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| Name | Class |
|---|---|
| Bristol-Myers Squibb | INDUSTRY |
| Sanofi | INDUSTRY |
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To determine whether higher as compared with lower maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele.
Clopidogrel blocks the P2Y12 ADP receptor on platelets and has been shown to reduce cardiovascular events in acute coronary syndrome (ACS) patients.However, inter-patient variability in the pharmacodynamic response to clopidogrel is well recognized, and patients with lesser degrees of platelet inhibition in response to clopidogrel have been shown to be at increased risk of cardiovascular events.
One potential source of this variability is the metabolism of clopidogrel, which is a pro-drug requiring biotransformation to become an active antiplatelet compound. Cytochrome P-450 (CYP) enzymes play a role in the metabolism, and carriers of reduced-function genetic variants in CYP2C19 (~30% of the population) have lower active clopidogrel metabolite levels, diminished platelet inhibition, and higher rates of adverse cardiovascular events as compared with non-carriers in the setting of treatment with standard maintenance doses of clopidogrel.
Aim: To determine whether higher as compared with lower maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele.
Hypotheses: The primary hypothesis is that subjects who carry a reduced-function CYP2C19 allele will have improvement in platelet inhibition with higher maintenance doses of clopidogrel.The secondary hypothesis is that higher maintenance doses of clopidogrel in carriers of a reduced-function CYP2C19 allele will result in similar platelet inhibition as compared to a standard maintenance dose of clopidogrel in non-carriers.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Clopidogrel - for CYP2C19*2 carriers | Active Comparator | Clopidogrel for CYP2C19*2 gene carriers |
|
| Clopidogrel - for CYP2C19*2 non-carriers | Active Comparator | Clopidogrel for CYP2C19*2 gene NON-carriers |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clopidogrel | Drug | Clopidogrel 75 mg daily, 150 mg daily, 225 mg daily, and 300 mg daily based on genotype |
|
| Measure | Description | Time Frame |
|---|---|---|
| Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | The outcome measurement was on-treatment PRI determined through flow cytometric assessment of phosphorylation status of VASP. | Approximately every 2 weeks for 8 weeks |
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Inclusion Criteria (major):
Exclusion Criteria (major):
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| Name | Affiliation | Role |
|---|---|---|
| Christian T Ruff, MD, MPH | The TIMI Study Group | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| TIMI Study Group | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22088980 | Result | Mega JL, Hochholzer W, Frelinger AL 3rd, Kluk MJ, Angiolillo DJ, Kereiakes DJ, Isserman S, Rogers WJ, Ruff CT, Contant C, Pencina MJ, Scirica BM, Longtine JA, Michelson AD, Sabatine MS. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA. 2011 Nov 23;306(20):2221-8. doi: 10.1001/jama.2011.1703. Epub 2011 Nov 16. | |
| 25060370 |
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335 patients enrolled, 2 patients not genotyped 333 patient allocated to initial treatment with 75 mg and 150 mg clopidogrel
335 patients from 32 sites were enrolled from October 2010 until September 2011.
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| ID | Title | Description |
|---|---|---|
| FG000 | CYP2C19*2 Non-Carrier | Period 1: clopidogrel 75 mg and 150 mg for 14 days each Period 2: crossover to sequences of clopidogrel (75 mg first, then 150 mg, and 150 mg first, then 75 mg) for 14 days each. |
| FG001 | CYP2C19*2 Carrier | Period 1: clopidogrel 75 mg and 150 mg for 14 days each Period 2: crossover to sequences of clopidogrel (225 mg first, then 300 mg, and 300 mg first, then 225 mg) for 14 days each. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Initial Treatment With 75 mg and 150 mg |
|
| ||||||||||||||||||
| Treatment With Different Dose Sequences |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | CYP2C19*2 Non-Carriers | |
| BG001 | CYP2C19*2 Carriers | |
| BG002 | Total |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | The outcome measurement was on-treatment PRI determined through flow cytometric assessment of phosphorylation status of VASP. | Non-carriers did not receive clopidogrel 225 mg or 300 mg | Posted | Mean | 95% Confidence Interval | % of PRI | Approximately every 2 weeks for 8 weeks |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | CYP2C19*2 Carriers 75 mg | Patient with a carrier of genotype given 75 mg of the drug |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Blood and lymphatic system disorder | Blood and lymphatic system disorders | Systematic Assessment | 1 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jessica L. Mega, MD, MPH | TIMI Study Group | 6172780145 | jmega@partners.org |
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| ID | Term |
|---|---|
| D009203 | Myocardial Infarction |
| ID | Term |
|---|---|
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D000077144 | Clopidogrel |
| ID | Term |
|---|---|
| D013988 | Ticlopidine |
| D058924 | Thienopyridines |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
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| Clopidogrel | Drug | Clopidogrel 75 mg daily, 150 mg daily |
|
| Result |
| Hochholzer W, Ruff CT, Mesa RA, Mattimore JF, Cyr JF, Lei L, Frelinger AL 3rd, Michelson AD, Berg DD, Angiolillo DJ, O'Donoghue ML, Sabatine MS, Mega JL. Variability of individual platelet reactivity over time in patients treated with clopidogrel: insights from the ELEVATE-TIMI 56 trial. J Am Coll Cardiol. 2014 Jul 29;64(4):361-8. doi: 10.1016/j.jacc.2014.03.051. |
| 27009617 | Result | Carreras ET, Hochholzer W, Frelinger AL 3rd, Nordio F, O'Donoghue ML, Wiviott SD, Angiolillo DJ, Michelson AD, Sabatine MS, Mega JL. Diabetes mellitus, CYP2C19 genotype, and response to escalating doses of clopidogrel. Insights from the ELEVATE-TIMI 56 Trial. Thromb Haemost. 2016 Jul 4;116(1):69-77. doi: 10.1160/TH15-12-0981. Epub 2016 Mar 24. |
| 150 mg First Then 75 mg |
|
| 225 mg First Then 300 mg |
|
| 300 mg First Then 225 mg |
|
| COMPLETED |
|
| NOT COMPLETED |
|
Total of all reporting groups
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| 1 |
| 82 |
| 0 |
| 82 |
| EG001 | CYP2C19*2 Carriers 150 mg | Patient with a carrier of genotype given 150 mg of the drug | 5 | 82 | 0 | 82 |
| EG002 | CYP2C19*2 Carriers 225 mg | Patient with a carrier of genotype given 225 mg of the drug | 0 | 82 | 0 | 82 |
| EG003 | CYP2C19*2 Carriers 300mg | Patient with a carrier of genotype given 300 mg of the drug | 0 | 82 | 0 | 82 |
| EG004 | CYP2C19*2 Noncarriers 75 mg | Patients who are non-carriers of the genotype given 75 mg of the drug | 24 | 233 | 0 | 233 |
| EG005 | CYP2C19*2 Noncarriers 150 mg | Patients who are non-carriers of the genotype given 150 mg of the drug | 16 | 233 | 0 | 233 |
|
| Cardiac disorders | Cardiac disorders | Systematic Assessment |
|
| Gastrointestinal disorders | Gastrointestinal disorders | Systematic Assessment |
|
| General disorders and administration site conditions | General disorders | Systematic Assessment |
|
| Infections and infestations | Infections and infestations | Systematic Assessment |
|
| Injury, poisoning and procedural complications | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Respiratory, thoracic and mediastinal disorders | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Vascular disorders | Vascular disorders | Systematic Assessment |
|
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| D007238 |
| Infarction |
| D007511 | Ischemia |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009336 | Necrosis |
| D009930 |
| Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |