E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with abdominal obesity at increased risk for cardiovascular events (myocardial infarctio, stroke and cardiovascular death) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051615 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the efficacy of rimonabant versus placebo for reducing the risk of myocardial infarction, stroke, or cardiovascular death in patients with abdominal obesity at increased risk for such events. |
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E.2.2 | Secondary objectives of the trial |
To demonstrate the efficacy of rimonabant versus placebo for reducing the risk of myocardial infarction, stroke, cardiovascular death, or hospitalization for cardiovascular cause (unstable angina, transient ischemic attack, cardiac rhythm disorder, congestive heart failure, syncope, or urgent revascularization procedure), in patients with abdominal obesity at increased risk for such events. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Metabolic Substudy: - conducted in selected sites, encompassing approximately 3000 patients. This substudy will assess rimonabant’s effects on fasting plasma glucose, insulin, HbA1c, triglyceride, HDL-cholesterol, and LDL-cholesterol levels compared to placebo, in a subset of CRESCENDO patients. Samples will be obtained at baseline and every six months thereafter, and at the End of Study visit. This study will be the subject of a separate protocol (Appendix 9) and informed consent.
Biomarker Substudy: - conducted based on the recommendation of the Executive Committee. The substudy will assess the effect of rimonabant 20 mg OD on hs-CRP, sCD40L, IL-6, PAI-1, sVCAM-1, P-selectin, myeloperoxidase, adiponectin, resistin, leptin, omentin, osteonectin, and visfatin. It will be the subject of a separate protocol (Appendix 10) and informed consent.
Genomics Substudy: - conducted based on the recommendation of the Executive Committee. This substudy will collect blood samples that may be used for future hypothesis generating and hypothesis testing research. Research that may be conducted on samples collected from this protocol or in combination with samples from other protocols can explore: 1) how variations in genes associate with clinical outcomes, eg, drug metabolizing enzyme variants with either pharmacokinetic endpoints or other clinical responses; 2) the associations among genetic variation, gene expression, and proteins and clinical conditions, such as obesity or metabolic disorders, and outcomes, such as MI, stroke, or cardiovascular death.. It will be the subject of a separate protocol (Appendix 11) and informed consent.
The analysis and reporting of the substudies will be totally separate from the main study. |
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E.3 | Principal inclusion criteria |
1. Written informed consent obtained 2. Men and women aged 55 or older, AND 3. Presence of abdominal obesity, with a waist circumference greater than 102 cm (40 inches) for males and greater than 88 cm (35 inches) for females on three successive measurements at the baseline visit, AND 4. Presence of at least one coronary heart disease (CHD) risk equivalent OR two major cardiovascular risk factors
Coronary heart disease risk equivalents:
a) Recent (within the past 3 years) myocardial infarction (MI) (two of the following three criteria must be satisfied): • Characteristic ischemic chest pain or pain in associated referral areas or anginal equivalent symptoms, • Elevation of CK (at least twice the upper limit of normal values for that laboratory) and/or CK-MB (at least twice the upper limit of normal values for the laboratory) and/or troponin T or I (at least above the upper limit of normal for the laboratory), • Development of Q waves in at least two adjacent ECG leads, or development of a new dominant R wave in V1.
b) Stable angina with documented multivessel coronary disease (defined as greater than 50% stenosis in at least two epicardial coronary arteries at angiography), and/or history of multivessel percutaneous coronary intervention (PCI) or multivessel coronary artery bypass graft (CABG) TOGETHER WITH at least one of the three following criteria: • Current exercise-induced angina pectoris • Positive ECG stress test (ST depression greater than 2 mm with normal baseline ST segments) • Reversible defect by myocardial perfusion imaging or stress-induced wall motion abnormality on stress echocardiography test
c) Recent (within the past 3 years) cerebrovascular disease, as evidenced by an ischemic cerebrovascular episode (all criteria must be satisfied): • A focal neurological deficit • Without evidence of a cardio-embolic origin • Without evidence of non-vascular origin on CT or MRI scan CT or MRI must have been performed to document whether there is a lesion and to rule-out non-ischemic neurological disease.
