E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetic patients with Non-Alcoholic Steato-Hepatitis |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
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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 |
The primary objective of this study is to demonstrate in patients with co-morbid Type 2 diabetes following 18 months treatment, the superiority of rimonabant 20 mg OD over placebo for improving the severity of NASH as measured by histological features of liver injury. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to demonstrate in patients with co-morbid diabetes following 18 months treatment, the superiority of rimonabant 20 mg OD over placebo: 1) In severity of hepatic fibrosis as measured by hepatic fibrosis stage; 2) In level of circulating plasma adiponectin; 3) In level of circulating hyaluronate; 4) In degree of insulin sensitivity; and, 5) In AST/ALT level. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients who are at least 18 years of age and with a diagnosis of NASH by liver biopsy performed within last 6 months (based on pre-defined histological criteria as confirmed by a central pathologist) 2. Confirmed Type 2 DM diagnosed by fasting plasma glucose ≥ 126 mg/dl or 2-hour post load glucose ≥ 200 mg/dl during an OGTT (equivalent of 75 g anhydrous glucose in water) of at least 6 months duration. |
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E.4 | Principal exclusion criteria |
Exclusion criteria related to study methodology 1. Refusal or inability to give informed consent to participate in the study 2. Average alcohol ingestion > 21 units/wk (males) or > 14 units/wk (females) [self-administered quantity-frequency and 7-day recall tests and confirmed by a family member] 3. History of or presence of Type 1 diabetes mellitus (requirement for insulin replacement and presence of autoantibodies, e.g., antipancreatic islet cell, insulin autoantibodies, tyrosine phosphate autoantibodies or GADAb) 4. Hemoglobin A1C > 8.5. 5. Other cause of chronic liver disease and/or hepatic steatosis: - Wilson’s Disease - Alpha-1-Antitrypsin deficiency - Viral hepatitis - Primary Biliary Cirrhosis - Autoimmune hepatitis - Genetic iron overload - History of sleep apnea (unless on Constant Positive Airway Pressure therapy) - History of or current HIV infection - Hypo- or hyper-thyroidism 6. Any contraindication to liver biopsy based on local standard for pre-liver biopsy risk assessment (as examples,: presence of a bleeding dyscrasia, platelets < 50-75K, prothrombin time > 3 sec above control as measured locally during pre-biopsy evaluation of coagulation parameters) 7. History of or planned gastrointestinal bypass surgery/intervention (i.e., bariatric surgery) 8. Hepatic Cirrhosis with a Child-Pugh classification of B or C (score > 6) 9. Concomitant Hepatocellular Carcinoma (HCC) (i.e., AFP > 100 ng/mL on screening Liver Disease Panel or otherwise unexplained liver mass visualized on ultrasound or computed tomography examination of the liver) 10. Previous hepatic transplantation 11. Recent significant weight loss (> 5% TBW within previous 6 months) 12. ALT or AST > 10 x ULN at screening or within 3 months of screening 13. Recent (within 6 months of baseline liver biopsy and screening visit) or concomitant use of agent known to cause hepatic steatosis: - corticosteroids - amiodarone - methotrexate - tamoxifen - tetracycline - high dose estrogens (standard HRT and oral contraceptive doses allowed) - valproic acid 14. Recent (within 3 months of baseline liver biopsy and screening visit) change in anti-diabetes treatment, such as a change in dose-regimen of anti-diabetes agent or introduction of new- antidiabetes agent (a specific diabetes medication /treatment page will be included in the CRF). 15. Recent (within 3 months of baseline liver biopsy and screening visit) change in dose/ regimen or introduction of: - Vitamin E, Vitamin C - betaine, s-adenosyl methionine (SAM), ursodeoxycholate (UDCA) - silymarin (silybin) - fibrate - statin - pentoxyfilline - angiotensin II inhibitor 16. Recent (within 3 months of baseline liver biopsy and screening visit) change in dose/ regimen or introduction of weight loss agent such as: - orlistat - sibutramine - rimonabant 17. Any situation that in the Investigator’s opinion, may interfere with optimal study participation such as alcohol or drug abuse, domicile too distant from study site, potential non-compliance during the study or inability to cooperate because of a language problem or poor mental development 18. Participation in any clinical study of an investigational agent within 30 days or five half-lives of the investigational agent, whichever is longer 19. Presence of clinically relevant cardiovascular, pulmonary, gastro-intestinal, hepatic, renal, metabolic, hematological, neurological, psychiatric, systemic, ocular, gynecologic (if female), or any acute infectious disease or signs of acute illness that, in the opinion of the Investigator, might compromise the patient’s safe participation in this trial 20. Presence or history of multiple allergic reactions to drugs 21. Presence or history of cancer within past 5 yrs with exception of adequately treated localized basal cell carcinoma of the skin, in situ cervical cancer or solid malignancy surgically excised in toto without recurrence for five years 22. Women of childbearing potential not protected by effective contraceptive method of birth control or surgical sterilization and/or who are unwilling or unable to be tested for pregnancy. Pregnancy status will be checked by serum pregnancy testing before initiation of study treatment and by urine pregnancy testing during the trial. 23. Patient is the Investigator or any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol Exclusion criteria related to the sanofi-aventis compound 24. Be pregnant or breastfeeding 25. Hypersensitivity to rimonabant or to any of the excipients |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the mean change per year in NAS (NAFLD Activity score) between baseline and end of study biopsy evaluation. |
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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 | No |
E.6.3 | Therapy | No |
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 | No |
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 | 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) | 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
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 69 |
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |