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

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT00799396
• Collaborator: National Institute of General Medical Sciences (NIGMS) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 682
• Location: 1
• Arm: 1
• Duration (Months): 67.1
• Patients Per Site Per Month: 10.2

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Platelet Aggregation Inhibitors; Coronary Heart Disease	Drug: Clopidogrel; Drug: Aspirin	Phase 4

Detailed 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 682 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacogenomics of Anti-Platelet Interventions (The PAPI Study)
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Overall Study Participants will receive clopidogrel treatment alone, followed by clopidogrel plus aspirin treatment on the last day of treatment.	Drug: Clopidogrel; 300 mg on first day, then 75 mg per day for the next 6 days; Drug: Aspirin; Single dose of 324 mg on the last day of clopidogrel treatment

Outcome Measures

Primary Outcome Measures

1. Changes in Platelet Function in Response to Clopidogrel [Measured at baseline, and after clopidogrel treatment]

   Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation.

2. Changes in Platelet Function in Response to Clopidogrel Plus Aspirin [Measured at baseline, and after clopidogrel plus aspirin treatment]

   Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Amish Research Clinic	Lancaster	Pennsylvania	United States	17601

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Alan R. Shuldiner, MD, University of Maryland School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• dbGaP submission for the PAPI study

Publications

None provided.

• Responsible Party: Alan Shuldiner, Associate Dean for Personalized Medicine; Director, Program in Personalized and Genomic Medicine; Head, Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT00799396
• Other Study ID Numbers: HP-00043419; U01 HL074518-01; U01GM074518
• First Posted: Nov 27, 2008
• Last Update Posted: Feb 24, 2022
• Last Verified: Feb 1, 2022

• Additional relevant MeSH terms: Heart Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Aspirin; Clopidogrel

Study Results

Participant Flow

Arm/Group Title	Overall Study
Arm/Group Description	Participants will receive clopidogrel treatment alone, followed by clopidogrel plus aspirin treatment on the last day of treatment. 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
Period Title: Clopidogrel Treatment
STARTED	682
COMPLETED	669
NOT COMPLETED	13
Period Title: Clopidogrel Treatment
STARTED	669
COMPLETED	663
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	Participants will receive clopidogrel treatment alone, followed by clopidogrel plus aspirin treatment on the last day of treatment. 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
Overall Participants	682
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.5 (13.5)
Sex: Female, Male (Count of Participants)
Female	343 50.3%
Male	339 49.7%
Region of Enrollment (participants) [Number]
United States	682 100%

Outcome Measures

1. Primary Outcome

Title	Changes in Platelet Function in Response to Clopidogrel
Description	Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation.
Time Frame	Measured at baseline, and after clopidogrel treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Overall Study
Arm/Group Description	Participants will receive clopidogrel treatment alone, followed by clopidogrel plus aspirin treatment on the last day of treatment. 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 PRP ADP 20 = Platelet Rich Plasma ADP-induced (20 microM) aggregation PRP Collagen 5 = Platelet Rich Plasma Collegan-induced (5 microM) aggregation
Measure Participants	669
PRP ADP 20	38.51 (14.30)
PRP Collagen 5	14.06 (15.01)

2. Primary Outcome

Title	Changes in Platelet Function in Response to Clopidogrel Plus Aspirin
Description	Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation
Time Frame	Measured at baseline, and after clopidogrel plus aspirin treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Overall Study
Arm/Group Description	Participants will receive clopidogrel treatment alone, followed by clopidogrel plus aspirin treatment on the last day of treatment. 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 PRP ADP 20 = Platelet Rich Plasma ADP-induced (20 microM) aggregation PRP Collagen 5 = Platelet Rich Plasma Collegan-induced (5 microM) aggregation
Measure Participants	663
PRP ADP 20	41.21 (13.09)
PRP Collagen 5	56.64 (14.44)

Adverse Events

Time Frame	37 days
Adverse Event Reporting Description	Adverse event data were collected during both intervention periods and for 30 days after the final study visit. There were 6 Adverse Events during the Clopidogrel Treatment Arm and 2 Adverse Events during the Clopidogrel plus Aspirin Arm. This does not exceed the threshold for reporting Other Adverse Events.
Arm/Group Title	Overall Study
Arm/Group Description	Participants will receive clopidogrel treatment alone, followed by clopidogrel plus aspirin treatment on the last day of treatment. 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
All Cause Mortality
	Overall Study
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Overall Study
	Affected / at Risk (%)	# Events
Total	0/682 (0%)
Other (Not Including Serious) Adverse Events
	Overall Study
	Affected / at Risk (%)	# Events
Total	0/682 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.