Acute Coronary SyndromesPHARMCLONCT03347435
Pharmacogenetics of Clopidogrel in Acute Coronary Syndromes
A study testing genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 and clinical algorithm in people with Acute Coronary Syndromes, run by Azienda Ospedaliero-Universitaria di Parma at 4 sites in Italy.
Trial summary
The antiplatelet agent clopidogrel is an effective drug for the prevention of thrombotic events in patients with acute coronary syndromes, and is therefore one of the most frequently prescribed drugs worldwide. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Coronary Syndromes
- What is being tested?
- genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 and clinical algorithm
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 889 participants
- Where
- 4 sitesItaly
- Study dates
- Jun 2013to Mar 2015
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of ACS (STE-ACS or NSTE-ACS) during the index hospitalisation
- Age >18 years
- Ability to sign the informed consent form
- Ability to attend scheduled visits
Who cannot join
- Cognitive or other causes of an inability to provide informed consent or follow study procedures
- Any contraindication to the use of ADP P2Y12 inhibitors
- Life expectancy <1 year
- Thrombolytic therapy within the previous 24 hours
- Known ABCB1, CYP2C19 *2 orCYP2C19 *17 genotype
Trial locations and contacts
4 sites in 1 country.
Italy4 sites
Ospedale Ramazzini
Carpi, Modena, 41012
Ospedale di Vaio
Fidenza, Parma, 43036
Azienda Ospedaliero Universitaria di Parma
Parma, 43123
Ospedale Guglielmo da Saliceto
Piacenza, 29121
About this study
The antiplatelet agent clopidogrel is an effective drug for the prevention of thrombotic events in patients with acute coronary syndromes, and is therefore one of the most frequently prescribed drugs worldwide. Accumulating data suggest that the response to clopidogrel is characterised by significant inter-patient variability in the degree of platelet inhibition and the risk of cardiovascular events. Recent research findings have highlighted the role of genetic variations in determining antiplatelet response variability, and this has aroused interest in genotyping all thienopyridine-eligible patients in order to identify those who would be at increased risk of harm if treated with clopidogrel. This is a prospective, multicentre, randomised study enrolling consecutive patients hospitalised because of an ACS with or without ST-segment elevation. The patients are randomised to undergo or not tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 genetic variants immediately after diagnosis. The genotyping is done using a Q3 System (a compact platform that enables the classic laboratory analysis of DNA by means of real-time PCR). The Q3 has been designed as a low entry-cost, portable, point-of-care instrument for foolproof use by unskilled personnel. The patients randomised to the pharmacogenomic arm receive one of the ADP receptor antagonists (clopidogrel/prasugrel/ticagrelor) on the basis of an algorithm that consider genetic and clinical variables. The patients randomised to the standard treatment arm receive clopidogrel or prasugrel or ticagrelor on the basis of the standard of care (clinical algorithm alone). For each patient, a record is made of the occurrence of cardiovascular death, non-fatal MI, stroke, BARC-defined bleeding, and definite or probable stent thrombosis. The primary endpoint is the composite of death due to cardiovascular causes, non-fatal MI and stroke. The secondary endpoints is the occurrence of definite or probable stent thrombosis, and BARC-defined major bleeding events (types 3-5).
Read the detailed description
Antiplatelet therapy is the cornerstone of medical treatment of patients experiencing an acute coronary syndrome (ACS). As a synergistic antiplatelet effect can be obtained by simultaneously inhibiting thromboxane-A2 and adenosine diphosphate P2Y12 platelet receptors, the current standard of care for all patients with ACS includes dual anti-platelet therapy with aspirin (the first choice treatment for blocking thromboxane-A2 receptors) and one of the three currently available ADP P2Y12 inhibitors: clopidogrel, prasugrel and ticagrelor.
Over the last few years, the clinical availability of the new potent P2Y12 inhibitors prasugrel and ticagrelor has changed the ACS treatment paradigm. The revised European guidelines downgrade clopidogrel to patients who cannot receive prasugrel and ticagrelor, and clearly recommend the latter for patients with ACS (Recommendation Class I, Evidence Level B for both). However, the choice of the optimal drug for each individual patient is still left to clinicians, thus continuing the uncertainty as to how these new potent drugs should be incorporated into everyday clinical practice.
