Safety Study of PZ-128 in Subjects With Multiple Coronary Artery Disease Risk Factors

Demonstration of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Antiplatelet Effect of PZ-128 in Subjects With Multiple Coronary Artery Disease Risk Factors

This study is a Phase I, intravenous, single-dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of PZ-128 (pepducin inhibitor of PAR1) in subjects with vascular disease or who have 2 or more coronary artery disease (CAD) risk factors.

Study Overview

• Status: Completed
• Conditions: Vascular Disease; Coronary Artery Disease Risk Factors Multiple
• Intervention / Treatment: Drug: PZ-128

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore (Sinai Center for Thrombosis Research)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female subjects between the ages of 18 to 75 with documented vascular disease (peripheral vascular disease, carotid artery disease or coronary artery disease) or 2 or more coronary artery risk factors.
• Women of childbearing potential must have a negative pregnancy test prior to enrollment and immediately before drug administration and agree to use two methods of effective barrier contraception, or a hormonal contraceptive to prevent pregnancy throughout the study.
• The subject is able to read and give written informed consent and has signed and dated an informed consent document and authorization permitting release of personal health information approved by the Investigator's Institutional Review Board (IRB).

Exclusion Criteria:

• The subject has participated in an investigational drug study within the last 30 days.
• The subject has a medical or surgical condition that may impair drug absorption or metabolism.
• Anticoagulants, P2Y12 inhibitors, nonsteroidal antiinflammatory drugs (no more than three times a week) or any other drug that the investigator deems to have potential interaction with platelets or PAR-1 receptor inhibition are prohibited from 2 weeks prior to study drug dosing through 2 weeks post dosing. Aspirin is allowed.
• The subject has previous history of anaphylaxis to drugs or any environmental stimuli including foods or hymenoptera (e.g., ants, bees, wasps) stings.
• Asthma requiring bronchodilator/inhaler therapy.
• Currently smoking ≥2 pack/day.
• Herbal supplements (i.e., Fish Oil/Omega-3, St. John's Wart, Ginseng, Garlic, Ginkgo, Saw Palmetto, Echinacea, Yohimbine, Licorice, and Black Cohosh) are prohibited from 1 week prior to dosing through 24 hours post dosing.
• Prior history or clinical suspicion of cerebral vascular malformations, intracranial tumor, transient ischemic attack, stroke, gastric ulcers and any form of bleeding disorder.
• Prior history of myocardial infarction within the last 3 months or unstable angina.
• Thrombocytopenia defined as a platelet count of <130,000/mm3 or low hematocrit defined as <30%.
• Renal function: serum creatinine >1.5 x ULN. However, subjects with an estimated creatinine clearance eGFR ≥60 mL/min, calculated using the Cockcroft-Gault formula, are eligible.
• Liver enzymes ≥ 3 x upper limit of normal.
• Alcohol consumption within 48 hrs prior to dosing, and for the duration of the in-house study period.
• Evidence of history of substance or alcohol abuse at screening, including positive urine test results for drugs or positive breath test for alcohol.
• Uncontrolled hypertension or hypotension defined as a sustained supine systolic pressure >160 mmHg or <100 mmHg; or a diastolic pressure >90 mmHg or < 50 mmHg.
• International normalized ratio (INR) >1.5
• Poor venous access (i.e., insufficient for intravenous drug delivery).
• History of hepatitis or HIV.
• The subject has undergone an invasive surgical procedure within the last 3 months, is anticipating one during the course of their study participation or is planning to have one within 1 month post dosing with the study drug.
• The subject has any condition which could interfere with or for which the treatment might interfere with the conduct of the study, or which would, in the opinion of the Investigator increase the risk of the subject's participation in the study. This would include, but is not limited to alcoholism, drug dependency or abuse, psychiatric disease, epilepsy or any unexplained blackouts, previous hypersensitivity to drugs, and severe asthma.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PZ-128	Drug: PZ-128; Sequential single-dose escalation; 1 to 2 hour continuous intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Participants Experience with Safety and Tolerability	Safety and tolerability of a single dose of PZ-128 as determined by adverse event reporting, clinical laboratory results, vital signs, physical examination, pulmonary function tests and electrocardiograms (ECGs).	30 days after drug infusion

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic profile of PZ-128	Assessments will be done up to 7 days post dosing
Evaluate inhibition of ex vivo platelet function in response to multiple agonists	Assessments will be done up to 7 days post dosing
Correlate PZ-128 plasma levels with inhibition of platelet aggregation	Assessments will be done up to 7 days post dosing
Evaluate changes in clotting characteristics at each dose level of PZ-128 relative to baseline	Assessments will be done up to 7 days post dosing

Collaborators and Investigators

• Sponsor: Tufts Medical Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Sinai Hospital of Baltimore
• Investigators: Principal Investigator: Paul A. Gurbel, MD, Sinai Hospital of Baltimore (Sinai Center for Thrombosis Research); Study Director: Athan Kuliopulos, MD, PhD, Tufts Medical Center (Hemostasis and Thrombosis Laboratory)

Publications and helpful links

General Publications

• Gurbel PA, Bliden KP, Turner SE, Tantry US, Gesheff MG, Barr TP, Covic L, Kuliopulos A. Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease. Arterioscler Thromb Vasc Biol. 2016 Jan;36(1):189-97. doi: 10.1161/ATVBAHA.115.306777.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: March 1, 2013
• First Submitted That Met QC Criteria: March 5, 2013
• First Posted (Estimate): March 7, 2013

Study Record Updates

• Last Update Posted (Estimate): April 21, 2016
• Last Update Submitted That Met QC Criteria: April 20, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Vascular Diseases; Cardiovascular Diseases; Coronary Artery Disease; Platelet Aggregation Inhibitors; Arteriosclerosis; Coronary Disease
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Vascular Diseases
• Other Study ID Numbers: TMC-A2012-04; P50HL110789 (U.S. NIH Grant/Contract)