Ignite Creation Date:
2024-05-05 @ 11:43 PM
Last Modification Date:
2024-10-26 @ 10:37 AM
Study NCT ID:
NCT01390974
Status:
COMPLETED
Last Update Posted:
2014-02-10
First Post:
2011-07-07
Brief Title:
Identification of Clopidogrel CYP2C19 Metabolizer and Thienopyridine Treatment After an Acute Coronary Syndrome
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Bedside Genetic Approach to Identify Clopidogrel CYP2C19 Metabolizer and Optimize Maintenance Thienopyridine Treatment After an Acute Coronary Syndrome The GAMMA Study
Status:
COMPLETED
Status Verified Date:
2014-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GAMMA
Brief Summary:
To demonstrate that a strategy of fast genetic testing performed in outpatient clinic allows to select adequately one of the 2 antiplatelet treatments approved in the same indication ACS with PCI - prasugrel 10mg MD or clopidogrel 75mg MD Patients will reach similar levels of platelet inhibition with the 2 different thienopyridines suggesting optimal riskbenefit ratio in most patients with individualized therapy
Detailed Description:
Rationale There are thresholds of on-treatment platelet reactivity that appear to expose patients either to a risk of thrombotic events high on-treatment platelet reactivity or to a risk of bleeding events low on-treatment platelet reactivity Clopidogrel is an oral platelet P2Y12 receptor inhibitor that requires metabolic activation catalyzed by several Cytochromes P450 CYP isoforms The loss-of-function polymorphism 2C192 carried by 30 of individuals is associated with high-on-treatment platelet reactivity low level of P2Y12 inhibition and a higher risk of stent thrombosis in patients exposed to clopidogrel OR345 214-557 The gain-of-function polymorphism 2C1917 is associated with low-on-treatment platelet reactivity high level of P2Y12 inhibition with a higher risk of TIMI major bleeding OR185 119 -286 Prasugrel is a new thienopyridine drug with improved ischemic outcomes compared with clopidogrel in acute coronary syndrome patients undergoing PCI but the drug was also associated with more bleeding complications Prasugrel is a more potent irreversible P2Y12inhibitor than clopidogrel but it also requires a metabolic conversion that is less or not affected by CYP2C19 variants unlike clopidogrel The recent pharmacogenetic literature suggests that individualized treatment choice between clopidogrel or prasugrel which both are possible in this indication based on the genetic information rapidly obtained is possible This would improve the riskbenefit of therapy Both common gain- and loss-of function CYP2C19 alleles can be combined to identify two metabolizers status rapid metabolizer ultra fast or UF 1717 5 of all comers and normal metabolizers or NM 11 et 117 50 of all comers at potential higher risk of bleeding and slow metabolizer Intermediate Metabolizers or IM 12 and 217 40 of all comers and Poor Metabolizers or PM 22 5 of all comers at potential higher risk of thrombosis Primary hypothesis genetic hypothesis the proportion of rapid metabolizers treated with a 75mg clopidogrel MD within the optimal range of P2Y12 inhibition at 30 days defined as a threshold of 220 AUmin up to 350 AUmin of ADP-induced platelet aggregation measured by the Multiple Electrode platelet Aggregometry - Multiplate analyzer DYNABYTE Munich Germany or a inhibition between 30 up to 80 using the VerifyNowTMP2Y12 platform is non inferior to the proportion of slow metabolizers treated with prasugrel 10mg MDSecondary hypothesis functional hypothesis At 30 days patients outside the pre-specified target of P2Y12 inhibition level will be adjusted prasugrel 10mg or clopidogrel 75mg The hypothesis is that PFT on top of genetic testing will improve the number of patients reaching the prespecified optimal target of P2Y12 inhibition Thus the proportion of slow metabolizers within the target at D45 is non inferior to that of rapid metabolizer as determined by the POC PFT Objectives To demonstrate that a strategy of fast genetic testing performed in outpatient clinic allows to select adequately one of the 2 antiplatelet treatments approved in the same indication ACS with PCI - prasugrel 10mg MD or clopidogrel 75mg MD Patients will reach similar levels of platelet inhibition with the 2 different thienopyridines suggesting optimal riskbenefit ratio in most patients with individualized therapy Study population ACS patients who recently underwent stent PCI who are stable and eligible for prasugrel or clopidogrel therapyStudy design Prospectivemulticenter study Genetic metabolizer status will be determined using the VerigeneTM Nanosphere technology platform during outpatient follow-up visit Thienopyridine treatment at enrolment will not affect eligibility Rapid metabolizers UF and NM will be treated by 75mg clopidogrel MD while slow metabolizers IM and PM will be allocated to prasugrel 10mg MD A first evaluation of platelet reactivity will be performed one month after to allow the comparison of the proportion of patients who are within the optimal prespecified window of P2Y12 inhibition primary hypothesis The investigators will evaluate the hypothesis that a treatment adjustment based on the results obtained by this pharmacodynamic evaluation will improve the rate of success In this second phase patients with a level of P2Y12 inhibition 80 220AUmin or 30 350 AUmin will be switched to 75mg clopidogrel MD and or to prasugrel 10mg MD respectively A second evaluation of the level of platelet reactivity will be performed at day 45 to allow the comparison of proportions of patients within the prespecified optimal window of P2Y12 inhibition between rapid and slow metabolizer genotypes Duration of inclusion 12 months Duration of participation of the patient 60 days Primary endpoint Proportion of patient who are within the optimal prespecified window of P2Y12 inhibition at 30 days defined as a threshold of 220 AUmin up to 350 AUmin of ADP-induced platelet aggregation measured by the Multiple Electrode platelet Aggregometry - Multiplate analyzer DYNABYTE Munich Germany or a inhibition between 30 up to 80 using the VerifyNowTMP2Y12 platformNumber of patients The investigators have estimated the proportion of prasugrel-treated patients within the prespecified target of P2Y12 inhibition to be 75 The investigators have formulated the hypothesis that 80 of rapid metabolizers on clopidogrel 75mg MD will stand in the optimal prespecified window of P2Y12 inhibition and the investigators wish to demonstrate that this proportion is not inferior to that of prasugrel-treated patients Considering a power of 80 an alpha-risk error of 005 and a non-inferiority margin of -10 a sample size of 122 patients per group are required Expected results The GAMMA study will provide answers to a major challenge that is whether rapid genetic information on 2C19 genotype can help in reaching the optimal target of IPA using 2 different thienopyridine that have different sensitivity to the CYP2C19 variants Statistical analysis The non inferiority will be considered as demonstrated according to the consent risk if the non inferiority margin of the 95 confidence interval of the difference in percentages is superior to the non inferiority margin ICH Statistical Procedures The non-inferiority margin has been established at -10 according to clinical considerations based on an acceptable maximal lost of efficacy
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2011-A00543-38 | OTHER | IDRCB | None |