Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA)

Condition(s) targeted: Arteriosclerosis

Intervention: Clopidogrel (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Sanofi-Aventis

Official(s) and/or principal investigator(s):
ICD CSD, Study Director, Affiliation: Sanofi-Aventis

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.

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 design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Occurrence of myocardial infarction,stroke or cardiovascular death.

Secondary outcome: severe bleeding

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.

Minimum age: 45 Years. Maximum age: N/A. Gender(s): Both.

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

Sanofi-aventis Administrative Office, Buenos Aires, Argentina

Sanofi-aventis Administrative Office, Macquarie Park, Australia

Sanofi-aventis Administrative Office, Wien, Austria

Sanofi-aventis Administrative Office, Diegem, Belgium

Sanofi-aventis Administrative Office, Sao Paulo, Brazil

Sanofi-aventis Administrative Office, Laval, Canada

Sanofi-aventis Administrative Office, Santiago, Chile

Sanofi-aventis Administrative Office, Praha, Czech Republic

Sanofi-aventis Administrative Office, Horsholm, Denmark

Sanofi-aventis Administrative Office, Helsinki, Finland

Sanofi-aventis Administrative Office, Paris, France

Sanofi-aventis Administrative Office, Berlin, Germany

Sanofi-aventis Administrative Office, Athens, Greece

Sanofi-aventis Administrative Office, Causeway Bay, Hong Kong

Sanofi-aventis Administrative Office, Budapest, Hungary

Sanofi-aventis Administrative Office, Milano, Italy

Sanofi-aventis Administrative Office, Kuala Lumpur, Malaysia

Sanofi-aventis Administrative Office, Mexico, Mexico

Sanofi-aventis Administrative Office, Gouda, Netherlands

Sanofi-aventis Administrative Office, Lysaker, Norway

Sanofi-aventis Administrative Office, Warszawa, Poland

Sanofi-aventis Administrative Office, Porto Salvo, Portugal

Sanofi-aventis Administrative Office, Moscow, Russian Federation

Sanofi-aventis Administrative Office, Singapore, Singapore

Sanofi-aventis Administrative Office, Midrand, South Africa

Sanofi-aventis Administrative Office, Barcelona, Spain

Sanofi-aventis Administrative Office, Bromma, Sweden

Sanofi-aventis Administrative Office, Geneva, Switzerland

Sanofi-aventis Administrative Office, Taipei, Taiwan

Sanofi-aventis Administrative Office, Istanbul, Turkey

Sanofi-aventis Administrative Office, Guildford Surrey, United Kingdom

The Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States

Starting date: October 2002
Ending date: August 2005
Last updated: June 16, 2008