Coronary Artery DiseasePhase 3CLOVIS2NCT00822666
Clopidogrel and Response Variability Investigation Study 2
A Phase 3 study testing clopidogrel in people with Coronary Artery Disease, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial summary
To evaluate the role of the genetic variant 2C19*2 on the pharmacodynamic response as assessed by optical aggregometry and on the pharmacokinetic response as assessed by measuring active metabolites following an oral administration of a loading dose of 300/900mg of clopidogrel in patients with established coronary… Read more about this study
- Who is it for?
- Ages 18 to 75 years, men only
- Conditions the study is for
- Coronary Artery Disease
- What is being tested?
- clopidogrel
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 109 participants
- Where
- 1 siteFrance
- Study dates
- Oct 2008to Dec 2009
- Phase
- Phase 3
- 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 to 75 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age > 18
- Male gender
- Included in the AFIJI registry
- No high bleeding risk profile
- No recent history of acute coronary syndrome (< 3 months)
- Written informed consent obtained
- Genotype CYP2C19 : *1/*1, *1/*2 ou *2/*2
- Genotype P2Y12 : H1/H1 ou H1/H2
Who cannot join
- Female gender
- Patient with a contraindication to clopidogrel
- Patient who has received a loading dose of clopidogrel in the past 7 days
- Patient treated with ticlopidine or GP2B/3A receptor antagonist prior to loading
- Non compliance
- Génotype P2Y12 : H2/H2.
Show all 10Show fewer
- Patient treated with drugs interacting with platelet aggregation (NSAID, persantine, serotonin inhibitors )
- Patient treated with drugs interacting 2C19
- Not affiliated to the national health insurance
- Patient participating to another randomized study
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effect of the Genetic Variant 2C19*2 on Clopidogrel Biological Response in Patients With Premature Coronary Artery Disease
To evaluate the role of the genetic variant 2C19*2 on the pharmacodynamic response as assessed by optical aggregometry and on the pharmacokinetic response as assessed by measuring active metabolites following an oral administration of a loading dose of 300/900mg of clopidogrel in patients with established coronary artery disease.
Read the detailed description
Rationale : Clopidogrel is a specific and irreversible of the P2Y12 platelet receptor leading to an inhibition of platelet aggregation. Clopidogrel is a prodrug that must be converted into an active metabolite that selectively and irreversibly binds to the P2Y12 platelet membrane receptor. As a consequence, a loading dose of 300 mg is necessary in percutaneous coronary intervention and in acute coronary syndrome, situations which require a rapid inhibition of platelet aggregation due to the high thrombotic risk.
High platelet reactivity on clopidogrel may be due to various reasons including polymorphism in the gene encoding the cytochrome P-450 2C19 enzyme (CYP2C19) which has been shown to contribute to the variability of platelet response to clopidogrel. CYP2C19 is a key enzyme in this activation process and our group was the first to describe an association between the presence of the loss of function CYP2C19 681G>A polymorphism (also called *2) with lower clopidogrel responsiveness in healthy subjects.
Poor responsiveness to clopidogrel has become a major concern given acute recurrent events following stent placement.
Objective : To evaluate the role of the genetic variant 2C19*2 on the pharmacodynamic response as assessed by optical aggregometry and on the pharmacokinetic response as assessed by measuring active metabolites following an oral administration of a loading dose of 300/900mg of clopidogrel in patients with established coronary artery disease.
Target population :Patients of less than 45 years of age and who survived a MI and enrolled in the AFIJI multicenter registry (Appraisal of risk Factors in young Ischemic patients Justifying aggressive Intervention).
Primary end-point :Comparison of inhibition of the intensity of residual platelet aggregation (IRPA) measured 6 minutes after induction by 20 μmol/L following 300mg or 900 mg of clopidogrel with respect to the presence of the genetic variant CYP2C19*2
- Maximum platelet aggregation instead of IRPA
- RPA with 5µM and 50 µM of ADP
- Measure of clopidogrel and its active metabolites (carboxylated and thiol) at different time points following the loading dose (H0, H1, H2 et H6) with respect to the presence of the genetic variant CYP2C19*2
- Relationship between active metabolites concentration and IRPA
- Relationship between active metabolites and dose of clopidogrel
- Comparison of 300mg vs 900mg on IRPA in the whole population irrespective of the genetic variant
Statistical analysis :Comparison of IRPA with respect to the presence of the genetic variant 2C19*2 by anova Area under the curve of the production of active metabolites with respect to the presence of the genetic variant 2C19*2 Agenda :November 2008 (inclusion of first patient) to december 2009 (analysis of the data)
- Conditions
- Coronary Artery Disease
- Being tested
- clopidogrel
- Keywords
- Platelet aggregation, Platelet, Thrombosis, Clopidogrel
- Medical subject headings
- Coronary Artery Disease, Thrombosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
clopidogrelDrug
comparison of two loading strategies of clopidogrel (300mg vs 900mg) in the two genetic profiles
| Study group | Role | What they receive |
|---|---|---|
| 1 | Active comparator | patients homozygous for the 2C19*1 genetic variant Receives: Drug: clopidogrel |
| 2 | Experimental | carriers of the 2C19*2 genetic variant (homozygous or heterozygous) Receives: Drug: clopidogrel |
What is being measured
The primary outcome is the main question the study is designed to answer.
