharmacokinetic profile of single and multiple ascending intravenous doses of 3K3A-APC in healthy adult subjects aged 18-55 years.
详细描述
This is a single-center, sequential-cohort, double-blind, placebo-controlled, single- and multiple-ascending dose study. Eligible adult subjects will be assigned sequentially to 1 of 10 cohorts, at successively higher single doses, followed by successively higher multiple doses.
Single IV Doses: 5 subjects per cohort, aged 18-55, will be randomized in a 4:1 manner to receive active drug (6, 30, 90, 180, 360, and TBD µg/kg) or to receive matching placebo (Cohorts 1-6).
Multiple IV Doses: 8 subjects per cohort, aged 18-55, will be randomized in a 3:1 manner to receive active drug (90, 180, 360, and TBD µg/kg) or to receive matching placebo every 12 hours for 5 doses (Cohorts 7-10).
Single-Dose Cohorts Subjects receiving a single dose will be confined in a Phase 1 unit for 12 hours prior to dosing, during dosing, and for 24 hours after dosing (Study Day 1-2) for observation and PK sampling. Subjects will return on Study Day 4 (~72 hours after infusion) and Study Day 15 for additional safety evaluations. A 28-Day follow-up phone call will be made to subjects to collect AEs that occur within 28-days of the dose.
Multiple-Dose Cohorts Subjects receiving multiple doses will be confined in a Phase 1 unit for 12 hours prior to dosing through 24 hours following the last dose (Study Day 1-4) for observation and PK sampling. Subjects will return on Study Day 6 (~72 hours after last infusion) and Study Day 15 for additional safety evaluations. A 28-Day follow-up phone call will be made to subjects to collect AEs that occur within 28-days of the last dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy males or non-pregnant, non-lactating females
- •Both men and women of child-bearing potential (i.e., not surgically sterile or post-menopausal defined as age > 40 years without menses for ≥ 2 years) must agree to use a barrier method of contraception plus a spermicide throughout the study.
- •Age 18 to 55 years, inclusive
- •Body Mass Index (BMI) of 19 to 30 kg/m2, inclusive (see APPENDIX B)
- •Willing and able to complete all study visits
- •Agreement to abstain from smoking and drinking alcoholic beverages from 48 hours prior to randomization through last Study Day (15)
- •Signed informed consent form (ICF)
排除标准
- •Any medical problem for which the subject is being evaluated and/or treated
- •Activated partial thromboplastin time (aPTT) greater than upper limit of normal (ULN)
- •Platelet count < 125,000 cells/mm3
- •International Normalized Ratio (INR) > 1.3
- •Any other clinically significant abnormalities in laboratory values (chemistries, hematology, coagulation studies, and urinalysis - see APPENDIX C)
- •Clinically significant abnormalities on electrocardiogram (ECG)
- •Positive serum βHCG pregnancy test at screening or on Study Day -1 (for all women, regardless of child-bearing potential)
- •Positive urine drug screen at screening or on Study Day -1 (see APPENDIX C)
- •Positive blood test for hepatitis B surface antigen, hepatitis C antibody, or HIV antibody
- •Known family history of bleeding or blood clotting disorders
- •History of bleeding diathesis
- •History of liver disease with ongoing coagulopathy
- •Use of any prescription or non-prescription medications or supplements within 7 days prior to Study Day -1, excluding hormonal contraceptives
- •Use of anticoagulant medication within 14 days prior to Study Day -1
- •Major surgery within 60 days prior to Study Day -1
- •Receipt of an investigational drug within 30 days prior to Study Day -1
- •Donation of blood or plasma within 30 days prior to Study Day -1
- •Any other condition, that in the opinion of the Site Investigator, may adversely affect the safety of the subject, the subject's ability to complete the study, or the outcome of the study
研究组 & 干预措施
6 µg/kg 3K3A-APC, single-dose
Cohort 1: 6 µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 20 mL IV infusion over 15 minutes
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
30 µg/kg 3K3A-APC, single-dose
Cohort 2: 30 µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 100 mL IV infusion over 15 minutes