The appropriate selection of antiplatelet agents has so far been guided only by the patients' phenotypic characteristics, but taken together, the evidence does not support a wide use of prasugrel and ticagrelor in clinical practice and considering subgroups with less clinical benefit and limitations of TRITON TIMI-38 and PLATO study design, not all 100% of patients with ACS appears eligible for treatment with new ADP receptors antagonists.
Recent research has highlighted the role of CYP enzyme and ABCB1 genetic variations in determining the variability of the patients' antiplatelet response to clopidogrel, and shown a clear relationship between lower levels of clopidogrel's active metabolite, reduced platelet inhibition, and a higher rate of major adverse cardiovascular events. Specifically, post-hoc analysis concerning association of CYP2C19 and ABCB1 genetic variants to clinical outcomes showed an absolute 7.3% reduction in the risk of death from cardiovascular causes, myocardial infarction or stroke among the study population who were not carriers of a CYP2C19 reduced-function allele, ABCB1 3435 TT homozygotes, or both, compared with individuals who did carry either.
The impact of CYP2C19 alleles and ABCB1 genotype seems to be restricted to patients taking clopidogrel as they do not significantly affect pharmacological or clinical outcomes in patients treated with prasugrel and ticagrelor.
The aim of this project is to test the impact on clinical outcomes of strategy of conducting dual antiplatelet therapy considering both genotype data and clinical variables in comparison with a strategy based on clinical variables alone.
Methodology:
This is a prospective, multicentre, randomised study enrolling 3,612 consecutive patients hospitalised because of an ACS with or without ST-segment elevation. The patients are randomised to undergo or not tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 genetic variants immediately after diagnosis. The genotyping is done using a Q3 System (a compact platform that enables the classic laboratory analysis of DNA by means of real-time PCR). The Q3 has been designed as a low entry-cost, portable, point-of-care instrument for foolproof use by unskilled personnel.
The patients randomised to the pharmacogenomic arm receive one of the ADP receptor antagonists (clopidogrel/prasugrel/ticagrelor) on the basis of an algorithm that consider genetic and clinical variables. The patients randomised to the standard treatment arm receive clopidogrel or prasugrel or ticagrelor on the basis of the standard of care (clinical algorithm alone).
Patient enrolment is to be completed in 24 months. Each patient will be followed up for 12 months by means of outpatient visits after one, six and 12 months.
For each patient, a record is made of the occurrence of cardiovascular death, non-fatal MI, stroke, BARC-defined bleeding, and definite or probable stent thrombosis.
The primary endpoint is the composite of death due to cardiovascular causes, non-fatal MI and stroke.
The secondary endpoints is the occurrence of definite or probable stent thrombosis, and BARC-defined major bleeding events (types 3-5).
The expected rate reduction of ischemic and bleeding events is 25% for a median of 12 months of follow-up (data derived from PLATO trial) and the target relative risk reduction for genotype-guided therapy versus standard therapy is 20%. It has been defined a 95% power, a type alpha error of 5% and two-tail test. Therefore approximately 1806 patients for each arm should be enrolled.
- Conditions
- Acute Coronary Syndromes
- Being tested
- genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435, clinical algorithm
- Keywords
- clopidogrel, pharmacogenetics, antiplatelet therapy, acute coronary syndromes
- Medical subject headings
- Acute Coronary Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435Genetic
The CYP2C19*2 (10q24.1-q24.3; rs4244285), CYP2C19*17 (10q24.1-q24.3; rs12248560) and ABCB1 3435 (7q21.1; rs1045642) genetic variants will be genotyped using an ST Q3 system. The conventional genotyping methods so far used for diagnostic purposes will not be used in this study because appropriate labs may not be readily available and the processing time is prohibitive. Q3 is a compact platform enabling the classical laboratory analysis of DNA by means of real-time PCR. The Q3 has been designed as a low entry-cost, portable, point-of-care instrument for foolproof use by unskilled personnel. Antiplatelet therapy will be choose on the basis of clinical and genetic algorithm.
