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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
ZZ Biotech, LLC
ClinicalTrials.gov Identifier:
NCT01660230
First received: July 25, 2012
Last updated: February 27, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Healthy
Biological: 3K3A-APC, diluted in 0.9% sodium chloride in water
Drug: 0.9% NaCl in water
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
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

Resource links provided by NLM:


Further study details as provided by ZZ Biotech, LLC:

Primary Outcome Measures:
  • Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in Protocol. [ Time Frame: Day 4 for single-dose cohorts ] [ Designated as safety issue: Yes ]
  • Adverse Events That Meet Dose-limiting Toxicity Criteria Specified in the Protocol. [ Time Frame: Day 6 for multiple-dose cohorts ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Non-compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    Single-dose cohorts

  • Time at Which Cmax is Observed (Tmax) for 3K3A-APC by Non-compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    Single-dose cohorts

  • 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 [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    Single-dose cohorts

  • Elimination Rate Constant (λz) for 3K3A-APC by Non-compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    Single-dose cohorts

  • Half-life (t1/2) of 3K3A-APC by Non-compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    Single-dose cohorts

  • Total Clearance (CL) of 3K3A-APC by Non-compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    Single-dose cohorts

  • Volume of Distribution (Vz) of 3K3A-APC by Non-compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    Single-dose cohorts

  • Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    Single-dose cohorts

  • Area Under the Plasma Concentration-time Curve From Time 0 to Infinity [AUC(0-inf)] for 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    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.

  • Elimination Rate Constant (λz) for 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    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.

  • Half-life (t1/2) of 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    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.

  • Total Clearance (CL) of 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    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.

  • Volume of Distribution (V) of 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours post‐dose ] [ Designated as safety issue: No ]
    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.

  • Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 20 minutes and 1 hour post for doses 1 and 5 ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0, 20 minutes and 1 hour post for doses 1 and 5 ] [ Designated as safety issue: No ]
    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.

  • Elimination Rate Constant (λz) for 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 20 minutes and 1 hour post for doses 1 and 5 ] [ Designated as safety issue: No ]
    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.

  • Half-life (t1/2) of 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 20 minutes and 1 hour post for doses 1 and 5 ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0, 20 minutes and 1 hour post for doses 1 and 5 ] [ Designated as safety issue: No ]
    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.

  • Volume of Distribution (V) of 3K3A-APC by Compartmental Analysis [ Time Frame: 0, 20 minutes and 1 hour post for doses 1 and 5 ] [ Designated as safety issue: No ]
    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.


Enrollment: 64
Study Start Date: August 2012
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01660230

Locations
Austria
Privatklinik Leech
Graz, Austria, 8010
Sponsors and Collaborators
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
  More Information

Additional Information:
No publications provided by ZZ Biotech, LLC

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: ZZ Biotech, LLC
ClinicalTrials.gov Identifier: NCT01660230     History of Changes
Other Study ID Numbers: ZZ-3K3A-001, 2011-000793-60
Study First Received: July 25, 2012
Results First Received: February 27, 2014
Last Updated: February 27, 2014
Health Authority: Austria: Austrian Medicines and Medical Devices Agency

Keywords provided by ZZ Biotech, LLC:
APC, 3K3A, 3K3A-APC, volunteer, healthy

ClinicalTrials.gov processed this record on September 16, 2014