Pharmacogenomics of Anti-platelet Intervention-2 (PAPI-2) Study

This study has been terminated.
(Terminated by study sponsor.)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Alan Shuldiner, University of Maryland
ClinicalTrials.gov Identifier:
NCT01452152
First received: October 10, 2011
Last updated: January 25, 2013
Last verified: January 2013
  Purpose

It is standard treatment to take anti-platelet medication after cardiac catheterization and stent placement to help prevent the formation of blood clots that may cause heart attack or stroke. The most commonly used anti-platelet medicine is clopidogrel (Plavix®). However, researchers have found that people vary in their response to clopidogrel, in part because of differences in their genes. Prasugrel (Effient®)is another anti-platelet medication used to prevent clots. The genetic differences that affect clopidogrel response do not affect prasugrel response. Recently, the FDA added a warning to the label of clopidogrel to notify doctors and patients with certain genetic differences may not get the full benefit from clopidogrel. Despite this, genetic testing for these variations is not usually done in standard medical practice. The purpose of this study is to see if patients with certain gene differences have fewer major cardiac events after stent placement if they are given anti-platelet therapy guided by their individual genetic type compared to standard anti-platelet therapy.


Condition Intervention Phase
Cardiovascular Diseases
Acute Coronary Syndrome
Drug: clopidogrel
Drug: prasugrel
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacogenomics of Anti-platelet Intervention-2 (PAPI-2) Study: A Prospective, Multicenter, Randomized Trial of Genotype-directed (G-D)Versus Standard of Care (SOC)Anti-platelet Therapy

Resource links provided by NLM:


Further study details as provided by University of Maryland:

Primary Outcome Measures:
  • Occurrence of post-randomization cardiovascular events [ Time Frame: One year ] [ Designated as safety issue: No ]
    Cardiovascular events include non-fatal myocardial infarction, non-fatal stroke, definite or probable stent thrombosis (ARC definition) and death secondary to any cardiovascular cause.


Secondary Outcome Measures:
  • Occurrence of bleeding events [ Time Frame: One year ] [ Designated as safety issue: Yes ]
    Bleeding events will classified by the Bleeding Academic Research Consortium definition.

  • Post-treatment platelet aggregation [ Time Frame: 10 days ] [ Designated as safety issue: No ]
    Platelet aggregation will be performed on a subset of subjects. Platelet aggregation studies are optional and will not be used to modulate antiplatelet therapy

  • Health care resource utilization and cost-effectiveness [ Time Frame: One year ] [ Designated as safety issue: No ]
  • Occurrence of adverse events [ Time Frame: One year ] [ Designated as safety issue: Yes ]
  • Composite of all-cause death, MI, stroke and repeat revascularization [ Time Frame: One year ] [ Designated as safety issue: No ]

Enrollment: 9
Study Start Date: February 2012
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Genotype-directed, clopidogrel
Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 extensive and ultrarapid metabolizers will receive clopidogrel.
Drug: clopidogrel
clopidogrel 75 mg/day plus aspirin 81-162 mg/day for one year
Other Name: Plavix
Experimental: Genotype-directed, prasugrel
Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 intermediate and poor metabolizers will receive prasugrel.
Drug: prasugrel
Prasugrel 5-10 mg/day plus aspirin 81-162 mg/day for one year
Other Name: Effient
No Intervention: Standard of Care
Participants randomized to the SOC group will not have CYP2C19 genotype analysis performed. They will receive dual anti-platelet therapy guided by the judgment of their treating physician according to standard medical practice irrespective of genotype.

Detailed Description:

Over a three-year period, a total of 7,200 patients undergoing percutaneous coronary intervention (PCI) in whom dual anti-platelet therapy is indicated for at least one year and meet the eligibility criteria, will be recruited from five or more clinical sites. Patients presenting to the cardiac clinics, emergency departments, catheterization laboratories, and other acute care units (e.g. CCU) who will have coronary angiography or have had angiography and PCI will be offered participation. Following informed consent, patients will have baseline data and specimens collected, and eligibility confirmed. Patients will be randomized in equal numbers to the G-D arm or SOC arm. Immediately following randomization, a blood sample from patients assigned to the G-D arm will be sent for CYP2C19 genotype analysis. Upon receipt of CYP2C19 genotype results, patients randomized to the G-D arm with the CYP2C19 *1/*1 genotype (extensive metabolizers) and *1/*17, and *17/*17 genotypes (ultrarapid metabolizers) will receive clopidogrel 75 mg/day plus aspirin 81-162 mg/day (group a). Those with *1/*2, *1/*3, *2/*17, and *3/*17 genotypes (intermediate metabolizers) and those with *2/*2, *2/*3, and *3/*3 genotypes (poor metabolizers) will receive prasugrel 5-10 mg/day plus aspirin 81-162 mg/day (group b). Patients randomized to the SOC arm will not be genotyped prospectively. They will receive dual anti-platelet therapy guided by the judgment of their treating physician according to standard medical practice irrespective of genotype (group c). Optionally, a subgroup of patients will return at 10 days after the randomization visit for platelet aggregation studies.