clinical algorithmOther
Antiplatelet therapy will be choose on the basis of clinical algorithm alone
| Study group | Role | What they receive |
|---|---|---|
| Genotype/ phenotype guided group | Experimental | The patients randomized to the genotype/phenotype guided group undergo genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 genetic variants immediately after diagnosis of ACS and receive one of the ADP receptor antagonists (clopidogrel/prasugrel/ticagrelor) on the basis of an algorithm that consider genetic and clinical variables. Receives: Genetic: genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 |
| phenotype only guided group | Active comparator | The patients randomized to the phenotype only guided group receive clopidogrel or prasugrel or ticagrelor on the basis of the standard of care on the basis of clinical algorithm alone. Receives: Other: clinical algorithm |
What is being measured
The primary outcome is the main question the study is designed to answer.
Composite of cardiovascular death, non fatal myocardial infarction, stroke and BARC-defined major bleeding events 3 to 5.
The primary endpoint will be the composite of cardiovascular death, non fatal myocardial infarction, stroke and BARC-defined major bleeding events 3 to 5 at 12 months follow-up.
Measured: 12 months
Secondary outcomes (5)
occurrence of definite or probable stent thrombosis.
The secondary endpoint variable will be the occurrence of definite or probable stent thrombosis at 12 months follow-up.
Measured: 12 months
cardiovascular death
individual components of primary endpoint at 12 months follow-up
Measured: 12 months
non fatal myocardial infarction
individual components of primary endpoint at 12 months follow-up
Measured: 12 months
stroke
individual components of primary endpoint at 12 months follow-up
Measured: 12 months
BARC-defined major bleeding events 3 to 5
individual components of primary endpoint at 12 months follow-up
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Nov 2017
- Study startJun 2013
- Primary completionMar 2015
- Study completionMar 2015
Why it stopped: Ethics Committe decision
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Acute Coronary SyndromesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 889 participants (actual)
Sponsor and investigators
- Lead sponsor
- Azienda Ospedaliero-Universitaria di Parma
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Diego Ardissino, Azienda Ospedaliero-Universitaria di Parma
- Investigators
- Diego Ardissino, MD, Principal investigator, Azienda Ospedaliero-Universitaria di Parma
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03347435
- Sponsor's protocol ID
- 11210
- Acronym
- PHARMCLO
- Status last verified
- Nov 2017
- First submitted
- 10 Nov 2017
- Last updated
- 20 Nov 2017
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D; ESC Committee for Practice Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011 Dec;32(23):2999-3054. doi: 10.1093/eurheartj/ehr236. Epub 2011 Aug 26. No abstract available.
PubMed 21873419Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators; Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi: 10.1056/NEJMoa0904327. Epub 2009 Aug 30.
PubMed 19717846Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. doi: 10.1056/NEJMoa0706482. Epub 2007 Nov 4.
PubMed 17982182Matetzky S, Shenkman B, Guetta V, Shechter M, Beinart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004 Jun 29;109(25):3171-5. doi: 10.1161/01.CIR.0000130846.46168.03. Epub 2004 Jun 7.
PubMed 15184279Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. doi: 10.1056/NEJMoa0809171. Epub 2008 Dec 22.
PubMed 19106084Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232.
PubMed 19706858Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010 Oct 16;376(9749):1312-9. doi: 10.1016/S0140-6736(10)61273-1.
PubMed 20801494Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC; PLATO investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010 Oct 16;376(9749):1320-8. doi: 10.1016/S0140-6736(10)61274-3.
PubMed 20801498Tiroch KA, Sibbing D, Koch W, Roosen-Runge T, Mehilli J, Schomig A, Kastrati A. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J. 2010 Sep;160(3):506-12. doi: 10.1016/j.ahj.2010.06.039.
PubMed 20826260Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010 Oct 27;304(16):1821-30. doi: 10.1001/jama.2010.1543.
PubMed 20978260Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schomig A, von Beckerath N, Kastrati A. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010 Feb 2;121(4):512-8. doi: 10.1161/CIRCULATIONAHA.109.885194. Epub 2010 Jan 18.
