E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-alcoholic steatohepatitis |
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E.1.1.1 | Medical condition in easily understood language |
Non-alcoholic steatohepatitis (NASH) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
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 |
1. Part 1: To demonstrate that treatment with semaglutide 2.4 mg administered subcutaneously (under the skin, s.c.) improves liver histology compared to placebo in subjects with NASH and fibrosis stage 2 or 3. 2. Part 2: To demonstrate that treatment with semaglutide s.c. 2.4 mg lowers the risk of liver-related clinical events compared to placebo in subjects with NASH and fibrosis stage 2 or 3. |
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E.2.2 | Secondary objectives of the trial |
1. To demonstrate that treatment with semaglutide s.c. 2.4 mg lowers body weight compared to placebo in subjects with NASH and fibrosis stages 2 or 3. 2. To demonstrate that treatment with semaglutide s.c. 2.4 mg improves patient-reported outcomes compared to placebo in subjects with NASH and fibrosis stages 2 or 3. 3. To compare the effects of semaglutide s.c. 2.4 mg versus placebo on cardiovascular disease and cardio-metabolic factors in subjects with NASH and fibrosis stages 2 or 3. 4. To compare the effect of semaglutide s.c. 2.4 mg versus placebo on biomarkers related to fibrosis in subjects with NASH and fibrosis stages 2 or 3. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age above or equal to 18 years at the time of signing informed consent. - Histological evidence of NASH based on a central pathologist evaluation of the baseline liver biopsy. The baseline liver biopsy can be a historical biopsy obtained within 180 days prior to screening visit. - Histological evidence of fibrosis stage 2 or stage 3 according to the NASH Clinical Research Network (CRN) classification 7 based on a central pathologist evaluation of the baseline liver biopsy. - A histological non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS 7) equal to or above 4 with a score of 1 or more in both steatosis, lobular inflammation and hepatocyte ballooning based on a central pathologist evaluation of the baseline liver biopsy. |
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E.4 | Principal exclusion criteria |
- Positive hepatitis B surface antigen (HBsAg), positive anti-human immunodeficiency virus (HIV), positive hepatitis C virus-ribonucleic acid (HCV-RNA) at screening or any known presence of HCV RNA or HBsAg within 2 years of screening. - Documented causes of chronic liver disease other than NAFLD. - Presence or history of ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis or liver transplantation at randomisation. - Known or suspected excessive consumption of alcohol (above 20 g/day for women or above 30 g/day for men) or alcohol dependence (assessed by the Alcohol Use Disorders Identification Test (AUDIT questionnaire). - Treatment with vitamin E (at doses equal to or above 800 IU/day) or pioglitazone or medications approved for treatment of NASH which has not been at a stable dose in the opinion of the investigator in the period from 90 days prior to the screening visit. In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until screening. - Treatment with GLP-1 RAs in the period from 90 days prior to the screening visit. In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, any treatment with GLP-1 RAs from time of biopsy until screening. - Treatment with glucose lowering agent(s) (other than GLP-1 RAs), lipid lowering medication or weight loss medication not stable in the opinion of the investigator in the period from 90 days prior to the screening visit. In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until screening. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1: 1. Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) 2. Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No)
Part 2: 3. Time to first liver-related clinical event (composite endpoint) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.- 2. From randomisation (week 0) to week 72 3. From randomisation (week 0) to week 240 |
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E.5.2 | Secondary end point(s) |
1. Progression of liver fibrosis (Yes/No) 2. Change in body weight 3. Change in Short Form 36 v2.0 acute (SF-36) Bodily Pain 4. Change in body weight 5. Improvement in steatohepatitis with at least a 2-point reduction in NAS and no worsening of fibrosis (Yes/No) 6. Change in histology-assessed liver collagen proportionate area 7. Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) 8. Worsening in steatohepatitis (Yes/No) 9. Improvement in histology-assessed ballooning (Yes/No) 10. Improvement in histology-assessed inflammation (Yes/No) 11. Improvement in histology-assessed steatosis (Yes/No) 12. Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) 13. Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) 14. Change in alanine aminotransferase (ALT) 15. Change in aspartate aminotransferase (AST) 16. Change in inflammation assessed by High Sensitive C-Reactive Protein (HsCRP) 17. Change in glycosylated haemoglobin (HbA1c) 18. Change in triglyceride 19. Change in free fatty acids 20. Change in low-density lipoprotein (LDL) cholesterol 21. Change in high-density lipoprotein (HDL) cholesterol 22. Changes in SF-36 Physical Component Summary 23. Changes in SF-36 Mental Component Summary 24. Changes in NASH-CHECK Pain 25. Time to first Major Adverse Cardiovascular event (MACE) (composite endpoint) 26. Time to first major cardio-hepatic event (composite endpoint) 27. Change in liver stiffness assessed by FibroScan®g 28. Change in Enhanced Liver Fibrosis (ELF) score |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. - 3. From randomisation (week 0) to week 72 4. From randomisation (week 0) to week 240 5. - 11. From randomisation (week 0) to week 72 12. - 13. From randomisation (week 0) to week 240 14.- 24. From randomisation (week 0) to week 72 25. - 26. From randomisation (week 0) to week 240 27. - 28. From randomisation (week 0) to week 72 |
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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 | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 120 |
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 | No |
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 |
Argentina |
Australia |
Brazil |
Canada |
China |
India |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Russian Federation |
Serbia |
South Africa |
Taiwan |
Turkey |
United States |
Norway |
Switzerland |
United Kingdom |
European Union |
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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 | 7 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 25 |