SEMAGLUTIDE for Non-alcoholic steatohepatitis (NASH)

Inclusion criteria

• {"criterion_text":"- Age above or equal to 18 years at the time of signing informed consent."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Histological evidence of fibrosis stage 2 or stage 3 according to the NASH CRN classification based on a central pathologist evaluation of the baseline liver biopsy."}
• {"criterion_text":"- A histological NAS ≥ 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

• {"criterion_text":"- Documented causes of chronic liver disease other than non-alcoholic fatty liver disease (NAFLD)"}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Presence or history of ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis or liver transplantation at randomisation."}
• {"criterion_text":"- Known or suspected excessive consumption of alcohol (> 20 g/day for women or > 30 g/day for men) or alcohol dependence (assessed by the Alcohol Use Disorders Identification Test (AUDIT questionnaire))."}
• {"criterion_text":"- Treatment with vitamin E (at doses ≥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."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- 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."}

Primary endpoints

• {"endpoint_text":"- Part 1 Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) from randomisation (week 0) to week 72","definition_or_measurement_approach":"Binary histology-assessed outcome (resolution of steatohepatitis and no worsening of liver fibrosis) assessed from randomisation to week 72 based on central pathologist evaluation of liver biopsy."}
• {"endpoint_text":"- Part 1 Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) from randomisation (week 0) to week 72","definition_or_measurement_approach":"Binary histology-assessed outcome (improvement in fibrosis and no worsening of steatohepatitis) assessed from randomisation to week 72 based on central pathologist evaluation of liver biopsy."}
• {"endpoint_text":"- Part 2 Cirrhosis-free survival (Yes/No) from randomisation (week 0) to week 240","definition_or_measurement_approach":"Time-to-event outcome assessing cirrhosis-free survival from randomisation to week 240 (composite clinical outcome related to liver events)."}

Secondary endpoints

• {"endpoint_text":"- Change in body weight from randomisation (week 0) to week 72","definition_or_measurement_approach":"Absolute or relative change in measured body weight from baseline to week 72."}
• {"endpoint_text":"- Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) from randomisation (week 0) to week 72","definition_or_measurement_approach":"Binary histology-assessed outcome combining resolution of steatohepatitis and improvement in fibrosis from baseline to week 72."}
• {"endpoint_text":"- Change in SF-36 Bodily Pain from randomisation (week 0) to week 72","definition_or_measurement_approach":"Change in SF-36 bodily pain domain score from baseline to week 72."}
• {"endpoint_text":"- Change in body weight from randomisation (week 0) to week 240","definition_or_measurement_approach":"Absolute or relative change in measured body weight from baseline to week 240."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Histology-assessed NAS reduction of ≥2 points with no fibrosis worsening from baseline to week 72."}
• {"endpoint_text":"- Change in histology-assessed liver collagen proportionate area from randomisation (week 0) to week 72","definition_or_measurement_approach":"Change in collagen proportionate area measured on liver histology from baseline to week 72."}
• {"endpoint_text":"- Worsening in steatohepatitis (Yes/No) from randomisation (week 0) to week 72","definition_or_measurement_approach":"Binary histology-assessed worsening of steatohepatitis from baseline to week 72."}
• {"endpoint_text":"- Improvement in histology-assessed ballooning (Yes/No) from randomisation (week 0) to week 72","definition_or_measurement_approach":"Histology-assessed improvement in hepatocellular ballooning from baseline to week 72."}
• {"endpoint_text":"- Improvement in histology-assessed inflammation (Yes/No) from randomisation (week 0) to week 72","definition_or_measurement_approach":"Histology-assessed improvement in lobular inflammation from baseline to week 72."}
• {"endpoint_text":"- Improvement in histology-assessed steatosis (Yes/No) from randomisation (week 0) to week 72","definition_or_measurement_approach":"Histology-assessed improvement in steatosis from baseline to week 72."}
• {"endpoint_text":"- NASH resolution (ballooning of 0, inflammation of 0-1) and ≥2point NAS reduction with no worsening of fibrosis from randomisation (week 0) to week 72","definition_or_measurement_approach":"Composite histologic endpoint requiring NASH resolution (ballooning=0 and inflammation 0–1) plus ≥2 point NAS reduction and no fibrosis worsening at week 72."}
• {"endpoint_text":"- Progression of liver fibrosis in patients with F2 at baseline (Yes/No) from randomisation (week 0) to week 72","definition_or_measurement_approach":"Binary outcome assessing fibrosis progression among participants with baseline F2 based on histology from baseline to week 72."}
• {"endpoint_text":"- Progression of liver fibrosis from randomisation (week 0) to week 72","definition_or_measurement_approach":"Histology-assessed change/progression in fibrosis stage from baseline to week 72."}
• {"endpoint_text":"- Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) from randomisation (week 0) to week 240","definition_or_measurement_approach":"Histology-assessed resolution of steatohepatitis with no fibrosis worsening assessed up to week 240."}
• {"endpoint_text":"- Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) from randomisation (week 0) to week 240","definition_or_measurement_approach":"Histology-assessed improvement in fibrosis with no worsening of steatohepatitis up to week 240."}
• {"endpoint_text":"- Changes in liver stiffness values assessed by transient elastography (FibroScan®) from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in liver stiffness (kPa) measured by FibroScan from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in ELF score from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in Enhanced Liver Fibrosis (ELF) score from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in ALT from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in alanine aminotransferase (ALT) levels from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in AST from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in aspartate aminotransferase (AST) levels from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in CAP values assessed by transient elastography (FibroScan) from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in controlled attenuation parameter (CAP) values from baseline to weeks 72 and 240 as measured by FibroScan."}
• {"endpoint_text":"- Change in FAST score from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in FAST (FibroScan-AST) score from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in Pro-C3 from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in Pro-C3 biomarker concentrations from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in inflammation assessed by hsCRP from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in high-sensitivity C-reactive protein (hsCRP) from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in HbA1c from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in glycosylated haemoglobin (HbA1c) from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in triglyceride from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in fasting triglyceride levels from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in free fatty acids from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in free fatty acid concentrations from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in LDL cholesterol from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in LDL-cholesterol from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in HDL cholesterol from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in HDL-cholesterol from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Time to first MACE (composite endpoint) from randomisation (week 0) to week 240","definition_or_measurement_approach":"Time-to-event for first major adverse cardiovascular event (MACE) from baseline to week 240."}
• {"endpoint_text":"- Major cardio-hepatic event-free survival (Yes/No) from randomisation (week 0) to week 240","definition_or_measurement_approach":"Composite time-to-event measure assessing freedom from major cardio-hepatic events to week 240."}
• {"endpoint_text":"- Changes in SF-36 Physical Component Summary from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in SF-36 physical component summary score from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Changes in SF-36 Mental Component Summary from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in SF-36 mental component summary score from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Change in SF-36 Bodily Pain from randomisation (week 0) to week 240","definition_or_measurement_approach":"Change in SF-36 bodily pain domain score from baseline to week 240."}
• {"endpoint_text":"- Changes in NASH-CHECK Abdominal Pain from randomisation (week 0) to week 72 and week 240","definition_or_measurement_approach":"Change in patient-reported abdominal pain as measured by NASH-CHECK from baseline to weeks 72 and 240."}
• {"endpoint_text":"- Absence of histological evidence of NASH (Yes/No) from randomisation (week 0) to week 240","definition_or_measurement_approach":"Histology-assessed absence of NASH at week 240 compared with baseline."}

