| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| atherosclerosis in Type 2 Diabetes Mellitus patients with cardiovascular disease |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003601 |
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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 compare RSG versus GLP on the progression of atherosclerosis as measured by IVUS-derived change in percent atheroma volume from baseline to 18 months in non-intervened coronary arteries of subjects with T2DM and CVD undergoing coronary angiography or percutaneous coronary intervention (PCI). |
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| E.2.2 | Secondary objectives of the trial |
• To assess the effects of RSG on other IVUS-derived atherosclerotic endpoints in non-intervened coronary arteries
• To assess the effects of RSG on IVUS-derived atherosclerotic endpoints in the proximal segment of intervened coronary arteries
• To assess the effects of RSG on the time to first occurrence of composite adjudicated major adverse cardiovascular events (MACE)
• To assess the effects of RSG on glycemia-related parameters
• To assess the effects of RSG on CV biomarkers and lipids
• To assess the safety and tolerability of RSG in subjects with T2DM and CVD.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study if ALL of the following criteria apply:
1. Male or female between 30 to 80 years of age, inclusive.
2. Established diagnosis of T2DM (based on diagnostic criteria of the American Diabetes Association (ADA), WHO guidelines or local national guidelines).
3. Subjects who are undergoing coronary angiography for evaluation of suspected or previously diagnosed coronary artery disease or who are undergoing PCI.
4. Subjects' prior anti-hyperglycemic diabetic therapy:
• Diet and exercise only (drug naïve), with HbA1c >7.0 and 10.0%.
• OAD monotherapy or low dose dual combination OAD therapy with
HbA1c > 6.5 and 8.5%.
5. Left ventricular ejection fraction (EF) 40% as assessed by contrast ventriculography (or previously documented in medical notes within one month prior to index procedure by other methods e.g. echocardiography or nuclear study)
6. Female subjects must be postmenopausal (i.e., >6 months without menstrual period), surgically sterile, or using effective contraceptive measures (oral contraceptives, Norplant, Depo-Provera, an intra-uterine device (IUD), a diaphragm with spermicide or a condom with spermicide). Women of childbearing potential must use effective contraceptive measures for at least 1 month prior to visit 1a, and should continue to use the same contraceptive method during the study and for 30 days after discontinuing study medication.
7. Willingness and ability to give informed consent prior to entering the study and available to complete the study.
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for this study if ANY of the following criteria apply:
1. Type 1 diabetes and/or history of diabetic ketoacidosis.
2. Exposure to a TZD or other PPAR- agonist within the 6 months prior to screening visit.
3. Subjects treated with triple OAD therapy or high dose dual combination OAD therapy .
4. Subjects who have required chronic insulin use in the last 6 months (except during pregnancy or acute episodes such as hospitalization, trauma or infection).
5. ST segment elevation myocardial infarction in the last 30 days.
6. Subjects who have a history or are scheduled to receive coronary artery bypass graft surgery (CABG), valve repair or replacement, aneurysmectomy or planned major non-cardiac surgery during the study period.
7. Subjects who have severe cardiac valvular disease.
8. Stroke or resuscitated in the past 6 months.
9. History of congestive heart failure (NYHA class I – IV).
10. History of significant hypersensitivity or reaction (e.g., difficulty swallowing, difficulty breathing, tachycardia or skin reaction) to any TZD, SU, biguanide or insulin.
11. Prior history of severe edema or edema requiring medical treatment.
12. Chronic disease requiring chronic or intermittent treatment with oral, intravenous, or injected corticosteroids (use of topical, inhaled, or nasal corticosteroids is permissible).
13. Recent history or suspicion of current drug abuse or alcohol abuse within the last 6 months.
14. Untreated hypo- or hyperthyroidism.
15. A diagnosis of cancer (other than superficial squamous, basal cell skin cancer, or adequately treated cervical carcinoma in situ) in the past 3 years or current treatment for the active cancer.
16. Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgement of the Investigator, would preclude safe completion of the study.
17. Blood pressure: SBP >170 or DBP > 100 mmHg.
18. Significant anemia (Hemoglobin < 11 g/dL for males and < 10 g/dL for females).
19. Significant renal disease manifested by serum creatinine (> 1.5mg/dL for males or > 1.4mg/dL for females), or where the use of metformin is contra-indicated.
20. Hepatic disease or biliary tract obstruction, or significant hepatic enzyme elevation (ALT or AST > 2.5 times upper limit of normal (ULN) or bilirubin >2x ULN).
21. History of myopathy or history of elevated creatine kinase (CK) > 3 times upper normal limit.
22. Use of an investigational drug within 30 days or 5 half-lives (whichever is the longer).
23. Women who are lactating, pregnant or planning to become pregnant during the course of the study.
24. Unwillingness or inability to comply with the procedures described in this protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change in percent atheroma volume (defined as total atheroma volume divided by total vessel volume x 100) within a 40mm segment in non-intervened coronary arteries from baseline to 18-months, based upon IVUS assessment. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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
| Information not present in EudraCT |
| 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.8.6 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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