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

NCT01452152 | Terminated Phase 4 Results DMC

• 2 other identifiers: HP-000473859U01HL105198-06
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Cardiovascular Diseases; Acute Coronary Syndrome

Keywords

Pharmacogenomics; Platelet Aggregation Inhibitors

Outcome Measures

Primary Outcomes (1)

• Occurrence of Post-randomization Cardiovascular Events

  Cardiovascular events include non-fatal myocardial infarction, non-fatal stroke, definite or probable stent thrombosis (ARC definition) and death secondary to any cardiovascular cause.

  One year

Secondary Outcomes (5)

• Occurrence of Bleeding Events

  One year

• Post-treatment Platelet Aggregation

  10 days

• Health Care Resource Utilization and Cost-effectiveness

  One year

• Occurrence of Adverse Events

  One year

• Composite of All-cause Death, Myocardial Infarction (MI), Stroke and Repeat Revascularization

  One year

Study Arms (3)

Genotype-directed, clopidogrel

EXPERIMENTAL

Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 extensive and ultrarapid metabolizers will receive clopidogrel.

Drug: clopidogrel

Genotype-directed, prasugrel

EXPERIMENTAL

Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 intermediate and poor metabolizers will receive prasugrel.

Drug: prasugrel

Standard of Care

NO INTERVENTION

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.

Interventions

clopidogrel DRUG

clopidogrel 75 mg/day plus aspirin 81-162 mg/day for one year

Also known as: Plavix

Genotype-directed, clopidogrel

prasugrel DRUG

Prasugrel 5-10 mg/day plus aspirin 81-162 mg/day for one year

Also known as: Effient

Genotype-directed, prasugrel

Eligibility Criteria

• Age: 20 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males or non-pregnant females between the ages of 20 and 74 years, inclusive
• Not more than four days post-PCI (percutaneous coronary intervention) with placement of one or more drug eluting or bare metal stents
• One or more stent(s) delivered with final TIMI 3 flow (thrombolysis in myocardial infarction grade 3) in the stented vessel(s)
• Must have evidence of one of the following:
• Three vessel disease;
• 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;
• 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 (myocardial infarction) preceding the PCI must have CK-MB (bound combination of creatine kinase M and creatine kinase B) 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

You may not qualify if:

• 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 (coronary artery bypass graft) 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

Sponsors & Collaborators

• University of Maryland, Baltimore: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (5)

Christiana Care Health System

Newark, Delaware, 19718, United States

Location

University of Maryland School of Medicine

Baltimore, Maryland, 21201, United States

Location

Sinai Center for Thrombosis Research

Baltimore, Maryland, 21209, United States

Location

The Johns Hopkins University School of Medicine

Baltimore, Maryland, 21287, United States

Location

Geisinger Health System

Danville, Pennsylvania, 17822, United States

Location

Related Publications (1)

• Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232.

  PMID: 19706858 BACKGROUND

MeSH Terms

Conditions

Cardiovascular Diseases; Acute Coronary Syndrome

Interventions

Clopidogrel; Prasugrel Hydrochloride

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Piperazines

Limitations and Caveats

The study was terminated early by the sponsor due to low enrollment.

Results Point of Contact

• Title: Dr. Alan R. Shuldiner
• Organization: University of Maryland School of Medicine

ashuldin@medicine.umaryland.edu

410-706-1623

Study Officials

• Alan R Shuldiner, M.D.

  University of Maryland

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, School of Medicine; Head, Division of Endocrinology, Diabetes and Nutrition

Study Record Dates

• First Submitted: October 10, 2011
• First Posted: October 14, 2011
• Study Start: February 1, 2012
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2013
• Last Updated: March 16, 2022
• Results First Posted: June 28, 2016

Record last verified: 2022-03

Locations

US (5)