Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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Semaglutide is a medicine studied in patients with NASH. Semaglutide is a well-known medicine, which is already used by doctors to treat type 2 diabetes in many countries. Participants will either get semaglutide or a dummy medicine - which treatment participants get is decided by chance. Participants will need to inject themselves with medicine under the skin. Participants will need to do this once a week. The study will last for about 5 years. Participants will have up to 21 clinic visits and 9 phone calls with the clinical staff during the study. Some of the clinic visits may be spread over more than one day. Participants with other chronic liver diseases cannot take part in this study. Women cannot take part in the study if they are pregnant, breast-feeding or plan to become pregnant during the study period.

Official Title
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The Effect of Semaglutide in Subjects With Non-cirrhotic Non-alcoholic Steatohepatitis

Conditions
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Non-alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 the screening visit (V1). Histological evidence of fibrosis stage 2 or stage 3 according to the NASH CRN (Clinical Research Network) classification based on a central pathologist evaluation of the baseline liver biopsy. A histological NAS (Non-alcoholic fatty liver disease Activity Score) above or equal to 4 with a score of 1 or more in steatosis, lobular inflammation and hepatocyte ballooning based on a central pathologist evaluation of the baseline liver biopsy. Exclusion Criteria: Documented causes of chronic liver disease other than non-alcoholic fatty liver disease (NAFLD) Positive HBsAg, positive anti-HIV, positive HCV RNA at screening (V2A) or any known presence of HCV RNA or HBsAg within 2 years of screening (V2A). Presence or history of ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis or liver transplantation at randomisation. Known or suspected excessive consumption of alcohol (greater than 20 g/day for women or greater than 30 g/day for men) or alcohol dependence (assessed by the Alcohol Use Disorders Identification Test (AUDIT questionnaire)). Treatment with vitamin E (at doses greater than or equal to 800 IU/day) or pioglitazone or medications approved for treatment of NASH which has not been at a stable dose in the period from 90 days prior to the screening visit (V2A). In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, treatment should be at a stable dose in from time of biopsy until screening. Treatment with GLP-1 RAs in the period from 90 days prior to the screening visit (V2A). 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 (V2A). 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 (V2A). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide OW (once weekly )<br>Semaglutide administrated subcutaneously once weekly | Drug: Semaglutide<br>* Semaglutide administrated subcutaneously (under the skin) once weekly there will be a period of dose escalation before reaching the target dose.<br>|
| Placebo Comparator: Placebo<br>Placebo administrated subcutaneously once weekly | Drug: Placebo<br>* Placebo administrated subcutaneously (under the skin) once weekly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) | Count of subjects (Resolution of steatohepatitis is defined as a NAFLD Activity Score (NAS) of 0-1 for inflammation, 0 for ballooning, and any value for steatosis (According to NASH CRN). Fibrosis is graded on the NASH CRN fibrosis scale from 0 to 4. ) | From randomisation (week 0) to week 72 | 
| Part 1: Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) | Count of subjects ( Improvement in fibrosis is defined as greater than or equal to 1 grade improvement on the NASH CRN fibrosis scale. No worsening of steatohepatitis is defined as no increase from baseline in NAS score for ballooning, inflammation, or steatosis. ) | From randomisation (week 0) to week 72 | 
| Part 2: Time to first liver-related clinical event (composite endpoint) | Days (The liver-related clinical event composite endpoint consists of: histological progression to cirrhosis, all-cause mortality, liver-induced MELD score greater than or equal to 15, liver transplant or hepatic decompensation events (ascites leading to treatment (diuretics, parascentesis and/or TIPS), spontaneous bacterial peritonitis (identified by analysis of ascites fluid (a polymorphonuclear cell count in the ascitic fluid greater than or equal to 250 cells/mm3 and/or a positive bacterial ascitic fluid culture) and/or a clinical assessment consistent with spontaneous bacterial peritonitis), hepatic encephalopathy greater than or equal to grade 2 according to the West Haven criteria or hospitalisation for gastro-oesophageal variceal bleeding). | From randomisation (week 0) to week 240 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression of liver fibrosis (Yes/No) | Count of subjects | From randomisation (week 0) to week 72 | 
| Change in body weight | Percentage | From randomisation (week 0) to week 72 | 
| Change in SF-36 (Short Form 36) Bodily Pain | Score points | From randomisation (week 0) to week 72 | 
| Change in body weight | Percentage | From randomisation (week 0) to week 240 | 
| Improvement in steatohepatitis with at least a 2-point reduction in NAS and no worsening of fibrosis (Yes/No) | Count of subjects (The 2-point reduction needs to include at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning) | From randomisation (week 0) to week 72 | 
| Change in histology-assessed liver collagen proportionate area | Ratio to baseline | From randomisation (week 0) to week 72 | 
| Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) | Count of subjects | From randomisation (week 0) to week 72 | 
| Worsening in steatohepatitis (Yes/No) | Count of subjects (Defined as increase in NAS for ballooning, inflammation, or steatosis) | From randomisation (week 0) to week 72 | 
| Improvement in histology-assessed ballooning (Yes/No) | Count of subjects | From randomisation (week 0) to week 72 | 
| Improvement in histology-assessed inflammation (Yes/No) | Count of subjects | From randomisation (week 0) to week 72 | 
| Improvement in histology-assessed steatosis (Yes/No) | Count of subjects | From randomisation (week 0) to week 72 | 
| Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) | Count of subjects | From randomisation (week 0) to week 240 | 
| Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) | Count of subjects | From randomisation (week 0) to week 240 | 
| Change in ALT (alanine aminotransferase) | Ratio to baseline | From randomisation (week 0) to week 72 | 
| Change in AST (aspartate aminotransferase) | Ratio to baseline | From randomisation (week 0) to week 72 | 
| Change in inflammation assessed by hsCRP (High Sensitive C-Reactive Protein) | Ratio to baseline | From randomisation (week 0) to week 72 | 
| Change in HbA1c (glycated haemoglobin) | Percentage-points (absolute change) (For subjects with type 2 diabetes) | From randomisation (week 0) to week 72 | 
| Change in triglyceride | Ratio to baseline | From randomisation (week 0) to week 72 | 
| Change in free fatty acids | Ratio to baseline | From randomisation (week 0) to week 72 | 
| Change in LDL (low-density lipoprotein) cholesterol | Ratio to baseline | From randomisation (week 0) to week 72 | 
| Change in HDL (High density lipoprotein ) cholesterol | Ratio to baseline | From randomisation (week 0) to week 72 | 
| Changes in SF-36 (Short Form 36 v2.0 acute ) Physical Component Summary | Score points | From randomisation (week 0) to week 72 | 
| Changes in SF-36 Mental Component Summary | Score points | From randomisation (week 0) to week 72 | 
| Changes in NASH-CHECK Pain | Score points | From randomisation (week 0) to week 72 | 
| Time to first MACE(Major Adverse Cardiovascular event ) (composite endpoint) | Days (The MACE composite endpoint consists of: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) | From randomisation (week 0) to week 240 | 
| Time to first major cardio-hepatic event (composite endpoint) | Days (The major cardio-hepatic event composite endpoint consists of: MACE, liver-related death, histological progression to cirrhosis, liver-induced MELD score above or equal to 15, liver transplant or hepatic decompensation event) | From randomisation (week 0) to week 240 | 
| Change in liver stiffness assessed by FibroScan® | Ratio to baseline (FibroScan® will only be assessed at sites that has the equipment available) | From randomisation (week 0) to week 72 | 
| Change in ELF (Enhanced Liver Fibrosis) score | Logarithm | From randomisation (week 0) to week 72 |