PubMed 20083681Notarangelo FM, Maglietta G, Bevilacqua P, Cereda M, Merlini PA, Villani GQ, Moruzzi P, Patrizi G, Malagoli Tagliazucchi G, Crocamo A, Guidorossi A, Pigazzani F, Nicosia E, Paoli G, Bianchessi M, Comelli MA, Caminiti C, Ardissino D. Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes: The PHARMCLO Trial. J Am Coll Cardiol. 2018 May 1;71(17):1869-1877. doi: 10.1016/j.jacc.2018.02.029. Epub 2018 Mar 11.
PubMed 29540324
Study at a glance
From the registry record, last updated by the sponsor on 20 Nov 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacogenetics of Clopidogrel in Acute Coronary Syndromes
- ClinicalTrials.gov ID
- NCT03347435
- Acronym / sponsor ID
- PHARMCLO / 11210
- Conditions
- Acute Coronary Syndromes
- Keywords
- clopidogrel, pharmacogenetics, antiplatelet therapy, acute coronary syndromes
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Ethics Committe decision
- Enrolment
- 889 participants (actual)
- Lead sponsor
- Azienda Ospedaliero-Universitaria di ParmaUniversity, hospital or other
- Study start
- Jun 2013
- Primary completion
- Mar 2015 (actual)
- Study completion
- Mar 2015 (actual)
- First posted
- 20 Nov 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The antiplatelet agent clopidogrel is an effective drug for the prevention of thrombotic events in patients with acute coronary syndromes, and is therefore one of the most frequently prescribed drugs worldwide. Accumulating data suggest that the response to clopidogrel is characterised by significant inter-patient variability in the degree of platelet inhibition and the risk of cardiovascular events. Recent research findings have highlighted the role of genetic variations in determining antiplatelet response variability, and this has aroused interest in genotyping all thienopyridine-eligible patients in order to identify those who would be at increased risk of harm if treated with clopidogrel. This is a prospective, multicentre, randomised study enrolling consecutive patients hospitalised because of an ACS with or without ST-segment elevation. The patients are randomised to undergo or not tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 genetic variants immediately after diagnosis. The genotyping is done using a Q3 System (a compact platform that enables the classic laboratory analysis of DNA by means of real-time PCR). The Q3 has been designed as a low entry-cost, portable, point-of-care instrument for foolproof use by unskilled personnel. The patients randomised to the pharmacogenomic arm receive one of the ADP receptor antagonists (clopidogrel/prasugrel/ticagrelor) on the basis of an algorithm that consider genetic and clinical variables. The patients randomised to the standard treatment arm receive clopidogrel or prasugrel or ticagrelor on the basis of the standard of care (clinical algorithm alone). For each patient, a record is made of the occurrence of cardiovascular death, non-fatal MI, stroke, BARC-defined bleeding, and definite or probable stent thrombosis. The primary endpoint is the composite of death due to cardiovascular causes, non-fatal MI and stroke. The secondary endpoints is the occurrence of definite or probable stent thrombosis, and BARC-defined major bleeding events (types 3-5).
Detailed description
Antiplatelet therapy is the cornerstone of medical treatment of patients experiencing an acute coronary syndrome (ACS). As a synergistic antiplatelet effect can be obtained by simultaneously inhibiting thromboxane-A2 and adenosine diphosphate P2Y12 platelet receptors, the current standard of care for all patients with ACS includes dual anti-platelet therapy with aspirin (the first choice treatment for blocking thromboxane-A2 receptors) and one of the three currently available ADP P2Y12 inhibitors: clopidogrel, prasugrel and ticagrelor.
Over the last few years, the clinical availability of the new potent P2Y12 inhibitors prasugrel and ticagrelor has changed the ACS treatment paradigm. The revised European guidelines downgrade clopidogrel to patients who cannot receive prasugrel and ticagrelor, and clearly recommend the latter for patients with ACS (Recommendation Class I, Evidence Level B for both). However, the choice of the optimal drug for each individual patient is still left to clinicians, thus continuing the uncertainty as to how these new potent drugs should be incorporated into everyday clinical practice.
The appropriate selection of antiplatelet agents has so far been guided only by the patients' phenotypic characteristics, but taken together, the evidence does not support a wide use of prasugrel and ticagrelor in clinical practice and considering subgroups with less clinical benefit and limitations of TRITON TIMI-38 and PLATO study design, not all 100% of patients with ACS appears eligible for treatment with new ADP receptors antagonists.
