Safety and Pharmacokinetics of Single and Multiple Ascending Doses of 3K3A-APC in Healthy Adult Volunteers

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
* Drug: 0.9% NaCl in water


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 6 µg/kg 3K3A-APC, single-dose<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Active Comparator: 30 µg/kg 3K3A-APC, single-dose<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Active Comparator: 90 µg/kg 3K3A-APC, single-dose<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Active Comparator: 180 µg/kg 3K3A-APC, single-dose<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Active Comparator: 360 µg/kg 3K3A-APC, single-dose<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Active Comparator: TBD µg/kg 3K3A-APC, single-dose<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Active Comparator: 90 µg/kg 3K3A-APC, q12h for 5 doses<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Active Comparator: 180 µg/kg 3K3A-APC, q12h for 5 doses<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Active Comparator: 360 µg/kg 3K3A-APC, q12h for 5 doses<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Active Comparator: TBD µg/kg 3K3A-APC, q12h for 5 doses<br>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 | Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water<br> <br> |
| Placebo Comparator: Matching Placebo, 0.9% NaCl in water<br>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) | Drug: 0.9% NaCl in water<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in Protocol. |  | Day 4 for single-dose cohorts | 
| Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in the Protocol. |  | Day 6 for multiple-dose cohorts | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Non-compartmental Analysis | Single-dose cohorts | 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose | 
| Time at Which Cmax is Observed (Tmax) for 3K3A-APC by Non-compartmental Analysis | Single-dose cohorts | 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 the Final Time With a Concentration ≥ Limit of Quantitation [AUC(0-t)] for 3K3A-APC by Non-compartmental Analysis | Single-dose cohorts | 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 | Single-dose cohorts | 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 | Single-dose cohorts | 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 | Single-dose cohorts | 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 | Single-dose cohorts | 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 | Single-dose cohorts | 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis | Single-dose cohorts | 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 Compartmental Analysis | Single-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 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 | Single-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 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 | Single-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 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 Compartmental Analysis | Single-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 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 | Single-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis | Multiple-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 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 | Multiple-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 0, 20 minutes and 1 hour post for doses 1 and 5 | 
| Elimination Rate Constant (λz) for 3K3A-APC by Compartmental Analysis | Multiple-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 0, 20 minutes and 1 hour post for doses 1 and 5 | 
| Half-life (t1/2) of 3K3A-APC by Compartmental Analysis | Multiple-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 0, 20 minutes and 1 hour post for doses 1 and 5 | 
| Total Clearance (CL) of 3K3A-APC by Compartmental Analysis | Multiple-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 0, 20 minutes and 1 hour post for doses 1 and 5 | 
| Volume of Distribution (V) of 3K3A-APC by Compartmental Analysis | Multiple-dose cohorts; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters. | 0, 20 minutes and 1 hour post for doses 1 and 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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APC, 3K3A, 3K3A-APC, volunteer, healthy