Research Study on Whether a Combination of 2 Medicines (NNC0194 0499 and Semaglutide) Works in People With Non-alcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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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.

Official Title
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Efficacy and Safety Investigation of NNC0194-0499 Co-administered With Semaglutide in Subjects With Non-alcoholic Steatohepatitis: a Dose-ranging, Placebo Controlled Trial

Conditions
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Non-alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: NNC0194 0499 50 mg/mL
* Drug: Placebo (NNC0194-0499)
* Drug: Semaglutide 3 mg/mL
* Drug: Semaglutide placebo
* Drug: NNC0174 0833 10 mg/mL
* Drug: NNC0174 0833 placebo


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NNC0194-0499 7.5 mg + semaglutide 2.4 mg<br>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. | Drug: NNC0194 0499 50 mg/mL<br>* Patients will receive subcutaneous (s.c., under the skin) injections of NNC0194-0499 once weekly The study will last for about 19 months<br>Drug: Semaglutide 3 mg/mL<br>* Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly The study will last for about 19 months<br>|
| Placebo Comparator: Placebo (NNC0194-0499) 7.5 mg + semaglutide placebo 2.4 mg<br>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. | Drug: Placebo (NNC0194-0499)<br>* Patients will receive subcutaneous (s.c., under the skin) injections of placebo once weekly The study will last for about 19 months<br>Drug: Semaglutide placebo<br>* Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months<br>|
| Experimental: NNC0194-0499 15 mg + semaglutide 2.4 mg<br>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. | Drug: NNC0194 0499 50 mg/mL<br>* Patients will receive subcutaneous (s.c., under the skin) injections of NNC0194-0499 once weekly The study will last for about 19 months<br>Drug: Semaglutide 3 mg/mL<br>* Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly The study will last for about 19 months<br>|
| Placebo Comparator: Placebo (NNC0194-0499) 15 mg + semaglutide placebo 2.4 mg<br>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. | Drug: Placebo (NNC0194-0499)<br>* Patients will receive subcutaneous (s.c., under the skin) injections of placebo once weekly The study will last for about 19 months<br>Drug: Semaglutide placebo<br>* Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months<br>|
| Experimental: NNC0194-0499 30 mg + semaglutide 2.4 mg<br>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. | Drug: NNC0194 0499 50 mg/mL<br>* Patients will receive subcutaneous (s.c., under the skin) injections of NNC0194-0499 once weekly The study will last for about 19 months<br>|
| Experimental: NNC0194-0499 30 mg + semaglutide placebo 2.4 mg<br>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. | Drug: NNC0194 0499 50 mg/mL<br>* Patients will receive subcutaneous (s.c., under the skin) injections of NNC0194-0499 once weekly The study will last for about 19 months<br>Drug: Semaglutide placebo<br>* Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months<br>|
| Active Comparator: Placebo (NNC0194-0499) 30 mg + semaglutide 2.4 mg<br>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. | Drug: Placebo (NNC0194-0499)<br>* Patients will receive subcutaneous (s.c., under the skin) injections of placebo once weekly The study will last for about 19 months<br>Drug: Semaglutide 3 mg/mL<br>* Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly The study will last for about 19 months<br>|
| Placebo Comparator: Placebo (NNC0194-0499) 30 mg + semaglutide placebo 2.4 mg<br>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. | Drug: Placebo (NNC0194-0499)<br>* Patients will receive subcutaneous (s.c., under the skin) injections of placebo once weekly The study will last for about 19 months<br>Drug: Semaglutide placebo<br>* Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months<br>|
| Experimental: NNC0174-0833 2.4 mg + semaglutide 2.4 mg<br>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. | Drug: Semaglutide 3 mg/mL<br>* Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly The study will last for about 19 months<br>Drug: NNC0174 0833 10 mg/mL<br>* Patients will receive subcutaneous (s.c., under the skin) injections of NNC0174-0833 once weekly The study will last for about 19 months<br>|
| Placebo Comparator: Placebo (NNC0174-0833) 2.4 mg + semaglutide placebo 2.4 mg<br>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. | Drug: Semaglutide placebo<br>* Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months<br>Drug: NNC0174 0833 placebo<br>* Patients will receive subcutaneous (s.c., under the skin) injections of NNC0174-0833 placebo once weekly The study will last for about 19 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in liver fibrosis and no worsening of NASH (Yes/No) | Count of subjects Improvement in fibrosis is defined as greater than or equal to 1 grade improvement on the NASH CRN fibrosis scale | From baseline (week 0) to week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) | 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. | 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) | Count of subjects The 2-point reduction must include at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning. | From baseline (week 0) to week 52 | 
| Change in histology-assessed liver collagen proportionate area | Ratio to baseline | From baseline (week 0) to week 52 | 
| Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) | 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 | From baseline (week 0) to week 52 | 
| Improvement in liver fibrosis (Yes/No) | Count of subjects Improvement in fibrosis is defined as greater than or equal to 1 grade improvement on the NASH CRN fibrosis scale | From baseline (week 0) to week 52 | 
| Progression of liver fibrosis (Yes/No) | Count of subjects For subjects with fibrosis stage 2 or 3 at baseline | From baseline (week 0) to week 52 | 
| Worsening in steatohepatitis (Yes/No) | Count of subjects Worsening in steatohepatitis is defined as increase in NAS score for ballooning, inflammation or steatosis | From baseline (week 0) to week 52 | 
| Improvement in ballooning (Yes/No) | Count of subjects | From baseline (week 0) to week 52 | 
| Improvement in inflammation (Yes/No) | Count of subjects | From baseline (week 0) to week 52 | 
| Improvement in steatosis (Yes/No) | Count of subjects | From baseline (week 0) to week 52 | 
| Change in ALT (alanine aminotransferase) | Ratio to baseline | From baseline (week 0) to week 52 | 
| Change in AST (aspartate aminotransferase) | Ratio to baseline | From baseline (week 0) to week 52 | 
| Change in inflammation assessed by HsCRP (high sensitivity C-reactive protein) | Ratio to baseline | From baseline (week 0) to week 52 | 
| Change in ELF (Enhanced Liver Fibrosis) score | Logarithm | From baseline (week 0) to week 52 | 
| Change in HbA1c. For subjects with type 2 diabetes | %-points (absolute change) | From baseline (week 0) to week 52 | 
| Change in triglycerides | Ratio to baseline | From baseline (week 0) to week 52 | 
| Change in free fatty acids | Ratio to baseline | From baseline (week 0) to week 52 | 
| Change in LDL (low density lipoprotein) cholesterol | Ratio to baseline | From baseline (week 0) to week 52 | 
| Change in HDL (high density lipoprotein) cholesterol | Ratio to baseline | From baseline (week 0) to week 52 | 
| Relative change in body weight | Percentage | From baseline (week 0) to week 52 | 
| Change in SF-36 (36-item Short Form Survey) bodily pain | Points | From baseline (week 0) to week 52 | 
| Change in NASH-CHECK (patient-reported outcome measure for non-alcoholic steatohepatitis)pain | Points | From baseline (week 0) to week 52 | 
| Change in PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue score | Points | From baseline (week 0) to week 52 | 
| Number of treatment emergent adverse events (TEAEs) | Count | From baseline (week 0) to week 59 |