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

Phase 1

Completed

• Conditions: Healthy
• Interventions: Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water; Drug: 0.9% NaCl in water

• Registration Number: NCT01660230
• Lead Sponsor: ZZ Biotech, LLC

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.

Study Timeline

• Study First Submitted: 2012-07-25
• Study Start: 2012-08
• Study First Submitted QC: 2012-08-03
• Study First Posted: 2012-08-08
• Primary Completion: 2012-12
• Study Completion: 2012-12
• Results First Submitted: 2014-02-27
• Results First Submitted QC: 2014-02-27
• Results First Posted: 2014-04-10
• Status Verified: 2018-01
• Last Update Submitted: 2018-01-09
• Last Update Posted: 2018-02-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 64

Inclusion Criteria

1. Healthy males or non-pregnant, non-lactating females
2. 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.
3. Age 18 to 55 years, inclusive
4. Body Mass Index (BMI) of 19 to 30 kg/m2, inclusive (see APPENDIX B)
5. Willing and able to complete all study visits
6. Agreement to abstain from smoking and drinking alcoholic beverages from 48 hours prior to randomization through last Study Day (15)
7. Signed informed consent form (ICF)

Exclusion Criteria

1. Any medical problem for which the subject is being evaluated and/or treated
2. Activated partial thromboplastin time (aPTT) greater than upper limit of normal (ULN)
3. Platelet count < 125,000 cells/mm3
4. International Normalized Ratio (INR) > 1.3
5. Any other clinically significant abnormalities in laboratory values (chemistries, hematology, coagulation studies, and urinalysis - see APPENDIX C)
6. Clinically significant abnormalities on electrocardiogram (ECG)
7. Positive serum βHCG pregnancy test at screening or on Study Day -1 (for all women, regardless of child-bearing potential)
8. Positive urine drug screen at screening or on Study Day -1 (see APPENDIX C)
9. Positive blood test for hepatitis B surface antigen, hepatitis C antibody, or HIV antibody
10. Known family history of bleeding or blood clotting disorders
11. History of bleeding diathesis
12. History of liver disease with ongoing coagulopathy
13. Use of any prescription or non-prescription medications or supplements within 7 days prior to Study Day -1, excluding hormonal contraceptives
14. Use of anticoagulant medication within 14 days prior to Study Day -1
15. Major surgery within 60 days prior to Study Day -1
16. Receipt of an investigational drug within 30 days prior to Study Day -1
17. Donation of blood or plasma within 30 days prior to Study Day -1
18. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
180 µg/kg 3K3A-APC, single-dose	3K3A-APC, diluted in 0.9% sodium chloride in water	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
360 µg/kg 3K3A-APC, q12h for 5 doses	3K3A-APC, diluted in 0.9% sodium chloride in water	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
TBD µg/kg 3K3A-APC, single-dose	3K3A-APC, diluted in 0.9% sodium chloride in water	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
6 µg/kg 3K3A-APC, single-dose	3K3A-APC, diluted in 0.9% sodium chloride in water	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
30 µg/kg 3K3A-APC, single-dose	3K3A-APC, diluted in 0.9% sodium chloride in water	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
180 µg/kg 3K3A-APC, q12h for 5 doses	3K3A-APC, diluted in 0.9% sodium chloride in water	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
TBD µg/kg 3K3A-APC, q12h for 5 doses	3K3A-APC, diluted in 0.9% sodium chloride in water	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
Matching Placebo, 0.9% NaCl in water	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)
90 µg/kg 3K3A-APC, single-dose	3K3A-APC, diluted in 0.9% sodium chloride in water	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
90 µg/kg 3K3A-APC, q12h for 5 doses	3K3A-APC, diluted in 0.9% sodium chloride in water	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
360 µg/kg 3K3A-APC, single-dose	3K3A-APC, diluted in 0.9% sodium chloride in water	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

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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	Single-dose cohorts
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	Single-dose cohorts
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	Single-dose cohorts
Volume of Distribution (V) of 3K3A-APC by Compartmental Analysis	0, 20 minutes and 1 hour post for doses 1 and 5	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.
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	Single-dose cohorts
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	Single-dose cohorts
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	Single-dose cohorts
Half-life (t1/2) of 3K3A-APC by Compartmental Analysis	0, 20 minutes and 1 hour post for doses 1 and 5	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.
Total Clearance (CL) of 3K3A-APC by Compartmental Analysis	0, 20 minutes and 1 hour post for doses 1 and 5	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.
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	Single-dose cohorts
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	Single-dose cohorts
Elimination Rate Constant (λz) for 3K3A-APC by Compartmental Analysis	0, 20 minutes and 1 hour post for doses 1 and 5	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.
Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis	0, 20 minutes and 1 hour post for doses 1 and 5	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.
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	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.

Trial Locations

Locations (1)

Privatklinik Leech; 🇦🇹 Graz, Austria