If our hypothesis is correct, i.e., that in intermediate and poor metabolizers, G-D anti-platelet therapy results in fewer cardiovascular events and has less or equivalent bleeding complications compared to SOC therapy, and is cost effective, this prospective randomized clinical trial will provide the evidence base to implement genotype-directed anti-platelet treatment algorithms broadly into clinical practice.

  Eligibility

Ages Eligible for Study:   20 Years to 74 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males or non-pregnant females between the ages of 20 and 74 years, inclusive
  • Not more than four days post-PCI with placement of one or more drug eluting or bare metal stents
  • One or more stent(s) delivered with final TIMI 3 flow in the stented vessel(s)
  • Must have evidence of one of the following:

    1. Three vessel disease;
    2. Two vessel disease with one of the following: estimated creatinine clearance <60, prior myocardial infarction, diabetes mellitus on treatment, peripheral artery disease, cerebrovascular disease, bifurcation stent, overlapping stents, or total stent deployment length > 40 mm in length;
    3. Single vessel disease with two of the following: estimated creatinine clearance <60, prior myocardial infarction, diabetes mellitus on treatment, peripheral artery disease, cerebrovascular disease, bifurcating stenting, overlapping stents, or total stent deployment length > 40 mm in length.
  • Patients with acute MI preceding the PCI must have CK-MB value lower than the prior value, before randomization
  • Patients with peri-procedural MI, defined by CK-MB three times greater than upper reference limit (URL), must have CK-MB value lower than the prior value, before randomization. Peri-procedural MI will be screened per clinical suspicion.
  • Have an indication for one year of dual anti-platelet therapy with a P2Y12 inhibitor and aspirin
  • Agreement of the treating physician to prescribe anti-platelet therapy according to randomization and study dosing algorithm
  • Ability to understand and comply with planned study procedures
  • Provide written informed consent prior to study entry
  • Agrees to authorize the collection and release of his/her medical information for the duration of the trial or until the subject withdraws

Exclusion Criteria:

  • History of a gastrointestinal bleed within three months or a major, life threatening bleeding event (e.g., sub-arachnoid or intracranial hemorrhage)
  • Active pathological bleeding (e.g. GI bleeding)
  • History of bleeding diathesis or coagulopathy
  • History of stroke or transient ischemic attack (TIA)
  • Non-cardiac surgery within the prior 3 months
  • Planned cardiac or non-cardiac surgery within the next 12 months
  • CYP2C19 genotype already known to subject or research team from prior genetic testing
  • Post-PCI CABG before randomization
  • Planned warfarin or dabigatran therapy any time during the study period
  • Known allergy to aspirin, clopidogrel or prasugrel
  • Platelet count <100,000/mm3
  • Hematocrit < 25%
  • Pregnancy
  • Concurrent enrollment in another trial that involves an investigational stent, antithrombotic or anti-platelet agent
  • Any condition that would, in the opinion of the site investigator, place them at an unacceptable risk or render them unable to meet the requirements of the protocol
  • Any subject, in the opinion of the investigator, not expected to tolerate or be adherent with one year of dual antiplatelet therapy
  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: NCT01452152

Locations
United States, Delaware
Christiana Care Health System
Newark, Delaware, United States, 19718
United States, Maryland
Sinai Center for Thrombosis Research
Baltimore, Maryland, United States, 21209
The Johns Hopkins University School of Medicine
Baltimore, Maryland, United States, 21287
University of Maryland School of Medicine
Baltimore, Maryland, United States, 21201
United States, Pennsylvania
Geisinger Health System
Danville, Pennsylvania, United States, 17822
Sponsors and Collaborators
University of Maryland
Investigators
Principal Investigator: Alan R Shuldiner, M.D. University of Maryland
  More Information

Publications:
Responsible Party: Alan Shuldiner, Professor, School of Medicine; Head, Division of Endocrinology, Diabetes and Nutrition, University of Maryland
ClinicalTrials.gov Identifier: NCT01452152     History of Changes
Other Study ID Numbers: HP-00047385, 9U01HL105198-06
Study First Received: October 10, 2011
Last Updated: January 25, 2013
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by University of Maryland:
Pharmacogenomics
Platelet Aggregation Inhibitors

Additional relevant MeSH terms:
Acute Coronary Syndrome
Cardiovascular Diseases
Angina Pectoris
Chest Pain
Heart Diseases
Myocardial Ischemia
Pain
Signs and Symptoms
Vascular Diseases
Clopidogrel
Platelet Aggregation Inhibitors
Prasugrel
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Purinergic Agents
Purinergic Antagonists
Purinergic P2 Receptor Antagonists
Purinergic P2Y Receptor Antagonists
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014