Non-alcoholic Steatohepatitis
Conditions
Brief summary
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.
Interventions
DRUGNNC0194 0499 50 mg/mL
Patients will receive subcutaneous (s.c., under the skin) injections of NNC0194-0499 once weekly The study will last for about 19 months
DRUGPlacebo (NNC0194-0499)
Patients will receive subcutaneous (s.c., under the skin) injections of placebo once weekly The study will last for about 19 months
Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly The study will last for about 19 months
Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months
DRUGNNC0174 0833 10 mg/mL
Patients will receive subcutaneous (s.c., under the skin) injections of NNC0174-0833 once weekly The study will last for about 19 months
DRUGNNC0174 0833 placebo
Patients will receive subcutaneous (s.c., under the skin) injections of NNC0174-0833 placebo once weekly The study will last for about 19 months
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a randomised, double-blind, active and placebo-controlled, double-dummy, parallel group, multinational trial investigating NNC0194-0499 at 3 different dose levels when co administered with semaglutide
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* 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 1. * 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.
Exclusion criteria
* 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 V3. An oesophagogastroduodenoscopy performed no more than 52 weeks prior to V3 must be available at V3. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in liver fibrosis and no worsening of NASH (Yes/No) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Count of subjects The 2-point reduction must include at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning. |
| Change in histology-assessed liver collagen proportionate area | From baseline (week 0) to week 52 | Ratio to baseline |
| Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) | From baseline (week 0) to week 52 | Count of subjects Resolution of steatohepatitis is defined as an NAS score of 0-1 for inflammation, 0 for ballooning and any value for steatosis (according to NASH CRN). Improvement in fibrosis is defined as greater than or equal to 1 grade improvement on the NASH CRN fibrosis scale |
| Improvement in liver fibrosis (Yes/No) | 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 |
| Progression of liver fibrosis (Yes/No) | From baseline (week 0) to week 52 | Count of subjects For subjects with fibrosis stage 2 or 3 at baseline |
| Worsening in steatohepatitis (Yes/No) | From baseline (week 0) to week 52 | Count of subjects Worsening in steatohepatitis is defined as increase in NAS score for ballooning, inflammation or steatosis |
| Improvement in ballooning (Yes/No) | From baseline (week 0) to week 52 | Count of subjects |
| Improvement in inflammation (Yes/No) | From baseline (week 0) to week 52 | Count of subjects |
| Improvement in steatosis (Yes/No) | From baseline (week 0) to week 52 | Count of subjects |
| Change in ALT (alanine aminotransferase) | From baseline (week 0) to week 52 | Ratio to baseline |
| Change in AST (aspartate aminotransferase) | From baseline (week 0) to week 52 | Ratio to baseline |
| Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) | From baseline (week 0) to week 52 | Count of subjects Resolution of steatohepatitis is defined as a NAS of 0-1 for inflammation, 0 for ballooning and any value for steatosis according to NASH CRN52. Fibrosis is graded on the NASH CRN (Non-Alcoholic Steatohepatitis Clinical Research Network) fibrosis scale from 0 to 4. |
| Change in ELF (Enhanced Liver Fibrosis) score | From baseline (week 0) to week 52 | Logarithm |
| Change in HbA1c. For subjects with type 2 diabetes | From baseline (week 0) to week 52 | %-points (absolute change) |
| Change in triglycerides | From baseline (week 0) to week 52 | Ratio to baseline |
| Change in free fatty acids | From baseline (week 0) to week 52 | Ratio to baseline |
| Change in LDL (low density lipoprotein) cholesterol | From baseline (week 0) to week 52 | Ratio to baseline |
| Change in HDL (high density lipoprotein) cholesterol | From baseline (week 0) to week 52 | Ratio to baseline |
| Relative change in body weight | From baseline (week 0) to week 52 | Percentage |
| Change in SF-36 (36-item Short Form Survey) bodily pain | From baseline (week 0) to week 52 | Points |
| Change in NASH-CHECK (patient-reported outcome measure for non-alcoholic steatohepatitis)pain | From baseline (week 0) to week 52 | Points |
| Change in PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue score | From baseline (week 0) to week 52 | Points |
| Number of treatment emergent adverse events (TEAEs) | From baseline (week 0) to week 59 | Count |
| Change in inflammation assessed by HsCRP (high sensitivity C-reactive protein) | From baseline (week 0) to week 52 | Ratio to baseline |
Countries
Australia, Belgium, Bulgaria, Canada, Czechia, Denmark, France, Germany, Greece, India, Italy, Japan, Malaysia, Poland, Portugal, Puerto Rico, Russia, Singapore, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Outcome results
None listed