Non-alcoholic Steatohepatitis
Conditions
Brief summary
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.
Interventions
DRUGSemaglutide
Semaglutide administrated subcutaneously (under the skin) once weekly there will be a period of dose escalation before reaching the target dose.
DRUGPlacebo
Placebo administrated subcutaneously (under the skin) once weekly.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Sponsor staff involved in the clinical trial is masked according to company standard procedures The trial has two parts, a part 1 and a part 2, in part 2 sponsor will be unblinded
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) | From randomisation (week 0) to week 72 | Count of subject |
| Part 1: Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) | From randomisation (week 0) to week 72 | Count of subject |
| Part 2: Cirrhosis-free survival (Yes/No) | From randomisation (week 0) to week 240 | Count of subject |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in SF-36 (Short Form 36) Bodily Pain | From randomisation (week 0) to week 72 | Score points |
| Improvement in steatohepatitis with at least a 2-point reduction in NAS and no worsening of fibrosis (Yes/No) | From randomisation (week 0) to week 72 | Count of subject |
| Change in histology-assessed liver collagen proportionate area | From randomisation (week 0) to week 72 | Ratio to baseline |
| Worsening in steatohepatitis (Yes/No) | From randomisation (week 0) to week 72 | Count of subject |
| Improvement in histology-assessed ballooning (Yes/No) | From randomisation (week 0) to week 72 | Count of subject |
| Improvement in histology-assessed inflammation (Yes/No) | From randomisation (week 0) to week 72 | Count of subject |
| Improvement in histology-assessed steatosis (Yes/No) | From randomisation (week 0) to week 72 | Count of subject |
| NASH resolution (ballooning of 0, inflammation of 0-1) and above or equal to 2point NAS reduction with no worsening of fibrosis | From randomisation (week 0) to week 72 | Count of subject |
| Progression of liver fibrosis in patients with F2 at baseline (Yes/No) | From randomisation (week 0) to week 72 | Count of subject |
| Progression of liver fibrosis | From randomisation (week 0) to week 72 | Count of subject |
| Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) | From randomisation (week 0) to week 240 | Count of subject |
| Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) | From randomisation (week 0) to week 240 | Count of subject |
| Absence of histological evidence of NASH (Yes/No) | From randomisation (week 0) to week 240 | Count of subject |
| Changes in liver stiffness values assessed by transient elastography (FibroScan®) | From randomisation (week 0) to week 72 and week 240 | Ratio to baseline |
| Change in ELF (Enhanced Liver Fibrosis) score | From randomisation (week 0) to week 72 and week 240 | Logarithm |
| Change in ALT (alanine aminotransferase) | From randomisation (week 0) to week 72 and week 240 | Ratio to baseline |
| Change in AST (aspartate aminotransferase) | From randomisation (week 0) to week 72 and week 240 | Ratio to baseline |
| Change in CAP (Controlled Attenuation Parameter) values assessed by transient elastography (FibroScan) | From randomisation (week 0) to week 72 and week 240 | Absolute change |
| Change in FAST (FibroScan-AST) score | From randomisation (week 0) to week 72 and week 240 | Probability (absolute change) |
| Change in Pro-C3 (pro-peptide of type III collagen) | From randomisation (week 0) to week 72 and week 240 | Logarithm |
| Change in inflammation assessed by hsCRP (High Sensitive C-Reactive Protein) | From randomisation (week 0) to week 72 and week 240 | Ratio to baseline |
| Change in HbA1c (glycated haemoglobin) | From randomisation (week 0) to week 72 and week 240 | Percentage-points (absolute change) |
| Change in triglyceride | From randomisation (week 0) to week 72 and week 240 | Ratio to baseline |
| Change in free fatty acids | From randomisation (week 0) to week 72 and week 240 | Ratio to baseline |
| Change in LDL (low-density lipoprotein) cholesterol | From randomisation (week 0) to week 72 and week 240 | Ratio to baseline |
| Change in HDL (High density lipoprotein ) cholesterol | From randomisation (week 0) to week 72 and week 240 | Ratio to baseline |
| Time to first MACE(Major Adverse Cardiovascular event ) (composite endpoint) | From randomisation (week 0) to week 240 | Days |
| Major cardio-hepatic event-free survival (Yes/No) | From randomisation (week 0) to week 240 | Count of subject |
| Changes in SF-36 (Short Form 36 v2.0 acute ) Physical Component Summary | From randomisation (week 0) to week 72 and week 240 | Score points |
| Changes in SF-36 Mental Component Summary | From randomisation (week 0) to week 72 and week 240 | Score points |
| Changes in NASH-CHECK Abdominal Pain | From randomisation (week 0) to week 72 and week 240 | Score points |
| Change in SF-36 Bodily Pain | From randomisation (week 0) to week 240 | Score points |
| Change in body weight | From randomisation (week 0) to week 72 | Percentage |
| Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) | From randomisation (week 0) to week 72 | Count of subject |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Croatia, Czechia, Denmark, France, Germany, Greece, India, Ireland, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Puerto Rico, Romania, Russia, Serbia, Singapore, Slovakia, South Africa, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Transparency (dept. 2834)
Novo Nordisk A/S
Outcome results
None listed