Recent research has highlighted the role of CYP enzyme and ABCB1 genetic variations in determining the variability of the patients' antiplatelet response to clopidogrel, and shown a clear relationship between lower levels of clopidogrel's active metabolite, reduced platelet inhibition, and a higher rate of major adverse cardiovascular events. Specifically, post-hoc analysis concerning association of CYP2C19 and ABCB1 genetic variants to clinical outcomes showed an absolute 7.3% reduction in the risk of death from cardiovascular causes, myocardial infarction or stroke among the study population who were not carriers of a CYP2C19 reduced-function allele, ABCB1 3435 TT homozygotes, or both, compared with individuals who did carry either.
The impact of CYP2C19 alleles and ABCB1 genotype seems to be restricted to patients taking clopidogrel as they do not significantly affect pharmacological or clinical outcomes in patients treated with prasugrel and ticagrelor.
The aim of this project is to test the impact on clinical outcomes of strategy of conducting dual antiplatelet therapy considering both genotype data and clinical variables in comparison with a strategy based on clinical variables alone.
Methodology:
This is a prospective, multicentre, randomised study enrolling 3,612 consecutive patients hospitalised because of an ACS with or without ST-segment elevation. The patients are randomised to undergo or not tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 genetic variants immediately after diagnosis. The genotyping is done using a Q3 System (a compact platform that enables the classic laboratory analysis of DNA by means of real-time PCR). The Q3 has been designed as a low entry-cost, portable, point-of-care instrument for foolproof use by unskilled personnel.
The patients randomised to the pharmacogenomic arm receive one of the ADP receptor antagonists (clopidogrel/prasugrel/ticagrelor) on the basis of an algorithm that consider genetic and clinical variables. The patients randomised to the standard treatment arm receive clopidogrel or prasugrel or ticagrelor on the basis of the standard of care (clinical algorithm alone).
Patient enrolment is to be completed in 24 months. Each patient will be followed up for 12 months by means of outpatient visits after one, six and 12 months.
For each patient, a record is made of the occurrence of cardiovascular death, non-fatal MI, stroke, BARC-defined bleeding, and definite or probable stent thrombosis.
The primary endpoint is the composite of death due to cardiovascular causes, non-fatal MI and stroke.
The secondary endpoints is the occurrence of definite or probable stent thrombosis, and BARC-defined major bleeding events (types 3-5).
The expected rate reduction of ischemic and bleeding events is 25% for a median of 12 months of follow-up (data derived from PLATO trial) and the target relative risk reduction for genotype-guided therapy versus standard therapy is 20%. It has been defined a 95% power, a type alpha error of 5% and two-tail test. Therefore approximately 1806 patients for each arm should be enrolled.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Genotype/ phenotype guided group | Experimental | Genetic: genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435The patients randomized to the genotype/phenotype guided group undergo genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 genetic variants immediately after diagnosis of ACS and receive one of the ADP receptor antagonists (clopidogrel/prasugrel/ticagrelor) on the basis of an algorithm that consider genetic and clinical variables. |
| phenotype only guided group | Active comparator | Other: clinical algorithmThe patients randomized to the phenotype only guided group receive clopidogrel or prasugrel or ticagrelor on the basis of the standard of care on the basis of clinical algorithm alone. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Diagnosis of ACS (STE-ACS or NSTE-ACS) during the index hospitalisation
- Age >18 years
- Ability to sign the informed consent form
- Ability to attend scheduled visits
Key exclusion criteria (5 listed)
- Cognitive or other causes of an inability to provide informed consent or follow study procedures
- Any contraindication to the use of ADP P2Y12 inhibitors
- Life expectancy <1 year
- Thrombolytic therapy within the previous 24 hours
- Known ABCB1, CYP2C19 *2 orCYP2C19 *17 genotype
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435The CYP2C19*2 (10q24.1-q24.3; rs4244285), CYP2C19*17 (10q24.1-q24.3; rs12248560) and ABCB1 3435 (7q21.1; rs1045642) genetic variants will be genotyped using an ST Q3 system. The conventional genotyping methods so far used for diagnostic purposes will not be used in this study because appropriate labs may not be readily available and the processing time is prohibitive. Q3 is a compact platform enabling the classical laboratory analysis of DNA by means of real-time PCR. The Q3 has been designed as a low entry-cost, portable, point-of-care instrument for foolproof use by unskilled personnel. Antiplatelet therapy will be choose on the basis of clinical and genetic algorithm. | Genetic | Genotype/ phenotype guided group |
| clinical algorithmAntiplatelet therapy will be choose on the basis of clinical algorithm alone | Other | phenotype only guided group |
Primary outcome
Composite of cardiovascular death, non fatal myocardial infarction, stroke and BARC-defined major bleeding events 3 to 5.