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
90 µg/kg 3K3A-APC, single-dose
Cohort 3: 90 µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 100 mL IV infusion over 15 minutes
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
180 µg/kg 3K3A-APC, single-dose
Cohort 4: 180 µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 100 mL IV infusion over 15 minutes
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
360 µg/kg 3K3A-APC, single-dose
Cohort 5: 360 µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 100 mL IV infusion over 15 minutes
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
TBD µg/kg 3K3A-APC, single-dose
Cohort 6: TBD (not to exceed 720) µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 100 mL IV infusion over 15 minutes
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
90 µg/kg 3K3A-APC, q12h for 5 doses
Cohort 7: 90 µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 100 mL IV infusion over 15 minutes; given every 12 hours for 5 doses
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
180 µg/kg 3K3A-APC, q12h for 5 doses
Cohort 8: 180 µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 100 mL IV infusion over 15 minutes; given every 12 hours for 5 doses
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
360 µg/kg 3K3A-APC, q12h for 5 doses
Cohort 9: 360 µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 100 mL IV infusion over 15 minutes; given every 12 hours for 5 doses
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
TBD µg/kg 3K3A-APC, q12h for 5 doses
Cohort 10: TBD (not to exceed 720) µg/kg 3K3A-APC, diluted in 0.9% sodium chloride in water and administered as an 100 mL IV infusion over 15 minutes; given every 12 hours for 5 doses
干预措施: 3K3A-APC, diluted in 0.9% sodium chloride in water (Biological)
Matching Placebo, 0.9% NaCl in water
Cohorts 1-10: 0.9% sodium chloride in water and administered as either 20 mL IV infusion over 15 minutes (Cohort 1), or 100 mL IV infusion over 15 minutes (Cohorts 2-10)
干预措施: 0.9% NaCl in water (Drug)
结局指标
主要结局
Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in Protocol.
时间窗: Day 4 for single-dose cohorts
Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in the Protocol.
时间窗: Day 6 for multiple-dose cohorts
次要结局
- Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Non-compartmental Analysis(0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose)
- Area Under the Plasma Concentration-time Curve From Time 0 to Infinity [AUC(0-inf)] for 3K3A-APC by Non-compartmental Analysis(0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose)
- Total Clearance (CL) of 3K3A-APC by Non-compartmental Analysis(0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose)
- Volume of Distribution (V) of 3K3A-APC by Compartmental Analysis(0, 20 minutes and 1 hour post for doses 1 and 5)
- Area Under the Plasma Concentration-time Curve From Time 0 to the Final Time With a Concentration ≥ Limit of Quantitation [AUC(0-t)] for 3K3A-APC by Non-compartmental Analysis(0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose)
- Elimination Rate Constant (λz) for 3K3A-APC by Non-compartmental Analysis(0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose)
- Half-life (t1/2) of 3K3A-APC by Non-compartmental Analysis(0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose)
- Half-life (t1/2) of 3K3A-APC by Compartmental Analysis(0, 20 minutes and 1 hour post for doses 1 and 5)
- Total Clearance (CL) of 3K3A-APC by Compartmental Analysis(0, 20 minutes and 1 hour post for doses 1 and 5)
- Time at Which Cmax is Observed (Tmax) for 3K3A-APC by Non-compartmental Analysis(0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose)
- Volume of Distribution (Vz) of 3K3A-APC by Non-compartmental Analysis(0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose)
- Elimination Rate Constant (λz) for 3K3A-APC by Compartmental Analysis(0, 20 minutes and 1 hour post for doses 1 and 5)
- Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis(0, 20 minutes and 1 hour post for doses 1 and 5)
- Area Under the Plasma Concentration-time Curve From Time 0 to Infinity [AUC(0-inf)] for 3K3A-APC by Compartmental Analysis(0, 20 minutes and 1 hour post for doses 1 and 5)