Safety of PZ-128 in Subjects Undergoing Non-Emergent Percutaneous Coronary Intervention

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety of PZ-128 in Subjects Undergoing Non-Emergent Percutaneous Coronary Intervention- Thrombin Receptor Inhibitory Pepducin in PCI (TRIP-PCI)

The object of the study is to determine whether different doses of PZ-128, when added to standard medical care in persons undergoing cardiac catheterization/percutaneous coronary intervention, will increase the risk of bleeding.

A secondary objective is to determine whether patients treated with PZ-128 have fewer cardiac events such as heart attack, bypass surgery or stroke compared with those persons treated with the standard of care.

Inclusion Criteria:

1. The subject is at least 18 years of age and may be of either sex/gender and of any race and ethnicity.

2. The subject is scheduled to undergo non-emergent PCI or non-emergent cardiac catheterization with the intention of performing PCI. The following classifications of the urgency of the procedure at the time the operator decides to perform it will be used for randomization stratification:

   • Elective: The cardiac catheterization procedure ± PCI can be performed on an outpatient basis or during a subsequent hospitalization without significant risk of MI or death. For stable inpatients, this is a procedure that is performed during the hospitalization for convenience and ease of scheduling only and not because the subject's clinical situation demands that the procedure be performed prior to discharge.

   OR

   • Urgent: The cardiac catheterization ± PCI procedure should be performed on an inpatient basis and before discharge because of significant concerns about the risk of myocardial ischemia, MI and/or death. For subjects who are outpatients or in the emergency department at the time that the cardiac catheterization is requested, this is a procedure that would warrant hospital admission based on clinical presentation.

3. There is no anticipation that the subject would require treatment with a GP IIb/IIIa inhibitor prior to the initiation of the cardiac catheterization ± PCI procedure if the subject were not a participant in the current research study, and no anticipation of use during the procedure.

4. The subject is willing and able to give appropriate informed consent and complete all study-related procedures, and able to adhere to dosing and visit schedules (i.e., subject signs an approved informed consent document(s) and provides HIPAA authorization);

5. The subject will undergo all of the pre-enrollment parameters according to the study protocol prior to randomization and have them completed within 14 days prior to the scheduled cardiac catheterization ± PCI procedure and study drug administration.

6. Women of childbearing potential (all postmenarchal women who are <1 year menopausal or who have not had surgical sterilization or a hysterectomy are considered to be women of child-bearing potential) must agree to use a medically accepted method of contraception from the time written informed consent is given up until 90 days following the study drug administration.

Subject Exclusion Criteria:

The subject will be excluded from entry if any of the criteria listed below are met:

(General Exclusions)

1. Subject is pregnant, intends to become pregnant or is breast-feeding (all women of child-bearing potential must have a negative pregnancy test result confirmed prior to randomization and it must be repeated to be within 24 hours prior to the study drug administration if necessary).

2. Any of the following allergy history(s):

   • History of an allergic reaction* or contraindication to any of the following protocol-directed drugs: aspirin, heparin, P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor), antihistamines (benadryl, famotidine); or

   • History of an allergic reaction* to contrast media; or

   • History of an allergic reaction* to a drug which required emergency medical treatment;

   • History of an allergic reaction* to a Hymenoptera sting which currently necessitates the subject to carry an EpiPen/injector or the subject has been prescribed one to treat an allergic reaction to a sting.

     • An allergic (anaphylactic) reaction is characterized by an adverse local or general response from exposure to an allergen involving skin/mucosal tissue manifestations (hives, pruritus, flushing, angioedema), and/or respiratory compromise (dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia), and/or hemodynamic effects (hypo/hypertension, hypotonia, syncope).

3. Participation in another research study of investigational therapy (drug or device) within the past 30 days prior to randomization or planned use of other investigational therapy(s) during this research study (until 90 days following the study drug administration).

4. Subject is part of the study staff personnel directly involved with this trial, or is a family member of the study staff (clinical site or sponsor).

5. Prior enrollment (randomization) in this research study.

6. Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the research study or which would, in the opinion of the investigator, unacceptably increase the subject's risk by participating in the research study. This would include, but is not limited to alcoholism, drug dependency or abuse, psychiatric disease, epilepsy or any unexplained blackouts.

