Pharmacogenomics of Antiplatelet Response - I (PARes-I)

• ClinicalTrials.gov Identifier: NCT01815008
• Recruitment Status: Completed
• First Posted: March 20, 2013
• Results First Posted: January 9, 2017
• Last Update Posted: January 9, 2017
• Sponsor: Johns Hopkins University
• Information provided by (Responsible Party): Rehan Qayyum, Johns Hopkins University

Study Description

Brief Summary:

This clinical trial is examining the role of genetic polymorphism on the effect of clopidogrel (with or without aspirin) on platelet response in persons at high-risk for myocardial infarction or stroke due to family history of early-onset coronary artery disease.

Condition or disease	Intervention/treatment	Phase
Platelet Aggregation; Platelet Transcriptome; Coronary Artery Disease	Drug: Clopidogrel; Drug: Aspirin	Phase 4

Detailed Description:

The main goal of this study is to explore the impact of the PEAR1 genetic variant (rs12041331) on responsiveness to clopidogrel. The investigators will further assess the role of other genetic variants in determining the response to single or dual anti-platelet therapy. Apparently healthy subjects (N= 2108) from high-risk families are being (a) identified from a proband with early-onset CAD and (b) genotyped on the Illumina 1 million platform, with imputation to 2.5 million single nucleotide polymorphisms. The investigators plan to characterize the variance in platelet aggregation to multiple agonists (ADP, collagen, and arachidonic acid) after 1-week therapy with clopidogrel in a high-risk subset of GeneSTAR subjects (N=100). The investigators further plan to determine the extent to which variants identified in the PEAR1 gene modify platelet responsiveness to inhibition by clopidogrel in this high-risk subset. In addition, the investigators aim is to determine the extent to which variants in other recently discovered genes, by themselves, and in combination with PEAR1, modify platelet responsiveness to clopidogrel alone and with aspirin in this high-risk subset. Lastly, the investigators also want to determine what changes in platelet mRNA are produced by aspirin alone and by aspirin with clopidogrel.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: PHARMACOGENOMICS OF ANTI-PLATELET RESPONSE - I
• Study Start Date: October 2012
• Actual Primary Completion Date: June 2014
• Actual Study Completion Date: June 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Clopidogrel; Clopidogrel 75 mg daily by mouth for 1 week then Clopidogrel 75 mg daily with aspirin 81 mg daily	Drug: Clopidogrel; Clopidogrel 75 mg daily; Other Name: Plavix; Drug: Aspirin; Aspirin 81 mg daily

Outcome Measures

Primary Outcome Measures :

1. Difference in ADP-induced Platelet Aggregation [ Time Frame: at baseline and at 1 week ]
   ADP-induced platelet aggregation will be measured using impedance aggregometry in whole blood before and after 1-week of clopidogrel. The difference between the baseline and after clopidogrel therapy will be determined. Higher impedance represent higher platelet aggregation.

Secondary Outcome Measures :

1. Difference in Arachidonic Acid-induced Platelet Aggregation [ Time Frame: At baseline and after 1-week ]
   Arachidonic Acid-induced platelet aggregation will be measured using impedance aggregometry in whole blood before and after 1-week of clopidogrel. The difference between the baseline and after clopidogrel therapy will be determined
2. Difference in Collagen-induced Platelet Aggregation [ Time Frame: At Baseline and at 1 week ]
   Collagen-induced platelet aggregation will be measured using impedance aggregometry in whole blood before and after 1-week of clopidogrel. The difference between the baseline and after clopidogrel therapy will be determined
3. Changes in Platelet Transcriptome With Clopidogrel [ Time Frame: At baseline and at 1 week ]
   Platelet transcriptome will be examined before and after 1 week of therapy with clopidogrel and differences will be determined

Eligibility Criteria

• Ages Eligible for Study: 45 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participants from the GeneSTAR cohort
• Unaffected with no overt coronary artery disease or serious vascular event (stroke or peripheral vascular disease diagnosis
• Presence of an occult coronary artery disease phenotype as defined by coronary artery calcium scores about the MESA (Multiethnic Study of Atherosclerosis) 75th percentile for age sex, and race or ≥ 1 stenoses in any of the major coronary arteries or main branches of > 50%, or coronary plaque volumetric scores above our own 75th percentile, or any combination on cardiac computed tomographic angiography (performed recently as part of the GeneSTAR study and present for all persons being recruited)/
• Presence of occult cerebrovascular disease defined as presence of white matter hyperintensities (WMH) thought to represent ischemic small vessel cerebrovascular disease, and /or the presence of lacunes (old small strokes), or the presence of an Atherosclerosis Risk in Communities Study (ARIC) silent stroke score on a visual analogue scales of 4 or more (on a scale of 0-9).
• Women who are postmenopausal.
• Women who use a reliable contraceptive method; a reliable contraceptive method will be defined as personal history of tubal ligation, ongoing use of intra-uterine device, or ongoing use of oral contraceptive pills.

Exclusion Criteria:

• Presence of any CAD or stroke, transient ischemic attacks, peripheral arterial disease
• Persons taking aspirin, NSAIDS, or any anti-coagulants who are medically unable to stop them for a two week pre-trial
• A history of allergy to aspirin or clopidogrel
• Weight < 60kg
• Age < 45 and > 75 years of age
• A history of recent or any active bleeding
• Serious or current co-morbidity (AIDS, cancer)
• Pregnant women as determined by urine dipstick pregnancy test
• Any aneurysms on cranial magnetic resonance imaging/magnetic resonance angiography (obtained recently in the GeneSTAR participants)
• Blood pressure above >=159/95mmHg
• History of a gastric or duodenal ulcer, or significant gastrointestinal disease, like regional enteritis
• Mental incompetence to make a decision to participate (developmentally disabled, and persons with diagnosed psychiatric disorders-documented in primary care records).

Contacts and Locations

Locations

United States, Maryland

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States, 21287

Sponsors and Collaborators

Johns Hopkins University

Investigators

• Principal Investigator: Rehan Qayyum, MD; Johns Hopkins University

More Information

Additional Information:

GeneSTAR Research Program 

• Responsible Party: Rehan Qayyum, Assistant Professor of Medicine, Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01815008
• Other Study ID Numbers: K23HL105897-PARes-I; K23HL105897 ( U.S. NIH Grant/Contract )
• First Posted: March 20, 2013
• Results First Posted: January 9, 2017
• Last Update Posted: January 9, 2017
• Last Verified: November 2016

Keywords provided by Rehan Qayyum, Johns Hopkins University:

Platelet aggregation; Clopidogrel; Platelet transcriptome

Additional relevant MeSH terms:

Coronary Artery Disease; Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Aspirin; Clopidogrel; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Neurotransmitter Agents