Inhibition of residual platelet activity 6 hours after a loading dose of clopidogrel
Measured: 6 hours
Secondary outcomes (5)
Maximum platelet aggregation instead of IRPA
Measured: during the study
RPA with 5µM and 50 µM of ADP
Measured: during the study
3. Measure of clopidogrel and its active metabolites (carboxylated and thiol) at different time points following the loading dose (H0, H1, H2 ,H6) with respect to the presence of the genetic variant CYP2C19*2
Measured: H0, H1, H2, H6
Relationship between active metabolites concentration and IRPA
Measured: during the study
Relationship between active metabolites and dose of clopidogrel
Measured: during the study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jan 2009 (estimated)
- Study startOct 2008
- Primary completionDec 2009
- Study completionDec 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Coronary Artery DiseaseStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 109 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jean-Philippe Collet, MD, Principal investigator, Assistance Publique - Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00822666
- Sponsor's protocol ID
- P070117
- Acronym
- CLOVIS2
- Status last verified
- Jan 2009
- First submitted
- 13 Jan 2009
- Last updated
- 11 Dec 2012
- Results posted
- No
- Data monitoring committee
- No
Publications
Hulot JS, Collet JP, Cayla G, Silvain J, Allanic F, Bellemain-Appaix A, Scott SA, Montalescot G. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv. 2011 Oct 1;4(5):422-8. doi: 10.1161/CIRCINTERVENTIONS.111.963025. Epub 2011 Oct 4.
PubMed 21972404Collet JP, Hulot JS, Anzaha G, Pena A, Chastre T, Caron C, Silvain J, Cayla G, Bellemain-Appaix A, Vignalou JB, Galier S, Barthelemy O, Beygui F, Gallois V, Montalescot G; CLOVIS-2 Investigators. High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2). JACC Cardiovasc Interv. 2011 Apr;4(4):392-402. doi: 10.1016/j.jcin.2011.03.002.
PubMed 21511218
Study at a glance
From the registry record, last updated by the sponsor on 11 Dec 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of the Genetic Variant 2C19*2 on Clopidogrel Biological Response in Patients With Premature Coronary Artery Disease
- ClinicalTrials.gov ID
- NCT00822666
- Acronym / sponsor ID
- CLOVIS2 / P070117
- Conditions
- Coronary Artery Disease
- Keywords
- Platelet aggregation, Platelet, Thrombosis, Clopidogrel
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 109 participants (actual)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Collaborators
- Institut National de la Santé Et de la Recherche Médicale, France
- Study start
- Oct 2008
- Primary completion
- Dec 2009 (actual)
- Study completion
- Dec 2009 (actual)
- First posted
- 14 Jan 2009 (estimated)
- 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.
To evaluate the role of the genetic variant 2C19*2 on the pharmacodynamic response as assessed by optical aggregometry and on the pharmacokinetic response as assessed by measuring active metabolites following an oral administration of a loading dose of 300/900mg of clopidogrel in patients with established coronary artery disease.
Detailed description
Rationale : Clopidogrel is a specific and irreversible of the P2Y12 platelet receptor leading to an inhibition of platelet aggregation. Clopidogrel is a prodrug that must be converted into an active metabolite that selectively and irreversibly binds to the P2Y12 platelet membrane receptor. As a consequence, a loading dose of 300 mg is necessary in percutaneous coronary intervention and in acute coronary syndrome, situations which require a rapid inhibition of platelet aggregation due to the high thrombotic risk.
High platelet reactivity on clopidogrel may be due to various reasons including polymorphism in the gene encoding the cytochrome P-450 2C19 enzyme (CYP2C19) which has been shown to contribute to the variability of platelet response to clopidogrel. CYP2C19 is a key enzyme in this activation process and our group was the first to describe an association between the presence of the loss of function CYP2C19 681G>A polymorphism (also called *2) with lower clopidogrel responsiveness in healthy subjects.