   (Exclusionary Prior/Concomitant Conditions)

7. Evidence of an ST-segment elevation myocardial infarction (STEMI) on presentation or during current hospitalization or a history of STEMI within the past 30 days prior to randomization.

8. Subject is scheduled to undergo PCI for known unprotected left main coronary artery (LMCA) disease (i.e., left main stenosis ≥50% not protected by at least 1 patent bypass graft).

9. Any history of a prior stroke (hemorrhagic or ischemic) or transient ischemic attack (TIA) of any etiology.

10. Cardiogenic or any type of shock on presentation or during current hospitalization (i.e., systolic blood pressure <90 mm Hg requiring vasopressor or hemodynamic support).

11. History of heparin-induced thrombocytopenia (HIT).

12. Any active bleeding within the past 30 days prior to randomization.

13. Any condition or personal belief (e.g., Jehovah's Witness) which would interfere with the subject's ability or willingness to undergo a blood transfusion.

14. Any of the following conditions associated with increased risk of bleeding:

    1. history of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra- articular bleeding;
    2. gastrointestinal bleeding within the past 30 days prior to randomization;
    3. gastric or duodenal ulcer disease verified by endoscopy or barium meal contrast technique within the past 6 months prior to randomization;
    4. history of bleeding disorder or diathesis;
    5. major surgical procedure or trauma within the past 60 days prior to randomization or a planned surgical procedure to take place within 30 days following the study drug administration;
    6. history or suspicion of intracranial neoplasm, arteriovenous malformation, or aneurysm; or
    7. clinical finding(s) in the judgment of the investigator that poses an increased risk of bleeding.

15. Sustained severe hypertension: systolic blood pressure >185 mm Hg or diastolic blood pressure >105 mm Hg with or without anti-hypertensive treatment (as demonstrated by repeated BP measurements >185/105 mm Hg including the final BP measurement before randomization).

16. Hypotension: systolic blood pressure <95 mm Hg (as demonstrated by repeated systolic BP measurements <95 mm Hg including the final systolic BP measurement prior to randomization).

17. Known active hepatobiliary disease, or known unexplained persistent increase in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) activity to ≥2.5 times the upper limit of the reference range within the past 30 days prior to randomization.

18. Hemoglobin <10 g/dL or hematocrit <30%.

19. Platelet count <75,000/mm3.

20. Stage 4-5 Chronic Kidney Disease (National Kidney Foundation) or on dialysis.

21. Active sepsis or suspected sepsis.

22. Body weight <60 kg or >175 kg.

23. Current evidence of invasive cancer (persistent disease excluding basal cell carcinoma of the skin) or treatment for invasive cancer within the past 6 months prior to randomization.

24. Left ventricular ejection fraction <25% if known (any imaging technique) or New York Heart Association (NYHA) Class IV congestive heart failure.

    (Exclusionary Prior/Concomitant/Anticipated Medication/Therapy)

25. Coronary interventional procedure of any kind within the past 30 days prior to randomization.

26. Anticipated subsequent staged multi-vessel PCI within 30 days following the study drug administration.

27. History of treatment with any parenteral GP IIb/IIIa inhibitor (GPI) within the past 30 days prior to randomization. (As stated in the Inclusion section, the planned treatment with a GPI prior to initiation of the cardiac catheterization ± PCI is not allowed; however, GPI for thrombotic bailout may be used during the PCI at the investigator's discretion).

28. Concurrent or anticipated treatment with a parenteral direct thrombin inhibitor (e.g., bivalirudin) for the cardiac catheterization ± PCI procedure.

29. History of treatment with another PAR1 inhibitor within the past 60 days prior to randomization or the concurrent/anticipated use after randomization up until 30 days following the study drug administration.

30. History of treatment with another IV anti-platelet drug within 30 days prior to randomization or the concurrent/anticipated use after randomization up until 30 days following the study drug administration.

31. Any of the following anticoagulant or thrombolytic/fibrinolytic treatment(s):

    • History of treatment with warfarin within 5 days prior to randomization or the concurrent/anticipated use after randomization up until 2 days following the study drug administration; or
    • History of treatment with oral Factor Xa or direct thrombin inhibitors within 2 days prior to randomization or the concurrent/anticipated use after randomization up until 2 days following the study drug administration; or
    • History of treatment with thrombolytic/fibrinolytic agents within 7 days prior to randomization or the concurrent/anticipated use of any of those agents after randomization up until 30 days following the study drug administration.