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

ZZ Biotech

Status and phase: Completed; Phase 1

Conditions: Healthy

Treatments: Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water; Drug: 0.9% NaCl in water

Study type: Interventional

Funder types: Industry

Identifiers

NCT01660230

ZZ-3K3A-001

2011-000793-60 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 64 patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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64 participants in 11 patient groups, including a placebo group

6 µg/kg 3K3A-APC, single-dose

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

30 µg/kg 3K3A-APC, single-dose

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

90 µg/kg 3K3A-APC, single-dose

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

180 µg/kg 3K3A-APC, single-dose

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

360 µg/kg 3K3A-APC, single-dose

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

TBD µg/kg 3K3A-APC, single-dose

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

90 µg/kg 3K3A-APC, q12h for 5 doses

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

180 µg/kg 3K3A-APC, q12h for 5 doses

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

360 µg/kg 3K3A-APC, q12h for 5 doses

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

TBD µg/kg 3K3A-APC, q12h for 5 doses

Active Comparator group

Description:

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

Treatment:

Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water

Matching Placebo, 0.9% NaCl in water

Placebo Comparator group

Description:

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)

Treatment:

Drug: 0.9% NaCl in water