| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Atherosclerosis progression in vein grafts in diabetic patients after coronary bypass surgery. |
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| MedDRA Classification |
| 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 |
The primary objective of the present study is to assess the efficacy of rosiglitazone to reduce atherosclerosis progression in vein grafts in diabetic patients after coronary bypass surgery by using intravascular ultrasound (IVUS) imaging after a 12-month follow-up.
Objective of Sub-Study:
The objective of the sub-study is to assess the efficacy of rosiglitazone on cardiac autonomic nervous system in diabetic patients. |
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| E.2.2 | Secondary objectives of the trial |
1) To prospectively compare the secondary intravascular ultrasound (IVUS) endpoints.
2) To prospectively compare the angiographic endpoints.
3) To prospectively compare the metabolic risk factor endpoints.
4) To prospectively compare the body composition and distribution endpoints.
5) To prospectively compare the clinical outcomes of rosiglitazone versus standard care using composite endpoints.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
PRINCIPLE INCLUSION CRITERIA AT SCREENING
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1) Either male or female, aged more than or equal to 40 years and less than or equal to 75 years.
2) Women of childbearing potential who use an acceptable contraceptive measure (oral contraceptive, Norplant® (levonorgestrel), Depo-Provera® (medroxyprogesterone acetate), an intra-uterin device, a diaphragm with spermicide and condoms or women of non-childbearing potential (post menopausal: no menstruation for 12 months) or surgically sterile. Women with a history of polycystic ovary disease, unless surgically sterilized, fall under women of childbearing potential and thus must be using an acceptable contraceptive measure, whether or not they have been menstruated in the last 12 months. Women of childbearing potential must use effective contraception for at least one month prior to screening and should continue to use the same contraceptive method during the study and for 30 days after completing the study. Abstinence by a female patient and vasectomy of a female patient’s partner are not considered acceptable contraceptive measures.
3) Patients with documented type 2 diabetes mellitus and as defined by the criteria of the Canadian Diabetes Association (refer to Annexe 3 of study protocol).
4) Patients with no new medication for hyperglycemia and no change in the dose of their oral hypoglycemic medication within the last 3 months prior to the screening.
5) Diabetic patients with ischemic heart disease and coronary bypass surgery with at least one saphenous graft (more than or equal to 1 year and less than or equal to 10 years).
6) The patient agrees to his participation into the study.
7) Patients must be legally capable of giving consent and must understand what their participation in this study entails, the potential risks and benefits, as well as their freedom to withdraw at any time without any prejudice to subsequent medical arrangement or treatment, and sign an informed consent form prior to any protocol specific procedure being performed.
INCLUSION CRITERIA AT IVUS AND ANGIOGRAPHY PROCEDURE VISIT (VISIT 2)
A subject will be eligible for inclusion in this study only if at least 1), 2) and 3) of the following criteria apply at visit 2 :
1) Patient with at least one patent saphenous vein graft (SVG).
2) Segment length of at least 40 mm in a SVG suitable for IVUS analysis.
3) Reference of the target (SVG) diameter more than or equal to 2.5 mm as assessed by visual estimation.
If anastomosed native coronary artery or non grafted coronary artery can be evaluated, the following criteria must be met:
4) Reference of the target anastomosed native coronary artery or non grafted coronary artery diameter more than or equal to 2.5 mm as assessed by visual estimation.
5) Segment length of at least 20 mm in the anastomosed native coronary artery corresponding to the SVG chosen or, in case of impossibility of performing IVUS in the anastomosed coronary artery, a non grafted coronary artery (more than or equal to 30 mm length segment) might be used for reference.
Refer to the Manual of Operating Procedures (MOP) for detailed information on the angiography and IVUS procedures and scenarios.
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| E.4 | Principal exclusion criteria |
EXCLUSION CRITERIA AT SCREENING
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1) Any clinically significant abnormality identified at screening which, in the judgement of the investigator, makes the patient unsuitable for inclusion in the study.