Time frame: 12 months
The primary endpoint will be the composite of cardiovascular death, non fatal myocardial infarction, stroke and BARC-defined major bleeding events 3 to 5 at 12 months follow-up.
5 secondary outcomes
occurrence of definite or probable stent thrombosis.
Time frame: 12 months
cardiovascular death
Time frame: 12 months
non fatal myocardial infarction
Time frame: 12 months
stroke
Time frame: 12 months
BARC-defined major bleeding events 3 to 5
Time frame: 12 months
Results and safety
The study was stopped early (reason given: Ethics Committe decision). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Nov 2017.
- Results publication: PubMed 21873419Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D; ESC Committee for Practice Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011 Dec;32(23):2999-3054. doi: 10.1093/eurheartj/ehr236. Epub 2011 Aug 26. No abstract available.
- Results publication: PubMed 19717846Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators; Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi: 10.1056/NEJMoa0904327. Epub 2009 Aug 30.
- Results publication: PubMed 17982182Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. doi: 10.1056/NEJMoa0706482. Epub 2007 Nov 4.
- Results publication: PubMed 15184279Matetzky S, Shenkman B, Guetta V, Shechter M, Beinart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004 Jun 29;109(25):3171-5. doi: 10.1161/01.CIR.0000130846.46168.03. Epub 2004 Jun 7.
- Results publication: PubMed 19106084Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. doi: 10.1056/NEJMoa0809171. Epub 2008 Dec 22.
- Results publication: PubMed 19706858Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232.
- Results publication: PubMed 20801494Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010 Oct 16;376(9749):1312-9. doi: 10.1016/S0140-6736(10)61273-1.
- Results publication: PubMed 20801498Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC; PLATO investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010 Oct 16;376(9749):1320-8. doi: 10.1016/S0140-6736(10)61274-3.
- Results publication: PubMed 20826260Tiroch KA, Sibbing D, Koch W, Roosen-Runge T, Mehilli J, Schomig A, Kastrati A. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J. 2010 Sep;160(3):506-12. doi: 10.1016/j.ahj.2010.06.039.
- Results publication: PubMed 20978260Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010 Oct 27;304(16):1821-30. doi: 10.1001/jama.2010.1543.
- Results publication: PubMed 20083681Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schomig A, von Beckerath N, Kastrati A. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010 Feb 2;121(4):512-8. doi: 10.1161/CIRCULATIONAHA.109.885194. Epub 2010 Jan 18.
- Derived from this study: PubMed 29540324Notarangelo FM, Maglietta G, Bevilacqua P, Cereda M, Merlini PA, Villani GQ, Moruzzi P, Patrizi G, Malagoli Tagliazucchi G, Crocamo A, Guidorossi A, Pigazzani F, Nicosia E, Paoli G, Bianchessi M, Comelli MA, Caminiti C, Ardissino D. Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes: The PHARMCLO Trial. J Am Coll Cardiol. 2018 May 1;71(17):1869-1877. doi: 10.1016/j.jacc.2018.02.029. Epub 2018 Mar 11.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Diego Ardissino, MD principal investigator
Azienda Ospedaliero-Universitaria di Parma
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 and clinical algorithm in people with Acute Coronary Syndromes, run by Azienda Ospedaliero-Universitaria di Parma at 4 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 Nov 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: Ethics Committe decision). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Composite of cardiovascular death, non fatal myocardial infarction, stroke and BARC-defined major bleeding events 3 to 5. (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03347435, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Nov 2017.