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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water; Drug: 0.9% NaCl in water

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 Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8010
    • Privatklinik Leech

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Active Comparator: 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	Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Placebo Comparator: 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)	Drug: 0.9% NaCl in water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: ZZ Biotech, LLC
• Investigators: Principal Investigator: Patrick D Lyden, MD, FAAN, Cedars-Sinai Medical Center; Study Director: Howard Levy, MD, PhD, MMM, ZZ Biotech, LLC

Publications and helpful links

General Publications

• Lyden P, Levy H, Weymer S, Pryor K, Kramer W, Griffin JH, Davis TP, Zlokovic B. Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Curr Pharm Des. 2013;19(42):7479-85. doi: 10.2174/1381612819666131230131454.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: July 25, 2012
• First Submitted That Met QC Criteria: August 3, 2012
• First Posted (Estimate): August 8, 2012

Study Record Updates

• Last Update Posted (Actual): February 5, 2018
• Last Update Submitted That Met QC Criteria: January 9, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: APC, 3K3A, 3K3A-APC, volunteer, healthy
• Other Study ID Numbers: ZZ-3K3A-001; 2011-000793-60 (EudraCT Number)