Escalating Clopidogrel by Involving a Genetic Strategy - Thrombolysis In Myocardial Infarction 56

Myocardial Infarction Clinical Trial

— ELEVATE  

Official title:

Escalating Clopidogrel by Involving a Genetic Strategy - Thrombolysis In Myocardial Infarction 56

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01235351
• Other study ID #: TIMI 56
• Status: Completed
• Phase: Phase 2
• Start date: October 2010
• Est. completion date: September 2011

Study information

• Verified date: November 2019
• Source: The TIMI Study Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 335
• Est. completion date: September 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria (major):

1. Between 18 and 75 years of age, inclusive.

2. Have an indication for the use of clopidogrel defined as either spontaneous MI [hospitalized with final diagnosis of MI, excluding periprocedural or definite secondary MI (e.g., due to anemia or hypertensive emergency)] or PCI within the past 6 months.

3. Clinically stable and at least 4 weeks following the MI or PCI.

Exclusion Criteria (major):

1. Conditions that alter platelet function.

2. Conditions that increase bleeding risk.

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction
• Percutaneous Coronary Intervention

Intervention

Drug:
• Clopidogrel
Clopidogrel 75 mg daily, 150 mg daily, 225 mg daily, and 300 mg daily based on genotype
• Clopidogrel
Clopidogrel 75 mg daily, 150 mg daily

Locations

Country	Name	City	State
United States	TIMI Study Group	Boston	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
The TIMI Study Group	Bristol-Myers Squibb, Sanofi

Country where clinical trial is conducted

United States, 

References & Publications (3)

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 Tr — View Citation

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: insight — View Citation

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 platel — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Approximately every 2 weeks for 8 weeks