Customized Choice of Oral P2Y12 Receptor Blocker

Acute Coronary Syndrome Clinical Trial

— PRU-MATRIX  

Official title:

Customized Choice of P2Y12 Oral Receptor Blocker Based on Phenotype Assessment Via Point of Care Testing

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01477775
• Other study ID #: RFBU 13-I-PRU
• Status: Recruiting
• Phase: Phase 4
• First received: October 27, 2011
• Last updated: September 1, 2014
• Start date: January 2012
• Est. completion date: December 2015

Study information

• Verified date: September 2014
• Source: Italian Society of Invasive Cardiology
• Contact: Marco Valgimigli, MD, PhD
• Phone: 3356478877
• Email: vlgmrc[@]unife.it
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial Summary

A subset of patients recruited in the main MATRIX study will be randomized after intervention but before discharge to standard of care (the treating physician will decide which oral P2Y12 inhibitor will be added on top of aspirin) versus a customized approach based on an algorithm which integrates phenotypic information, including but not limited to residual on-treatment platelet reactivity assessed via VerifyNow P2Y12 Assay.

Description:

Up to 20-30% of clopidogrel treated patients do not adequately respond to the drug and are at higher risk for ischemic events including death, myocardial infarction, stroke and stent thrombosis.

Residual high on-treatment platelet reactivity while the patient is on clopidogrel depends on a complex interplay of phenotypic (spontaneous platelet reactivity, inflammatory status, acuity of the clinical presentation, age, renal function) and genetic variables.

Two main Loss of function alleles have been identified: 1) CYP450 2C19*2 is present in around 25% of the Caucasian population and result in a lower amount of clopidogrel active metabolite. Carriers of 2C19*2 are at higher risk for death or MI and 2.7 fold increase in the risk of stent thrombosis if treated with conventional clopidogrel; 2) ABCB-1 C carriers have reduced clopidogrel absorption and they have similarly been shown to be at higher risk for ischemic adverse events if treated with clopidogrel. Many investigators have recently shown however, that the positive predictive value of genetic testing alone at the time of PCI is limited and the knowledge of genetic status alone with respect to the two previously described loss of function alleles is only poorly able to identify to long-term clopidogrel poor responders. An Algorithm has therefore been developed, combining phenotype information which has been shown to risk stratify both ischemic and bleeding events up to one year follow-up in PCI patients.

This algorithm has been developed from a single center retrospective registry. To prospectively validate it in the context of a prospective multicenter study, the first 320 patients recruited in the present study will undergo phenotype at discharge and at 30 days and genotype assessment at the time of randomization, irrespective of the group which they have been assigned to (i.e. standard of care or gene and phenotype). The hypothesis behind this mechanistic sub-study is that the use of this combined phenotype-genotype algorithm will increase the proportion of patients at 30 days who will be in the therapeutic range according to PRU values from 50% in the standard of care versus 70% in the gene and phenotype group.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 4000
• Est. completion date: December 2015
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• patients recruited in the main MATRIX study who underwent coronary angioplasty with stent placement.

Exclusion Criteria:

• unwillingness to sign this sub study specific informed consent

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Coronary Angioplasty

Intervention

Drug:
• Oral P2Y12 receptor blocker
Free choice among clopidogrel, prasugrel or ticagrelor
• Customized choice for the oral P2Y12 receptor blocker
one drug among clopidogrel, prasugrel or ticagrelor based on an algorithm integrating phenotype information.

Locations

Country	Name	City	State
Italy	Spedali Civili di Brescia	Brescia
Italy	Azienda USL Sirai	Carbonia
Italy	Azienda Ospedaliera Pugliese Ciaccio	Catanzaro	Calabria
Italy	University Hospital of Ferrara	Ferrara
Italy	Ospedale di Lodi	Lodi
Italy	Azienda Ospedaliera Fatebenefratelli e Oftalmico	Milano	MI
Italy	Ospedale dei Colli, Cardiologia SUN	Naples
Italy	Ospedale degli Infermi di Rimini	Rimini
Italy	Ospedale San Giovanni Bosco	Torino
Italy	A. O. Ospedale Civile di Vimercate	Vimercate
Italy	Policlinico San Marco	Zingonia

Sponsors (2)

Lead Sponsor	Collaborator
Italian Society of Invasive Cardiology	Eustrategy

Country where clinical trial is conducted

Italy, 

References & Publications (4)

Campo G, Ferraresi P, Marchesini J, Bernardi F, Valgimigli M. Relationship between paraoxonase Q192R gene polymorphism and on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention. J Thromb Haemost. 2011 Oct;9(10):2106-8. doi: 10.1111/j.1538-7836.2011.04457.x. — View Citation

Campo G, Miccoli M, Tebaldi M, Marchesini J, Fileti L, Monti M, Valgimigli M, Ferrari R. Genetic determinants of on-clopidogrel high platelet reactivity. Platelets. 2011;22(6):399-407. doi: 10.3109/09537104.2011.579648. Epub 2011 May 31. Review. — View Citation

Campo G, Parrinello G, Ferraresi P, Lunghi B, Tebaldi M, Miccoli M, Marchesini J, Bernardi F, Ferrari R, Valgimigli M. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol. 2011 Jun 21;57(25):2474-83. doi: 10.1016/j.jacc.2010.12.047. — View Citation

Valgimigli M, Campo G, de Cesare N, Meliga E, Vranckx P, Furgieri A, Angiolillo DJ, Sabatè M, Hamon M, Repetto A, Colangelo S, Brugaletta S, Parrinello G, Percoco G, Ferrari R; Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R) Investigators. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel study. Circulation. 2009 Jun 30;119(25):3215-22. doi: 10.1161/CIRCULATIONAHA.108.833236. Epub 2009 Jun 15. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cardiovascular death, myocardial infarction, stroke or BARC defined bleeding type 2, 3 or 5	The time to first occurrence of any of the variables listed above will be reported as primary study outcome.	1 year	Yes
Primary	Proportion of patients in the therapeutic range for residual P2Y12 pathway activity according to PRU values.	We expect that the prospective use of the previously generated combined phenotype and genotype algorithm will result in an higher proportion of patients being in the therapeutic range with respect to the P2Y12 residual activity (70%) as compared to patients in who the P2Y12 inhibitor is left to the discretion of the treating physician. The first 320 patients recruited in the present study will participate into this mechanistic sub-study.	30 days	No
Secondary	Overall death		1	Yes
Secondary	cardiovascular death		1 year	Yes
Secondary	myocardial infarction		1 year	Yes
Secondary	stroke		1 year	Yes
Secondary	BARC bleeding type 2		1 year	Yes
Secondary	BARC bleeding type 3		1 year	Yes
Secondary	BARC bleeding type 5		1 year	Yes
Secondary	Bleeding classified according to the Bleedscore		1 year	Yes
Secondary	Stent thrombosis	Stent thrombosis will be reported according to the ARC classification	1 year	Yes