2) Patients with type 1 diabetes or known history of diabetic ketoacidosis.
3) Patients with uncontrolled type 2 diabetes mellitus (HbA1c > 9.0%).
4) Recent myocardial infarction or acute coronary syndrome (≤ 90 days).
5) History of significant hypersensitivity to thiazolidinediones or compounds with similar chemical structures.
6) Last left ventricular ejection fraction ≤ 35%.
7) Systolic blood pressure > 170 mmHg or diastolic blood pressure> 100 mmHg at screening/baseline (visit 1) should be appropriately treated and under control prior to the randomization visit (visit 2). If systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 mmHg remains elevated at visit 2, the patient should not be randomized. If white coat syndrome is suspected, 24?hour blood pressure monitoring should be considered.
8) Presence of unstable or Canadian Cardiovascular Society (CCS) class III and IV angina, acute heart failure or congestive heart failure.
9) Patients with a prior history of hepatocellular reaction or severe oedema or other potentially fluid-related AE associated with use of any thiazolidinedione or PPAR-g agonist in clinical or investigational use.
10) Presence of clinically significant hepatic disease or renal dysfunction.
11) Anemia.
12) Patients with TG ³ 10 mmol/L.
13) History of percutaneous coronary interventions (PCI) in all SVG(s).
14) Patients with known occlusion(s) of all SVG(s).
15) Treatment involving thiazolidinediones within 3 months prior to screening.
16) Subjects who have required chronic use (≥ 6 months) of insulin for glycemic control at any time in the past (except for previous pregnancy) or those requiring the administration of insulin any time within the last 12 months. EXCEPTION: Subjects necessitating short term (≤ 14 days) use of insulin to maintain glycemic control for a hospitalization or medical procedure/intervention (between 12 months and 30 days prior to screening).
17) Allergy to contrast agents.
18) Patients who are currently taking anorectic agents or have been taken off an anorectic agent or equivalent within 3 months prior to screening.
19) Patients for whom oral or injectable corticosteroids are used on a regular or recurrent basis. Inhaled corticosteroids for the treatment of asthma, chronic obstructive pulmonary disease (COPD), or allergic rhinitis are acceptable.
20) Drug or alcohol abuse.
21) Women who are lactating, pregnant, or planning to become pregnant.
22) Other illness that precludes survival.
23) Patient with an history of malignancy (with the exception of basal cell carcinoma of the skin or in situ prostate cancer) within the last 5 years.
24) Concurrent participation in other investigational device or drug studies and/or having received any experimental therapeutic agents within 30 days of the screening.
25) Use of any investigational drug for glycemic control within 3 months of the screening.
26) Patient expects to be travelling out of town/country for periods exceeding 2 months.
27) Patient has a medical condition which may interfere with intake and/or absorption of the study medication.
28) Patients unwilling or unable to comply with the procedures described in this protocol.
29) Recent major surgery within 90 days of the screening.
EXCLUSION CRITERIA AT IVUS AND ANGIOGRAPHY PROCEDURE VISIT (VISIT 2)
A subject will be excluded to continue participation in the study if, at visit 2, any of the following criteria is met:
1) A PCI was performed on the target segment(s) after the coronary artery bypass graft (CABG) surgery.
2) Target SVG and/or target native coronary artery show ≥ 50% angiographic lesion by visual estimate precluding the IVUS examination.
3) There is a thrombus or a thrombus aspect in the target vessels chosen.
4) A target vessel has been subjected to surgical endarterectomy (i.e. right coronary artery).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of the study will be the change (12 month intravascular ultrasound (IVUS) – Baseline IVUS) in plaque volume in a segment of at least 40 mm in one SVG as measured by IVUS.
Endpoints for Sub-Study:
Changes in heart rate variability (HRV), electrocardiogram (ECG) and exercise treadmill test performance will be evaluated from baseline to 12 months. |
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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 | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| 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 | Information not present in EudraCT |
| 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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| Last visit of the last subject undergoing the clinical 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 | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
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