Efficacy and Safety Investigation of NNC0194-0499 Co-administered With Semaglutide in Subjects With Non-alcoholic Steatohepatitis: a Dose-ranging, Placebo Controlled Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 698
- 试验地点
- 254
- 主要终点
- Improvement in liver fibrosis and no worsening of NASH (Yes/No)
研究概览
简要总结
This study is being done to see if a combination of 2 medicines (called NNC0194-0499 and semaglutide) can reduce liver damage in patients with non alcoholic steatohepatitis (NASH).
NNC0194-0499 is a new medicine which works in the liver. Semaglutide is a well-known medicine, which is already used by doctors to treat type 2 diabetes in many countries. It also helps with weight loss and may reduce liver damage, and so prevent future liver complications. It works in a different way to NNC0194 0499. The 2 medicines may work better together than on their own.
The study will also look at a combination of semaglutide and another weight-loss medicine called NNC0174-0833, which may be another treatment option for NASH.
Each week, participants will get 2 injections. These could be 2 of the 3 medicines OR 1 of the medicines and a placebo OR 2 placebo injections. Which treatment participants get is decided by chance. A placebo is a dummy medicine which looks like the real medicine but doesn't contain any active medicine.
The study will last for about 19 months. Participants will have 14 clinic visits and 9 phone calls with the study doctor.
Participants will have 1 or 2 liver biopsies (tiny pieces of liver tissue) - one at the start (if participants have not had a biopsy recently) and one at the end of the study treatment.
Women: Women cannot take part if pregnant, breast-feeding or planning to become pregnant during the study period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged greater than or equal to 18 years at the time of signing informed consent. In Republic of Korea, subjects must be aged greater than or equal to 19 years. In Japan, subjects must be aged greater than or equal to 20 years. In Singapore, subjects must be aged greater than or equal to 21 years.
- •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 Visit
- •Histological evidence of fibrosis stage 2, 3 or 4 according to the NASH CRN classification based on a central pathologist evaluation of the baseline liver biopsy.
- •Histological non-alcoholic fatty liver disease (NAFLD) activity score (NAS) greater than or equal to 4 for subjects with F2/F3 or greater than or equal to 3 for subjects with F4 based on a central pathologist evaluation of the baseline liver biopsy. All subjects must have a score of 1 or more in steatosis, lobular inflammation and hepatocyte ballooning.
排除标准
- •Documented causes of chronic liver disease other than 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 more than grade 1, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis or liver transplantation at V2A.
- •For subjects with F4, presence or history of gastro-oesophageal varices more than or equal to grade 2 at V
- •An oesophagogastroduodenoscopy performed no more than 52 weeks prior to V3 must be available at V
- •Known or suspected excessive consumption of alcohol (more than 20 g/day for women or more 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 more than or equal to 800 IU/day) or pioglitazone or medications approved for the 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 V2A. In addition, for subjects with a historical liver biopsy taken more than 90 days prior to V2A, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until V2A.
- •Treatment with GLP-1 RAs within 90 days prior to V2A. Subjects with a historical liver biopsy taken more than 90 days prior to V2A are excluded if they receive treatment with GLP-1 RAs from time of biopsy until 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 V2A. In addition, for subjects with a historical liver biopsy taken more than 90 days prior to V2A, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until V2A.
研究组 & 干预措施
NNC0194-0499 7.5 mg + semaglutide 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: NNC0194 0499 50 mg/mL (Drug)
NNC0194-0499 7.5 mg + semaglutide 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Semaglutide 3 mg/mL (Drug)
Placebo (NNC0194-0499) 7.5 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Placebo (NNC0194-0499) (Drug)
Placebo (NNC0194-0499) 7.5 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Semaglutide placebo (Drug)
NNC0194-0499 15 mg + semaglutide 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: NNC0194 0499 50 mg/mL (Drug)
NNC0194-0499 15 mg + semaglutide 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Semaglutide 3 mg/mL (Drug)
Placebo (NNC0194-0499) 15 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Placebo (NNC0194-0499) (Drug)
Placebo (NNC0194-0499) 15 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Semaglutide placebo (Drug)
NNC0194-0499 30 mg + semaglutide 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: NNC0194 0499 50 mg/mL (Drug)
NNC0194-0499 30 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: NNC0194 0499 50 mg/mL (Drug)
NNC0194-0499 30 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Semaglutide placebo (Drug)
Placebo (NNC0194-0499) 30 mg + semaglutide 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Placebo (NNC0194-0499) (Drug)
Placebo (NNC0194-0499) 30 mg + semaglutide 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Semaglutide 3 mg/mL (Drug)
Placebo (NNC0194-0499) 30 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Placebo (NNC0194-0499) (Drug)
Placebo (NNC0194-0499) 30 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Semaglutide placebo (Drug)
NNC0174-0833 2.4 mg + semaglutide 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Semaglutide 3 mg/mL (Drug)
NNC0174-0833 2.4 mg + semaglutide 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: NNC0174 0833 10 mg/mL (Drug)
Placebo (NNC0174-0833) 2.4 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: Semaglutide placebo (Drug)
Placebo (NNC0174-0833) 2.4 mg + semaglutide placebo 2.4 mg
Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.
干预措施: NNC0174 0833 placebo (Drug)
结局指标
主要结局
Improvement in liver fibrosis and no worsening of NASH (Yes/No)
时间窗: From baseline (week 0) to week 52
Count of subjects Improvement in fibrosis is defined as greater than or equal to 1 grade improvement on the NASH CRN fibrosis scale
次要结局
- Improvement in liver fibrosis (Yes/No)(From baseline (week 0) to week 52)
- Worsening in steatohepatitis (Yes/No)(From baseline (week 0) to week 52)
- Progression of liver fibrosis (Yes/No)(From baseline (week 0) to week 52)
- Improvement in ballooning (Yes/No)(From baseline (week 0) to week 52)
- Improvement in inflammation (Yes/No)(From baseline (week 0) to week 52)
- Improvement in steatosis (Yes/No)(From baseline (week 0) to week 52)
- Change in ALT (alanine aminotransferase)(From baseline (week 0) to week 52)
- Change in AST (aspartate aminotransferase)(From baseline (week 0) to week 52)
- Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No)(From baseline (week 0) to week 52)
- Improvement in steatohepatitis with at least a 2-point reduction in NAS and no worsening of fibrosis (Yes/No)(From baseline (week 0) to week 52)
- Change in histology-assessed liver collagen proportionate area(From baseline (week 0) to week 52)
- Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No)(From baseline (week 0) to week 52)
- Change in inflammation assessed by HsCRP (high sensitivity C-reactive protein)(From baseline (week 0) to week 52)
- Change in ELF (Enhanced Liver Fibrosis) score(From baseline (week 0) to week 52)
- Change in HbA1c. For subjects with type 2 diabetes(From baseline (week 0) to week 52)
- Change in triglycerides(From baseline (week 0) to week 52)
- Change in free fatty acids(From baseline (week 0) to week 52)
- Change in LDL (low density lipoprotein) cholesterol(From baseline (week 0) to week 52)
- Change in HDL (high density lipoprotein) cholesterol(From baseline (week 0) to week 52)
- Relative change in body weight(From baseline (week 0) to week 52)
- Change in SF-36 (36-item Short Form Survey) bodily pain(From baseline (week 0) to week 52)
- Change in NASH-CHECK (patient-reported outcome measure for non-alcoholic steatohepatitis)pain(From baseline (week 0) to week 52)
- Change in PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue score(From baseline (week 0) to week 52)
- Number of treatment emergent adverse events (TEAEs)(From baseline (week 0) to week 59)