Clinical trial NCT00050817: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA)
Official title: A Phase III, Multicenter, Multinational, Randomized, Parallel Group, Double-blind Trial of Clopidogrel Versus Placebo in High-risk Patients Aged 45 Years and Older, at Risk of Atherothrombotic Events, and Who Are Receiving Background Therapy Including Low-dose ASA.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Arteriosclerosis
Keywords: Embolism
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2002-12-23
Enrollment: 15603
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE:

* Atherothrombosis is a progressive and generalized vascular disease resulting in events leading to myocardial infarction (heart attack), stroke, and vascular death.
* In patients at risk for this disease, it is characterized by an unpredictable, sudden disruption of atherosclerotic plaques, which may lead to total occlusion of artery due to formation of a clot. The use of aspirin (blood thinner agent) for reducing those major ischemic events is either indicated, or recommended by international guidelines. However, aspirin fails to prevent a high percentage of such life-threatening events. Therefore, more effective blood thinning therapy may provide additional clinical benefit to such patients.
* The results of the CURE trial in patients with unstable angina demonstrate the additional benefit of long-term treatment (up to one year) with clopidogrel, (a blood thinner agent), when administered in combination with standard therapy including aspirin. The purpose of CHARISMA is to investigate whether a similar clinical benefit of clopidogrel may apply to a broad population of high-risk patients receiving low-dose aspirin therapy. Such population includes patients with previous cardiovascular, neurovascular or peripheral arterial manifestations of atherothrombosis and patients with combinations of recognized risk factors for atherosclerosis.

OBJECTIVES:

* To assess the efficacy of clopidogrel 75 mg once-daily by comparison with a placebo, in preventing cardiovascular morbidity/mortality. The study will compare the efficacy of the two regimens in preventing the occurrence of major cardiovascular complications (stroke, heart attack, cardiovascular death) in high-risk patients who are otherwise receiving low-dose aspirin therapy (75-162 mg daily).
* To evaluate the safety of clopidogrel in this population, and more specifically the incidence of fatal or severe bleeding (as per GUSTO definition), in order to estimate the global benefit of clopidogrel in this patient population.

Detailed description: TREATMENTS:

* Clopidogrel (Plavix® and/or Iscover®) is an agent inhibiting platelet aggregation involved in clot formation. Each tablet contains 75mg of clopidogrel. A matching placebo of clopidogrel is an inactive substance that looks similar to the active clopidogrel tablet.

TREATMENT PLAN:

* There will be two treatment groups; one will receive clopidogrel 75 mg (1 tablet qd), the second matching placebo of clopidogrel (1 tablet qd). These study drugs will be administered on top of low-dose aspirin (75-162 mg qd) systematically prescribed to such patients. In addition, patients enrolled in CHARISMA will be managed as appropriate for their risk factors for atherosclerosis: eg. high blood pressure, high cholesterol, diabetes...etc.

PRIMARY ENDPOINT:

* Combined endpoint of cardiovascular mortality, stroke, acute myocardial infarction.

STUDY EXECUTION:

* Some 7,600 patients per group will be recruited within two years. Patients will be observed over a maximum of 3.5 years.

STUDY TERRITORY:

* Approximately 900 sites throughout North/South America, Europe, Asia, Australia, and South Africa.

Eligibility criteria: INCLUSION:

Be at least 45 years old and comply with at least one of the four categories of inclusion criteria:

* Combination of atherothrombotic risk factors (2 major or 3 minor or 1 major + 2 minor risk factors among those listed below)

Major atherothrombotic risk factors

* Type I or II diabetes (under drug therapy)
* Diabetic nephropathy
* Ankle brachial index (ABI) \< 0.9
* Asymptomatic carotid stenosis \>= 70%
* At least one carotid plaque as evidenced by intima-media thickness (IMT)

Minor atherothrombotic risk factors

* Systolic blood pressure (SBP) \>= 150 mmHg, despite appropriate therapy for at least 3 months
* Primary hypercholesterolemia
* Current smoking \> 15 cigarettes per day
* Male \>= 65 years
* Female \>= 70 years

and/or

* Documented cerebrovascular disease (TIA or IS within 5 years) and/or
* Documented coronary artery disease (stable angina with documented multivessel coronary disease, previous documented MI, multivessel PCI or CABG within 1 year, multivessel CABG older than 1 year associated with current angina) and/or
* Documented symptomatic PAD

EXCLUSION:

* Absolute indication for the use of clopidogrel, high-dose aspirin (\>162 mg), NSAIDs, or oral anti-thrombotic drugs
* Absolute contraindication to the use of clopidogrel or aspirin
* Clinical conditions likely to interfere with follow-up leading to inability to complete the trial

