Back to resultsDetermining Genetic Role in Treatment Response to Anti-Platelet Interventions (The PAPI Study)
Primary Purpose
Platelet Aggregation Inhibitors, Coronary Heart Disease
Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Clopidogrel
Aspirin
Sponsored by
About this trial
This is an interventional treatment trial for Platelet Aggregation Inhibitors
Eligibility Criteria
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
Sites / Locations
- Amish Research Clinic
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Overall Study
Arm Description
Participants will receive clopidogrel treatment alone, followed by clopidogrel plus aspirin treatment on the last day of treatment.
Outcomes
Primary Outcome Measures
Changes in Platelet Function in Response to Clopidogrel
Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation.
Changes in Platelet Function in Response to Clopidogrel Plus Aspirin
Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation
Secondary Outcome Measures
Full Information
NCT ID
NCT00799396
First Posted
November 26, 2008
Last Updated
February 22, 2022
Sponsor
University of Maryland, Baltimore
Collaborators
National Institute of General Medical Sciences (NIGMS), National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT00799396
Brief Title
Determining Genetic Role in Treatment Response to Anti-Platelet Interventions (The PAPI Study)
Official Title
Pharmacogenomics of Anti-Platelet Interventions (The PAPI Study)
Study Type
Interventional
2. Study Status
Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
July 2006 (undefined)
Primary Completion Date
February 2012 (Actual)
Study Completion Date
February 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Maryland, Baltimore
Collaborators
National Institute of General Medical Sciences (NIGMS), National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Platelet Aggregation Inhibitors, Coronary Heart Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
682 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Overall Study
Arm Type
Experimental
Arm Description
Participants will receive clopidogrel treatment alone, followed by clopidogrel plus aspirin treatment on the last day of treatment.
Intervention Type
Drug
Intervention Name(s)
Clopidogrel
Intervention Description
300 mg on first day, then 75 mg per day for the next 6 days
Intervention Type
Drug
Intervention Name(s)
Aspirin
Intervention Description
Single dose of 324 mg on the last day of clopidogrel treatment
Primary Outcome Measure Information:
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
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alan R. Shuldiner, MD
Organizational Affiliation
University of Maryland, Baltimore
Official's Role
Principal Investigator
Facility Information:
Facility Name
Amish Research Clinic
City
Lancaster
State/Province
Pennsylvania
ZIP/Postal Code
17601
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
19706858
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 effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232.
Results Reference
result
PubMed Identifier
26374108
Citation
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 Pharmacol. 2016;14(1):116-24. doi: 10.2174/1570161113666150916094829.
Results Reference
result
PubMed Identifier
23392654
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 variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes. Circ Cardiovasc Genet. 2013 Apr;6(2):184-92. doi: 10.1161/CIRCGENETICS.111.964627. Epub 2013 Feb 7.
Results Reference
result
PubMed Identifier
23111421
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 increased clopidogrel active metabolite levels and greater clopidogrel response. Pharmacogenet Genomics. 2013 Jan;23(1):1-8. doi: 10.1097/FPC.0b013e32835aa8a2.
Results Reference
result
PubMed Identifier
21881565
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. 2011 Oct;90(4):568-74. doi: 10.1038/clpt.2011.194. Epub 2011 Aug 31. Erratum In: Clin Pharmacol Ther. 2012 Apr;91(4):751.
Results Reference
result
PubMed Identifier
23809542
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. doi: 10.1111/jth.12342.
Results Reference
result
PubMed Identifier
29653637
Citation
Bergmeijer TO, Reny JL, Pakyz RE, Gong L, Lewis JP, Kim EY, Aradi D, Fernandez-Cadenas I, Horenstein RB, Lee MTM, Whaley RM, Montaner J, Gensini GF, Cleator JH, Chang K, Holmvang L, Hochholzer W, Roden DM, Winter S, Altman RB, Alexopoulos D, Kim HS, Dery JP, Gawaz M, Bliden K, Valgimigli M, Marcucci R, Campo G, Schaeffeler E, Dridi NP, Wen MS, Shin JG, Simon T, Fontana P, Giusti B, Geisler T, Kubo M, Trenk D, Siller-Matula JM, Ten Berg JM, Gurbel PA, Hulot JS, Mitchell BD, Schwab M, Ritchie MD, Klein TE, Shuldiner AR; ICPC Investigators. Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am Heart J. 2018 Apr;198:152-159. doi: 10.1016/j.ahj.2017.12.010. Epub 2017 Dec 17.
Results Reference
derived
PubMed Identifier
27799230
Citation
Salimi S, Lewis JP, Yerges-Armstrong LM, Mitchell BD, Saeed F, O'Connell JR, Perry JA, Ryan KA, Shuldiner AR, Parsa A. Clopidogrel Improves Skin Microcirculatory Endothelial Function in Persons With Heightened Platelet Aggregation. J Am Heart Assoc. 2016 Oct 31;5(11):e003751. doi: 10.1161/JAHA.116.003751. Erratum In: J Am Heart Assoc. 2017 Feb 14;6(2):
Results Reference
derived
Links:
URL
http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000391.v1.p1
Description
dbGaP submission for the PAPI study
Learn more about this trial
Determining Genetic Role in Treatment Response to Anti-Platelet Interventions (The PAPI Study)
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