Poor responsiveness to clopidogrel has become a major concern given acute recurrent events following stent placement.
Objective : To evaluate the role of the genetic variant 2C19*2 on the pharmacodynamic response as assessed by optical aggregometry and on the pharmacokinetic response as assessed by measuring active metabolites following an oral administration of a loading dose of 300/900mg of clopidogrel in patients with established coronary artery disease.
Target population :Patients of less than 45 years of age and who survived a MI and enrolled in the AFIJI multicenter registry (Appraisal of risk Factors in young Ischemic patients Justifying aggressive Intervention).
Primary end-point :Comparison of inhibition of the intensity of residual platelet aggregation (IRPA) measured 6 minutes after induction by 20 μmol/L following 300mg or 900 mg of clopidogrel with respect to the presence of the genetic variant CYP2C19*2
- Maximum platelet aggregation instead of IRPA
- RPA with 5µM and 50 µM of ADP
- Measure of clopidogrel and its active metabolites (carboxylated and thiol) at different time points following the loading dose (H0, H1, H2 et H6) with respect to the presence of the genetic variant CYP2C19*2
- Relationship between active metabolites concentration and IRPA
- Relationship between active metabolites and dose of clopidogrel
- Comparison of 300mg vs 900mg on IRPA in the whole population irrespective of the genetic variant
Statistical analysis :Comparison of IRPA with respect to the presence of the genetic variant 2C19*2 by anova Area under the curve of the production of active metabolites with respect to the presence of the genetic variant 2C19*2 Agenda :November 2008 (inclusion of first patient) to december 2009 (analysis of the data)
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Active comparator | Drug: clopidogrelpatients homozygous for the 2C19*1 genetic variant |
| 2 | Experimental | Drug: clopidogrelcarriers of the 2C19*2 genetic variant (homozygous or heterozygous) |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Age > 18
- Male gender
- Included in the AFIJI registry
- No high bleeding risk profile
- No recent history of acute coronary syndrome (< 3 months)
Key exclusion criteria (10 listed)
- Female gender
- Patient with a contraindication to clopidogrel
- Patient who has received a loading dose of clopidogrel in the past 7 days
- Patient treated with ticlopidine or GP2B/3A receptor antagonist prior to loading
- Non compliance
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 |
|---|---|---|
| clopidogrelcomparison of two loading strategies of clopidogrel (300mg vs 900mg) in the two genetic profiles | Drug | 1, 2 |
Primary outcome
Inhibition of residual platelet activity 6 hours after a loading dose of clopidogrel
Time frame: 6 hours
5 secondary outcomes
Maximum platelet aggregation instead of IRPA
Time frame: during the study
RPA with 5µM and 50 µM of ADP
Time frame: during the study
3. Measure of clopidogrel and its active metabolites (carboxylated and thiol) at different time points following the loading dose (H0, H1, H2 ,H6) with respect to the presence of the genetic variant CYP2C19*2
Time frame: H0, H1, H2, H6
Relationship between active metabolites concentration and IRPA
Time frame: during the study
Relationship between active metabolites and dose of clopidogrel
Time frame: during the study
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Dec 2012.
- Derived from this study: PubMed 21972404Hulot JS, Collet JP, Cayla G, Silvain J, Allanic F, Bellemain-Appaix A, Scott SA, Montalescot G. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv. 2011 Oct 1;4(5):422-8. doi: 10.1161/CIRCINTERVENTIONS.111.963025. Epub 2011 Oct 4.
- Derived from this study: PubMed 21511218Collet JP, Hulot JS, Anzaha G, Pena A, Chastre T, Caron C, Silvain J, Cayla G, Bellemain-Appaix A, Vignalou JB, Galier S, Barthelemy O, Beygui F, Gallois V, Montalescot G; CLOVIS-2 Investigators. High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2). JACC Cardiovasc Interv. 2011 Apr;4(4):392-402. doi: 10.1016/j.jcin.2011.03.002.
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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.
Jean-Philippe Collet, MD principal investigator
Assistance Publique - Hôpitaux de Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing clopidogrel in people with Coronary Artery Disease, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
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 8 inclusion and 10 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: finished, as of the sponsor's last update on 11 Dec 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. 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.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Inhibition of residual platelet activity 6 hours after a loading dose of clopidogrel (time frame: 6 hours). 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 NCT00822666, which also lists 2 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 11 Dec 2012.