Primary outcomes:
measure: Occurrence of myocardial infarction,stroke or cardiovascular death.
Secondary outcomes:
measure: severe bleeding
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Buenos Aires
country: Argentina
facility: Sanofi-aventis Administrative Office
city: Macquarie Park
country: Australia
facility: Sanofi-aventis Administrative Office
city: Wien
country: Austria
facility: Sanofi-aventis Administrative Office
city: Diegem
country: Belgium
facility: Sanofi-aventis Administrative Office
city: Sao Paulo
country: Brazil
facility: Sanofi-aventis Administrative Office
city: Laval
country: Canada
facility: Sanofi-aventis Administrative Office
city: Santiago
country: Chile
facility: Sanofi-aventis Administrative Office
city: Praha
country: Czech Republic
facility: Sanofi-aventis Administrative Office
city: Horsholm
country: Denmark
facility: Sanofi-aventis Administrative Office
city: Helsinki
country: Finland
facility: Sanofi-aventis Administrative Office
city: Paris
country: France
facility: Sanofi-aventis Administrative Office
city: Berlin
country: Germany
facility: Sanofi-aventis Administrative Office
city: Athens
country: Greece
facility: Sanofi-aventis Administrative Office
city: Causeway Bay
country: Hong Kong
facility: Sanofi-aventis Administrative Office
city: Budapest
country: Hungary
facility: Sanofi-aventis Administrative Office
city: Milano
country: Italy
facility: Sanofi-aventis Administrative Office
city: Kuala Lumpur
country: Malaysia
facility: Sanofi-aventis Administrative Office
city: Mexico
country: Mexico
facility: Sanofi-aventis Administrative Office
city: Gouda
country: Netherlands
facility: Sanofi-aventis Administrative Office
city: Lysaker
country: Norway
facility: Sanofi-aventis Administrative Office
city: Warszawa
country: Poland
facility: Sanofi-aventis Administrative Office
city: Porto Salvo
country: Portugal
facility: Sanofi-aventis Administrative Office
city: Moscow
country: Russian Federation
facility: Sanofi-aventis Administrative Office
city: Singapore
country: Singapore
facility: Sanofi-aventis Administrative Office
city: Midrand
country: South Africa
facility: Sanofi-aventis Administrative Office
city: Barcelona
country: Spain
facility: Sanofi-aventis Administrative Office
city: Bromma
country: Sweden
facility: Sanofi-aventis Administrative Office
city: Geneva
country: Switzerland
facility: Sanofi-aventis Administrative Office
city: Taipei
country: Taiwan
facility: Sanofi-aventis Administrative Office
city: Istanbul
country: Turkey
facility: Sanofi-aventis Administrative Office
city: Guildford Surrey
country: United Kingdom
facility: Sanofi-aventis Administrative Office
Study officials:
affiliation: Sanofi
name: ICD CSD
role: STUDY_DIRECTOR
References:
citation: Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006 Apr 20;354(16):1706-17. doi: 10.1056/NEJMoa060989. Epub 2006 Mar 12.
citation: Bhatt DL, Pare G, Eikelboom JW, Simonsen KL, Emison ES, Fox KA, Steg PG, Montalescot G, Bhakta N, Hacke W, Flather MD, Mak KH, Cacoub P, Creager MA, Berger PB, Steinhubl SR, Murugesan G, Mehta SR, Kottke-Marchant K, Lincoff AM, Topol EJ; CHARISMA Investigators. The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study. Eur Heart J. 2012 Sep;33(17):2143-50. doi: 10.1093/eurheartj/ehs059. Epub 2012 Mar 26.
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citation: Bangalore S, Bhatt DL, Steg PG, Weber MA, Boden WE, Hamm CW, Montalescot G, Hsu A, Fox KA, Lincoff AM. beta-blockers and cardiovascular events in patients with and without myocardial infarction: post hoc analysis from the CHARISMA trial. Circ Cardiovasc Qual Outcomes. 2014 Nov;7(6):872-81. doi: 10.1161/CIRCOUTCOMES.114.001073. Epub 2014 Sep 30.
citation: Berger PB, Bhatt DL, Fuster V, Steg PG, Fox KA, Shao M, Brennan DM, Hacke W, Montalescot G, Steinhubl SR, Topol EJ; CHARISMA Investigators. Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Circulation. 2010 Jun 15;121(23):2575-83. doi: 10.1161/CIRCULATIONAHA.109.895342. Epub 2010 Jun 1.
citation: Steinhubl SR, Bhatt DL, Brennan DM, Montalescot G, Hankey GJ, Eikelboom JW, Berger PB, Topol EJ; CHARISMA Investigators. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med. 2009 Mar 17;150(6):379-86. doi: 10.7326/0003-4819-150-6-200903170-00006.
citation: Mak KH, Bhatt DL, Shao M, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Montalescot G, Steg PG, Steinhubl SR, Fox KA, Topol EJ. The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease. Eur Heart J. 2009 Apr;30(7):857-65. doi: 10.1093/eurheartj/ehp037. Epub 2009 Feb 20.
citation: Eikelboom JW, Hankey GJ, Thom J, Bhatt DL, Steg PG, Montalescot G, Johnston SC, Steinhubl SR, Mak KH, Easton JD, Hamm C, Hu T, Fox KA, Topol EJ; Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Investigators. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation. 2008 Oct 21;118(17):1705-12. doi: 10.1161/CIRCULATIONAHA.108.768283. Epub 2008 Oct 6.
citation: Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Fabry-Ribaudo L, Hu T, Topol EJ, Fox KA; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007 May 15;49(19):1982-8. doi: 10.1016/j.jacc.2007.03.025. Epub 2007 Apr 11.