d) Documented symptomatic peripheral arterial disease (PAD) (one of the following primary criteria must be satisfied): • current intermittent claudication (WHO criteria, eg, leg pain occurring only while walking and disappearing in less than 10 minutes on standing) of presumed atherosclerotic origin TOGETHER WITH ankle-brachial index equal to or less than 0.85 in either leg at rest, OR • history of intermittent claudication (WHO criteria as above) TOGETHER WITH either previous intervention by amputation, or reconstructive vascular surgery, or angioplasty in one or both legs because of atherosclerotic disease,
Major cardiovascular risk factors:
e) Type 2 diabetes mellitus (fasting plasma glucose equal to or greater than 126 mg/dL [7.0 mmol/L] on two or more occasions)
f) Metabolic syndrome, as diagnosed by the presence of at least 2 of the following risk factors (if 3 of the risk factors listed below are fulfilled, this is equivalent to two major risk factors and the patient is eligible): o Fasting triglyceride level equal to or greater than 150 mg/dL (1.69 mmol/L) o HDL-cholesterol less than 40 mg/dL (1.03 mmol/L) for males or less than 50 mg/dL (1.28 mmol/L) for females o Fasting plasma glucose equal to or greater than 110 mg/dL (6.1 mmol/L) o Blood pressure equal to or greater than 130 mm Hg systolic and/or 85 mm Hg diastolic at baseline visit
g) Cerebrovascular disease (at least one of the following three criteria must be satisfied): o Asymptomatic disease of the carotid, intracranial, and/or vertebral arteries, with greater than 50% stenosis o At least one carotid plaque on ultrasonography, defined as a distinct area with an intima-media thickness (IMT) exceeding twice that of neighboring sites, OR o Prior cerebrovascular revascularization procedure
h) Renal artery disease, with greater than 60% stenosis on MR angiography, CT angiography, or angiography, or prior revascularization procedure
i) Previous history of abdominal aortic aneurysm repair
j) Asymptomatic ankle-brachial index less than 0.85
k) Elevated hs-CRP greater than 3 mg/L
l) Males 65 years or older or females 70 years or older |
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E.4 | Principal exclusion criteria |
Related to general patient characteristics 1. Obesity due to known endocrine disorder, such as hypothyroidism, or hypopituitary or other endocrine disease
2. Pregnant or breast-feeding women, or women planning to become pregnant or to breast feed
3. Very low-calorie diet (1200 calories a day or less) or surgical procedure for weight loss (eg, stomach stapling, bypass, etc) within 6 months prior to baseline visit
4. Presence of any severe medical condition or advanced age such that the patient is not expected to survive for the planned study follow-up period
5. Presence of any severe medical or psychological condition that, in the opinion of the Investigator, would compromise the patient’s safe participation
6. Presence of any condition (medical, psychological, social, or geographical), actual or anticipated, that the Investigator feels would restrict or limit the patient’s successful participation for the duration of the study
7. Receipt of any investigational treatment (drug or device) within 30 days prior to baseline visit
8. Previous participation in a rimonabant study
9. Known allergy to rimonabant or excipients
Related to cardiovascular condition
10. Clinically significant cardiovascular disease that, in the opinion of the investigator, is likely to require intervention (PCI, CABG, valve repair/replacement, heart transplantation, PTA, peripheral bypass surgery, endarterectomy, etc) within the next one month after randomization |
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E.5 End points |
E.5.1 | Primary end point(s) |
The first occurrence of any component of the following cluster, as adjudicated by the Clinical Events Committee: • Any MI (nonfatal or fatal) • Any stroke (nonfatal or fatal) • Cardiovascular death
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Information not present in EudraCT |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 234 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 50 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 50 |