A randomised, double-blind, placebo-controlled, multicentre, Phase III trial evaluating long-term efficacy and safety of survodutide weekly injections in adult participants with noncirrhotic non-alcoholic steatohepatitis/metabolic associated steatohepatitis (NASH/MASH) and (F2) - (F3) stage of liver fibrosis
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 1,800
- 试验地点
- 16
- 主要终点
- Part 1: Resolution of MASH without worsening of liver fibrosis on MASH Clinical Research Network (CRN) fibrosis score
研究概览
简要总结
This study is open to adults who are at least 18 years old 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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- Participant and Investigator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Male or female participants greater than or equal to 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] greater than or equal to 4, with at least 1 point in inflammation and ballooning each) and fibrosis stage F2-F3 proven by a biopsy conducted during the screening period or by a historical biopsy conducted within the last 6 months prior to randomization
- •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.
排除标准
- •Any of the following liver laboratory test abnormalities at screening:.
- •Serum AST and/or alanine aminotransferase (ALT) elevation greater than or equal to 5x upper limit of normal (ULN).
- •Platelet count less than 140 000/mm 3 (less than140 GI/L).
- •Alkaline phosphatase greater than 2x upper limit of normal (ULN).
- •Abnormal synthetic liver function as defined by screening central laboratory evaluation: a) Albumin below less than 3.5 g/dL (35.0 g/L) b) OR International normalised ratio (INR) of prothrombin time greater than 1.3 (unless participant is on anticoagulants) c) OR total serum bilirubin concentration greater than or equal to 1.5x ULN (participants with a documented history of Gilberts syndrome can be enrolled if the direct bilirubin is within normal reference range)
- •Any history or evidence of acute or chronic liver disease other than MASH
- •Histologically documented liver cirrhosis (fibrosis stage F4), either at screening or in a historical biopsy
- •History of or current diagnosis of hepatocellular carcinoma
- •History of or planned liver transplant
- •Inability or unwillingness to undergo a liver biopsy at screening (if a suitable historical biopsy is unavailable for central review), or during trial conduct
- •History of portal hypertension or presence of decompensated liver disease (including hepatic encephalopathy, variceal bleeding, ascites, and spontaneous bacterial peritonitis)
- •Model for end-stage liver disease (MELD) score greater than or equal to 12 due to liver disease
- •Treatment with any medication for the indication obesity within 3 months before screening biopsy or historical biopsy time point
- •History of either chronic or acute pancreatitis or elevation of serum lipase or amylase greater than 2x ULN as measured by the central laboratory at screening
- •Major surgery (in the opinion of the investigator) performed within 3 months prior to screening or planned during the trial
- •Further exclusion criteria apply.
结局指标
主要结局
Part 1: Resolution of MASH without worsening of liver fibrosis on MASH Clinical Research Network (CRN) fibrosis score
时间窗: Part 1: Baseline and at Week 52 | Part 2: Up to 7 years
Part 1: At least a 1-point improvement in fibrosis stage with no worsening of MASH
时间窗: Part 1: Baseline and at Week 52 | Part 2: Up to 7 years
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 greater than or equal to 15, progression to CSPH
时间窗: Part 1: Baseline and at Week 52 | Part 2: Up to 7 years
次要结局
- part 1: Percentage change from baseline in body weight(Baseline and at Week 52)
- part 1: Absolute change from baseline in glycosylated haemoglobin (HbA1c)(Baseline and at Week 52)
- part 1: Absolute change from baseline in enhanced liver fibrosis (ELF) score(Baseline and at Week 52)
- part 1: Absolute change from baseline in liver stiffness assessed by vibration-controlled transient elastography (VCTE)(Baseline and at Week 52)
- part 1: Achievement of no progression of fibrosis assessed by central pathology (yes/no)(Baseline and at Week 52)
- part 2: Percentage change from baseline in body weight(At baseline and at Week 114)
- part 2: Absolute change from baseline in HbA1c(At baseline and at Week 114)
- part 2: Absolute change from baseline in ELF score(At baseline and at Week 114)
- part 2: Absolute change from baseline in liver stiffness assessed by VCTE(At baseline and at Week 114)
- part 2: Achievement of no progression of fibrosis assessed by central pathology (yes/no)(At baseline and at 7 years)
- part 2: Occurrence of all-cause hospitalisation (first and recurrent)(Up to 7 years)
- part 2: Time to first occurrence of any of the adjudicated components of the composite endpoint 5-point major adverse cardiac event (5P-MACE)5-point major adverse cardiac event (5P-MACE)(Up to 7 years)
- Part 1: Improvement of liver fat content (LFC)(At baseline and at Week 52)
- Part 2: Improvement of LFC(At baseline and at Week 114)
- Part 1: Absolute change from baseline in LFC in MRI-PDFF(At baseline and at Week 52)
- Part 2: Absolute change from baseline in LFC in MRI-PDFF(At baseline and at Week 114)
- Part 1: Absolute change from baseline in alanine aminotransferase (ALT) [U/L](At baseline and at Week 52)
- Part 2: Absolute change from baseline in alanine aminotransferase (ALT) [U/L](At baseline and at Week 114)
- Part 1: Absolute change from baseline in aspartate aminotransferase (AST) [U/L](At baseline and at Week 52)
- Part 2: Absolute change from baseline in aspartate aminotransferase (AST) [U/L](At baseline and at Week 114)
- Part 1: Absolute change from baseline in systolic blood pressure (SBP) [mmHg](At baseline and at Week 52)
- Part 2: Absolute change from baseline in systolic blood pressure (SBP) [mmHg](At baseline and at Week 114.)
- Part 1: Absolute change from baseline in diastolic blood pressure (DBP) [mmHg](At baseline and at Week 52)
- Part 2: Absolute change from baseline in diastolic blood pressure (DBP) [mmHg](At baseline and at Week 114)
- Part 1: Absolute changes from baseline in lipids [mg/dL] (including but not limited to: total cholesterol, low-density lipoprotein [LDL] cholesterol, very low density lipoprotein [VLDL], high-density lipoprotein [HDL] cholesterol, triglycerides [TG])(At baseline and at Week 52)
- Part 2: Absolute changes from baseline in lipids [mg/dL] (including but not limited to: total cholesterol, low-density lipoprotein [LDL] cholesterol, very low density lipoprotein [VLDL], high-density lipoprotein [HDL] cholesterol, triglycerides [TG])(At baseline and at Week 114)
- Part 1: Absolute change from baseline in free fatty acids [mg/dL](At baseline and at Week 52)
- Part 2: Absolute change from baseline in free fatty acids [mg/dL](At baseline and at Week 114.)
- Part 1: Progression to cirrhosis (defined as histological fibrosis score CRN F4) (yes/no)(At baseline and at Week 52)