E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-alcoholic steatohepatits (NASH) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012601 |
E.1.2 | Term | Diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10024670 |
E.1.2 | Term | Liver disorder |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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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 investigate the safety and efficacy of 48 weeks treatment with once-daily injections of liraglutide in damaged liver tissue in overweight patients with non-alcoholic steatohepatitis [NASH] (i.e. the more severe, inflammatory form of fatty liver disease). To investigate whether the effect of liraglutide on NASH warrants further investigation. |
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E.2.2 | Secondary objectives of the trial |
To investigate whether 48 weeks treatment with once-daily injections of liraglutide in overweight patients with non-alcoholic steatohepatitis effects the following, whilst maintaining the safety of the trial particpants: 1. reducing fat accumulation in the liver 2. reducing liver inflammation and scarring 3. reducing body weight, blood pressure, cholesterol and sugar levels (all of which are risk factors for heart disease, diabetes and increased risk of premature death) 4. improving the livers control of dangerous fats and high sugar levels in response to the hormone, insulin. 5. improving the patients nutrional intake and quality of life (analysed in questionnaire format) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. A 'Definite' diagnosis of Non-Alcoholic Steatohepatitis (NASH) on liver biopsy performed within 6 months of screening. 2. Age ≥ 18 < 70 years old 3. Body Mass Index (BMI) ≥ 25 , ≤45 4. Specific criteria if patient has Type 2 Diabetes: a. Subjects oral hypoglycaemic therapy at a stable dose for ≥ 3 months prior to randomisation, including one of the following: Metformin monotherapy Sulphonylurea monotherapy Metformin and Sulphonylurea 5. Specific criteria for Non-Diabetic subjects (based on two separate fasting plasma glucose levels > 48 hours apart and/or Oral Glucose Tolerance Test (OGTT)): a. Impaired fasting glucose (IFG), defined using the European Criteria between 6.1 and 6.9 mmol/L AND/OR b.Impaired glucose tolerance (IGT), defined as two-hour plasma glucose levels between 7.8 and 11.0 mmol/ on the 75-g OGTT OR c. Normal Fasting Plasma Glucose (FPG) < 6.1 mmol and Normal two-hour plasma glucose levels < 7.8 on the 75g OGTT. |
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E.4 | Principal exclusion criteria |
1. Patients with a BMI > 45 kg/m2 2. Refusal or lacks capacity to give informed consent to participate in the trial 3. Participation in any clinical trial of an investigational therapy or agent within 3 months of randomisation 4. Patient (or carer) deemed not competent at using the correct site and technique for subcutaneous injection of the trial treatment (containing dummy drug on practice) at visit 2 5. Child’s Pugh stage B or C Liver cirrhosis 6. Past medical history of multiple drug allergies (>3 signficant drug allergies) 7. Presence of any acute/chronic infections or illness that at the discretion of the chief investigator might compromise the patient’s health and safety in the trial 8. Pregnancy or breastfeeding 9. Women, of child-bearing age, who are not willing to practise effective contraception for the 48 week duration of the trial and for one-month after the last administration of the drug. 10. Men, sexually active with women of child-bearing age, who are not willing to practise effective contraception for the 48 week duration of the trial and for one-month after the last administration of the drug. 11. Liver disease of other aetiologies (i.e. drug-induced, viral hepatitis, autoimmune hepatitis, PBC, PSC, harmochromatosis, A1AT deficiency, Wilsons disease) 12. Past medical/surgery history of;Gastric bypass surgery, Orthotopic liver transplant (OLT) or listed for OLT, Hepatocellular or pancreatic carcinoma, Acute or chronic pancreatitis, Total Parenteral Nutrition, within 6 months of randomisation. 13. Hepatocellular Carcinoma – dysplastic or intermediate nodules to be excluded. Borderline cases to be discussed at Birmingham’s tertiary hepato-biliary multidisciplinary team (MDT) meeting. Regenerative and other nodules to be included at the discretion of the chief investigator and the MDT. 14. Clinical evidence of decompensated chronic liver disease: o Radiological or clinical evidence of ascites o Current or previous hepatic encephalopathy o Evidence of portal hypertensive haemorrhage or varices on endoscopy 15. Malignancy within the last 3 years (with the exception of treated skin malignancies) 16. Abnormal clinical examination of thyroid (i.e. unexplained goitre or palpable nodules) 17. Blood levels of Alanine transaminase (ALT) or Aspartate Aminotransferase (AST) greater than 10 x upper limit of normal (local reference ranges will apply) 18. Average alcohol consumption per week > 21 units (168g) male, >14 units (112g) female within the last 5 years. 19. >5% weight loss between the diagnostic liver biopsy (preceding the study) and screening. 20. Recent or concomitant use of the following drugs within 6 months of randomisation; o Inducers of Hepatic steatosis - steroids, methotrexate, amiodarone, diltiazem o Weight-reducing therapies – Orlistat, Sibutramine 21. Addition or change in dose (as judged by the chief investigator) of the following drugs, within 6 months of randomisation; o Angiotensin converting enzymes (ACE)-inhibitors or Angiotensin receptor blockers (ARBs), Multi-vitamins (containg Vitamin E) 22. Known positivity for antibody to Human Immunodeficiency virus (HIV) 23. Serum creatinine > 150 μmol/L or Renal Replacement Therapy 25. Subjects with Type II Diabetes exclusion criteria (specific): • Current or previous insulin therapy, with exception of previous short-term insulin treatment in connection with intercurrent illness is allowed (≥ 3 months prior to screening), at the discretion of the chief investigator. • Subjects receiving Thiazolidinediones (TZDs), Dipeptidy Peptidase (DPP) IV inhibitors and other GLP-1 agonists (i.e. Exenatide) • HbA1c ≥ 9.0% • Recurrent major hypoglycaemia or hypoglycaemic unawareness as judged by the chief investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective is to investigate whether 48 weeks treatment with once-daily injections of liraglutide results in an improvement in liver histology in overweight patients with NASH. Both of the following criteria MUST be met in order to report an improvement in liver histology after treatment; • Disappearance of NASH (i.e. disappearance of hepatocyte ballooning) • No worsening in fibrosis stage (as defined by Kleiner et al, 2005) |
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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 | 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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
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 | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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The LEAN Trial will end when the final participant has completed their follow-up visit (visit 8 i.e. assessment 24 weeks after the final day of trial treatment) in both the UK and Germany. Estimated date = 1st June 2013 |
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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 | 3 |
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 | 3 |