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
Overview
- Phase
- Phase 1
- Intervention
- 3K3A-APC, diluted in 0.9% sodium chloride in water
- Conditions
- Healthy
- Sponsor
- ZZ Biotech, LLC
- Enrollment
- 64
- Locations
- 1
- Primary Endpoint
- Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in Protocol.
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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)
Exclusion Criteria
- •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
Arms & Interventions
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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
Intervention: 3K3A-APC, diluted in 0.9% sodium chloride in water
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)
Intervention: 0.9% NaCl in water
Outcomes
Primary Outcomes
Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in Protocol.
Time Frame: Day 4 for single-dose cohorts
Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in the Protocol.
Time Frame: Day 6 for multiple-dose cohorts
Secondary Outcomes
- 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)