Clinical trial NCT01660230: Safety and Pharmacokinetics of Single and Multiple Ascending Doses of 3K3A-APC in Healthy Adult Volunteers
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: APC, 3K3A, 3K3A-APC, volunteer, healthy
Lead sponsor: ZZ Biotech, LLC
Sponsor class: INDUSTRY
First posted: 2012-08-08
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in Protocol.
timeFrame: Day 4 for single-dose cohorts
measure: Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in the Protocol.
timeFrame: Day 6 for multiple-dose cohorts
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Non-compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Time at Which Cmax is Observed (Tmax) for 3K3A-APC by Non-compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: 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
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity [AUC(0-inf)] for 3K3A-APC by Non-compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Elimination Rate Constant (λz) for 3K3A-APC by Non-compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Half-life (t1/2) of 3K3A-APC by Non-compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Total Clearance (CL) of 3K3A-APC by Non-compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Volume of Distribution (Vz) of 3K3A-APC by Non-compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity [AUC(0-inf)] for 3K3A-APC by Compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Elimination Rate Constant (λz) for 3K3A-APC by Compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Half-life (t1/2) of 3K3A-APC by Compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Total Clearance (CL) of 3K3A-APC by Compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Volume of Distribution (V) of 3K3A-APC by Compartmental Analysis
timeFrame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis
timeFrame: 0, 20 minutes and 1 hour post for doses 1 and 5
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity [AUC(0-inf)] for 3K3A-APC by Compartmental Analysis
timeFrame: 0, 20 minutes and 1 hour post for doses 1 and 5
measure: Elimination Rate Constant (λz) for 3K3A-APC by Compartmental Analysis
timeFrame: 0, 20 minutes and 1 hour post for doses 1 and 5
measure: Half-life (t1/2) of 3K3A-APC by Compartmental Analysis
timeFrame: 0, 20 minutes and 1 hour post for doses 1 and 5
measure: Total Clearance (CL) of 3K3A-APC by Compartmental Analysis
timeFrame: 0, 20 minutes and 1 hour post for doses 1 and 5
measure: Volume of Distribution (V) of 3K3A-APC by Compartmental Analysis
timeFrame: 0, 20 minutes and 1 hour post for doses 1 and 5
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Privatklinik Leech
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Patrick D Lyden, MD, FAAN
role: PRINCIPAL_INVESTIGATOR
affiliation: ZZ Biotech, LLC
name: Howard Levy, MD, PhD, MMM
role: STUDY_DIRECTOR
References:
citation: 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.