Determining Genetic Role in Treatment Response to Anti-Platelet Interventions (The PAPI Study)

Coronary Heart Disease Clinical Trial

Official title:

Pharmacogenomics of Anti-Platelet Interventions (The PAPI Study)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00799396
• Other study ID #: HP-00043419
• Secondary ID: U01 HL074518-01U
• Status: Completed
• Phase: Phase 4
• Start date: July 2006
• Est. completion date: February 2012

Study information

• Verified date: February 2022
• Source: University of Maryland, Baltimore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

One of the most common ways for preventing coronary heart disease (CHD) is to take aspirin or clopidogrel. However, studies have shown that not all people respond to these medications. The variance in treatment response may be linked to genetics. This study will examine the effects of aspirin and clopidogrel in a population whose genes are well known in order to determine the role that genes play in treatment responses.

Description:

CHD is the leading cause of death in the United States. Anti-platelet agents lessen platelet aggregation and are used commonly to prevent recurrent CHD events. Two of the most common anti-platelet agents are aspirin and clopidogrel. However, up to 25% to 30% of people do not respond to these medications. Evidence indicates that treatment response may be related to genetics. The purpose of this study is to determine specific gene variants that predict response to aspirin and clopidogrel therapy.

This study is part of a larger group of studies called the Pharmacogenomics Research Network (PGRN). Participants will include the Old Order Amish of Lancaster, Pennsylvania. They are well suited for genetic studies because they are a homogenous, closed, founder population. Participants will receive 300 mg of clopidogrel on the first day, then 75 mg of clopidogrel per day for the next 6 days. On the last day of clopidogrel treatment, participants will take a single dose of 324 mg aspirin. Participants will undergo platelet function tests before and after clopidogrel alone, and then again after taking clopidogrel plus aspirin. Using the gene variation profiles across the genome, researchers will analyze which genes correspond to treatment response.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 682
• Est. completion date: February 2012
• Est. primary completion date: February 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

• Of Old Order Amish descent

Exclusion Criteria:

• Currently pregnant or less than 6 months have passed since delivery

• Has a history of a bleeding disorder or major spontaneous bleed, such as peptic ulcer, epistasis, or intracranial bleed

• Has severe hypertension, defined by a blood pressure above 160/95 mm Hg, making it unethical not to recommend prompt treatment

• Takes medications that would affect the outcome(s) to be measured and cannot willingly and safely, in the opinion of the treating physician and study physician, discontinue these medications for 1 week prior to protocol initiation

• Is taking vitamins or other supplements and is unwilling to discontinue their use for at least 1 week prior to study

• Has a coexisting malignancy

• Has a creatinine level greater than 2.0 mg/dl, aspartate transaminase (AST) or alanine transaminase (ALT) greater than two times the upper limit of normal, hematocrit less than 32%, or a thyroid-stimulating hormone (TSH) less than 0.4 or greater than 5.5 mIU/L

• Has a bleeding disorder or history of gastrointestinal bleeding or other major bleeding episode

• Is currently taking aspirin, clopidogrel, or other anti-coagulant, such as warfarin, heparin, or GPIIb/IIIa antagonists, and have conditions that might place them at increased risk from withdrawal of these medications 14 days prior to protocol initiation, including history of unstable angina, heart attack, angioplasty (including stent placement), coronary artery bypass surgery, atrial fibrillation, stroke or transient ischemic attacks, diabetes, or deep vein thrombosis or other thrombosis

• Has polycythemia, or thrombocytosis, defined by a platelet count greater than 500,000

• Has thrombocytopenia, defined by a platelet count less than 75,000

• Has had surgery within the last 6 months

• Has an aspirin or clopidogrel allergy

• Currently breast feeding

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Coronary Heart Disease
• Heart Diseases
• Myocardial Ischemia
• Platelet Aggregation Inhibitors

Intervention

Drug:
• Clopidogrel
300 mg on first day, then 75 mg per day for the next 6 days
• Aspirin
Single dose of 324 mg on the last day of clopidogrel treatment

Locations

Country	Name	City	State
United States	Amish Research Clinic	Lancaster	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
University of Maryland, Baltimore	National Heart, Lung, and Blood Institute (NHLBI), National Institute of General Medical Sciences (NIGMS)

Country where clinical trial is conducted

United States, 

References & Publications (6)

Bozzi LM, Mitchell BD, Lewis JP, Ryan KA, Herzog WR, O'Connell JR, Horenstein RB, Shuldiner AR, Yerges-Armstrong LM. The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study: Variation in Platelet Response to Clopidogrel and Aspirin. Curr Vasc Phar — View Citation

Lewis JP, Fisch AS, Ryan K, O'Connell JR, Gibson Q, Mitchell BD, Shen H, Tanner K, Horenstein RB, Pakzy R, Tantry US, Bliden KP, Gurbel PA, Shuldiner AR. Paraoxonase 1 (PON1) gene variants are not associated with clopidogrel response. Clin Pharmacol Ther. — View Citation

Lewis JP, Horenstein RB, Ryan K, O'Connell JR, Gibson Q, Mitchell BD, Tanner K, Chai S, Bliden KP, Tantry US, Peer CJ, Figg WD, Spencer SD, Pacanowski MA, Gurbel PA, Shuldiner AR. The functional G143E variant of carboxylesterase 1 is associated with incre — View Citation

Lewis JP, Ryan K, O'Connell JR, Horenstein RB, Damcott CM, Gibson Q, Pollin TI, Mitchell BD, Beitelshees AL, Pakzy R, Tanner K, Parsa A, Tantry US, Bliden KP, Post WS, Faraday N, Herzog W, Gong Y, Pepine CJ, Johnson JA, Gurbel PA, Shuldiner AR. Genetic va — View Citation

Lewis JP, Stephens SH, Horenstein RB, O'Connell JR, Ryan K, Peer CJ, Figg WD, Spencer SD, Pacanowski MA, Mitchell BD, Shuldiner AR. The CYP2C19*17 variant is not independently associated with clopidogrel response. J Thromb Haemost. 2013 Sep;11(9):1640-6. — View Citation

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 e — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in Platelet Function in Response to Clopidogrel	Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation.	Measured at baseline, and after clopidogrel treatment
Primary	Changes in Platelet Function in Response to Clopidogrel Plus Aspirin	Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation	Measured at baseline, and after clopidogrel plus aspirin treatment

External Links

•   dbGaP submission for the PAPI study