Primary sponsor

Full Name

Novo Nordisk A/S

Organisation Type

Pharmaceutical company

Country Of Registered Address

Denmark

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Operational CRO functions (listed duties include Firecrest, Protocol e-Learning, Event Adjudication and other CRO services across entries)

Name

Perceptive Eclinical Limited

Responsibilities

IWRS Supplier

Third parties

• {"country":"Germany","full_name":"Hannover Medical School","duties_or_roles":"Cognitive tests- PSE","organisation_type":"Educational Institution"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Firecrest, Protocol e-Learning; other operational support noted (also listed for Event Adjudication and other roles across entries).","organisation_type":"Contract Research Organisation / Pharmaceutical company (listed)"}
• {"country":"United Kingdom","full_name":"Perceptive Eclinical Limited","duties_or_roles":"IWRS Supplier","organisation_type":"Pharmaceutical company / eClinical vendor"}
• {"country":"United Kingdom","full_name":"Vivos Technology Limited","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Celerion Switzerland AG","duties_or_roles":"Special Laboratory","organisation_type":"Pharmaceutical company / Laboratory"}
• {"country":"United Kingdom","full_name":"Signant Health Management Limited","duties_or_roles":"Electronic Clinical Outcome","organisation_type":"Pharmaceutical company / eCOA vendor"}
• {"country":"United States","full_name":"Pathai Inc.","duties_or_roles":"Digital Pathology Services","organisation_type":"Pharmaceutical company / digital pathology vendor"}
• {"country":"United States","full_name":"Stoelting","duties_or_roles":"Cognitive tests- STROOP","organisation_type":"Industry"}
• {"country":"Germany","full_name":"MARKEN Germany GmbH","duties_or_roles":"Direct transfer of trial drug to patients/DTP, Logistics","organisation_type":"Pharmaceutical company / logistics provider"}
• {"country":"Germany","full_name":"Abbott GmbH","duties_or_roles":"BG Meter","organisation_type":"Pharmaceutical company"}
• {"country":"Denmark","full_name":"Oracle Danmark ApS","duties_or_roles":"CRF Supplier","organisation_type":"Industry / IT vendor"}
• {"country":"Greece","full_name":"Bioiatriki Private Medical Polyclinic S.A.","duties_or_roles":"Opthalmological Examinations","organisation_type":"Hospital/Clinic/Other health care facility"}