A Research Study on How Semaglutide Works in People With Fatty Liver Disease and Liver Damage

Study Overview
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Brief Summary
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Semaglutide is a medicine studied in patients with non-alcoholic steatohepatitis (NASH), as it may improve liver damage. Participants will either get semaglutide or placebo (a dummy medicine) - which treatment participants get is decided by chance. The study will last for about 61 weeks in total. Participants will have 10 clinic visits and 3 phone calls with the study doctor or staff during the study. Some of the clinic visits may be spread over more days. Participants will need to inject themselves with medicine under the skin. Participants will have to do this once a week for 48 weeks. The study includes magnetic resonance imaging (MRI) scans of the liver, 1 or 2 liver tissue samples, ultrasound scans of the stomach and a possible examination of the food pipe. For some tests participants may need to remove some items of clothing. Participants will stop in the study if the doctor thinks that there are any risks for their health. The information collected from participants during the study may help them and other patients with NASH in the future. Women cannot take part if pregnant, breast-feeding or planning to become pregnant during the study period.

Official Title
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Investigation of Efficacy and Safety of Semaglutide s.c. Once-weekly Versus Placebo in Subjects With Non-alcoholic Steatohepatitis and Compensated Liver Cirrhosis

Conditions
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Non-alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Placebo (semaglutide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent. Histologic evidence of NASH and fibrosis stage 4 according to the NASH CRN classification based on central pathologist evaluation of a liver biopsy obtained within 360 days prior to screening. In subjects who have never had a liver biopsy showing NASH and F4, liver stiffness above 14 kPa by FibroScan® at screening must be documented before subjects can have a trial-related liver biopsy A histological NAFLD activity score (NAS) equal to or above 3 with a score of 1 or more in lobular inflammation and hepatocyte ballooning based on central pathologist evaluation Body mass index equal to or above 27 kg/m^2 Exclusion Criteria: Presence or history of hepatic decompensation (e.g. ascites, variceal bleeding, hepatic encephalopathy or spontaneous bacterial peritonitis) or liver transplantation Presence or history of gastroesophageal varices within the past 360 days prior to screening. For subjects with no known history of gastroesophageal varices and with a Fibroscan® equal to or above 20 kPa and thrombocytes equal to or below 150,000, a esophagogastroduodenoscopy must be performed to evaluate presence of gastroesophageal varices Presence or history of hepatocellular carcinoma Treatment with vitamin E (at doses equal to or above 800 IU/day) or pioglitazone which has not been at a stable dose in the opinion of the investigator in the period from 90 days prior to screening Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the period from 90 days prior to screening Treatment with other glucose lowering agent(s) (apart from what is listed in the exclusion criterion above) or weight loss medication not stable in the opinion of the investigator in the period from 28 days prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide<br>Dose escalation to 2.4 mg of semaglutide once-weekly | Drug: Semaglutide<br>* Semaglutide given subcutaneously (s.c., under the skin) once-weekly for 48 weeks<br>|
| Placebo Comparator: Placebo<br>Semaglutide placebo once-weekly | Drug: Placebo (semaglutide)<br>* Semaglutide placebo s.c. given once-weekly for 48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| At least 1 stage of liver fibrosis improvement with no worsening of NASH after 48 weeks (yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation, hepatocyte ballooning or steatosis according to NASH CRN criteria) | Yes/no | From baseline (week 0) to visit 12 (week 48) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative change in liver fat content (percent) measured by magnetic resonance imaging - Proton density fat fraction (MRI-PDFF) | Ratio to baseline | From baseline (week 0) to visit 12 (week 48) | 
| Relative change in liver stiffness measured by MRE | Ratio to baseline | From baseline (week 0) to visit 12 (week 48) | 
| NASH resolution (defined by the NASH CRN as lobular inflammation 0 - 1 and ballooning 0) | Yes/no | From baseline (week 0) to visit 12 (week 48) | 
| Change in stage of fibrosis according to the NASH CRN fibrosis score | Scale (0-4) (range of values on absolute scale at one time-point) | From baseline (week 0) to visit 12 (week 48) | 
| Change in non-alcoholic fatty liver disease (NAFLD) activity score (NAS) according to the NASH CRN criteria | Scale (0-8) (range of values on absolute scale at one time-point) | From baseline (week 0) to visit 12 (week 48) | 
| Number of treatment emergent adverse events | Count | From baseline (week 0) to visit 12 (week 48) |