This study is open to adults who are at least 18 years old living with obesity and have:
* a confirmed liver disease called non-alcoholic steatohepatitis (NASH)/metabolic associated steatohepatitis (MASH) and * moderate or advanced liver fibrosis
People with a history of acute or chronic liver diseases other than MASH or chronic alcohol intake cannot take part in this study. The purpose of this study is to find out whether a medicine called survodutide helps people with MASH and moderate or advanced liver fibrosis improve their liver function.
This study has 2 parts. The purpose of the first part of this study is to find out the effect of survodutide on MASH and liver fibrosis. The purpose of the second part is to find out how safe and effective survodutide is in improving liver function. Participants are put into 2 groups randomly, which means by chance. 1 group gets survodutide and 1 group gets placebo. Placebo looks like survodutide but does not contain any medicine. Each participant has twice the chance of getting survodutide. Participants and doctors do not know who is in which group. Participants inject survodutide or placebo under their skin once a week. The survodutide doses are slowly increased until the target dose is reached. All participants receive counselling to make changes to their diet and to exercise regularly.
Participants are in the study for up to 7 years. During this time, they regularly visit the study site or have remote visits by video call. For about the first year of the study, participants have these visits every 2 weeks, increasing to every 4 weeks and then every 6 weeks. After being in the study for a little over a year participants will then alternate between visiting the study site or having a remote visit every 3 months until the end of the study.
The doctors check participants' health and take note of any unwanted effects. The participants' body weight and effects on the stomach and intestines are regularly measured. At some visits the liver is measured using different imaging methods. At 2 or 3 visits doctors take a small sample of liver tissue (biopsy). The participants also fill in questionnaires about their symptoms and quality of life. The results are compared between the groups to see whether the treatment works.
Male or female participants ≥18 years (or who are of legal age in countries where that is greater than 18 years) of age at time of consent
Diagnosis of MASH (non-alcoholic fatty liver disease (NAFLD)) activity score [NAS] ≥4
Stable body weight defined as less than 5% self-reported change in body weight 3 months prior to the screening or during the period between the historical biopsy and randomisation, if a historical biopsy is used
Be willing to maintain a stable diet and physical activity levels throughout the entire trial Further inclusion criteria apply
Serum AST and/or alanine aminotransferase (ALT) elevation ≥5x upper limit of normal (ULN)
Platelet count <140 000/mm^3 (<140 GI/L)
Alkaline phosphatase >2x upper limit of normal (ULN)
Albumin below <3.5 g/dL (35.0 g/L)
Parallel
Survodutide
Combination productSubcutaneous injection, prefilled syringe
Placebo
Combination productSubcutaneous injection, prefilled syringe
Part 1: Resolution of MASH without worsening of liver fibrosis on MASH Clinical Research Network (CRN) fibrosis score
Part 1: At least a 1-point improvement in fibrosis stage with no worsening of MASH
Part 2: Time to first occurrence of any of components of the composite endpoint consisting of progression to cirrhosis, all-cause mortality, liver transplant, hepatic decompensation event(s), worsening of MELD score to ≥15, progression to CSPH
Progression to cirrhosis is defined as histological fibrosis score CRN F4. MELD = Model for End-stage Liver Disease CSPH =clinically significant portal hypertension
Key secondary endpoint part 1: Percentage change from baseline in body weight [kg]
Key secondary endpoint part 1: Absolute change from baseline in glycosylated haemoglobin (HbA1c) [%]
This endpoint is specified only for the participants with type 2 diabetes mellitus.
Key secondary endpoint part 1: Absolute change from baseline in enhanced liver fibrosis (ELF) score
Key secondary endpoint part 1: Absolute change from baseline in liver stiffness [kPa] assessed by vibration-controlled transient elastography (VCTE)
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