Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH) (ESSENCE)

• ClinicalTrials.gov Identifier: NCT04822181
• Recruitment Status: Recruiting
• First Posted: March 30, 2021
• Last Update Posted: May 31, 2023
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Tracking Information

• First Submitted Date: March 26, 2021
• First Posted Date: March 30, 2021
• Last Update Posted Date: May 31, 2023
• Actual Study Start Date: April 1, 2021
• Estimated Primary Completion Date: April 7, 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 26, 2021)

• Part 1: Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects (Resolution of steatohepatitis is defined as a NAFLD Activity Score (NAS) of 0-1 for inflammation, 0 for ballooning, and any value for steatosis (According to NASH CRN). Fibrosis is graded on the NASH CRN fibrosis scale from 0 to 4. )
• Part 1: Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects ( Improvement in fibrosis is defined as greater than or equal to 1 grade improvement on the NASH CRN fibrosis scale. No worsening of steatohepatitis is defined as no increase from baseline in NAS score for ballooning, inflammation, or steatosis. )
• Part 2: Time to first liver-related clinical event (composite endpoint) [ Time Frame: From randomisation (week 0) to week 240 ]
  Days (The liver-related clinical event composite endpoint consists of: histological progression to cirrhosis, all-cause mortality, liver-induced MELD score greater than or equal to 15, liver transplant or hepatic decompensation events (ascites leading to treatment (diuretics, parascentesis and/or TIPS), spontaneous bacterial peritonitis (identified by analysis of ascites fluid (a polymorphonuclear cell count in the ascitic fluid greater than or equal to 250 cells/mm3 and/or a positive bacterial ascitic fluid culture) and/or a clinical assessment consistent with spontaneous bacterial peritonitis), hepatic encephalopathy greater than or equal to grade 2 according to the West Haven criteria or hospitalisation for gastro-oesophageal variceal bleeding).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 4, 2021)

• Progression of liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Change in body weight [ Time Frame: From randomisation (week 0) to week 72 ]
  Percentage
• Change in SF-36 (Short Form 36) Bodily Pain [ Time Frame: From randomisation (week 0) to week 72 ]
  Score points
• Change in body weight [ Time Frame: From randomisation (week 0) to week 240 ]
  Percentage
• Improvement in steatohepatitis with at least a 2-point reduction in NAS and no worsening of fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects (The 2-point reduction needs to include at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning)
• Change in histology-assessed liver collagen proportionate area [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Worsening in steatohepatitis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects (Defined as increase in NAS for ballooning, inflammation, or steatosis)
• Improvement in histology-assessed ballooning (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Improvement in histology-assessed inflammation (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Improvement in histology-assessed steatosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 240 ]
  Count of subjects
• Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) [ Time Frame: From randomisation (week 0) to week 240 ]
  Count of subjects
• Change in ALT (alanine aminotransferase) [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in AST (aspartate aminotransferase) [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in inflammation assessed by hsCRP (High Sensitive C-Reactive Protein) [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in HbA1c (glycated haemoglobin) [ Time Frame: From randomisation (week 0) to week 72 ]
  Percentage-points (absolute change) (For subjects with type 2 diabetes)
• Change in triglyceride [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in free fatty acids [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in LDL (low-density lipoprotein) cholesterol [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in HDL (High density lipoprotein ) cholesterol [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Changes in SF-36 (Short Form 36 v2.0 acute ) Physical Component Summary [ Time Frame: From randomisation (week 0) to week 72 ]
  Score points
• Changes in SF-36 Mental Component Summary [ Time Frame: From randomisation (week 0) to week 72 ]
  Score points
• Changes in NASH-CHECK Pain [ Time Frame: From randomisation (week 0) to week 72 ]
  Score points
• Time to first MACE(Major Adverse Cardiovascular event ) (composite endpoint) [ Time Frame: From randomisation (week 0) to week 240 ]
  Days (The MACE composite endpoint consists of: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke)
• Time to first major cardio-hepatic event (composite endpoint) [ Time Frame: From randomisation (week 0) to week 240 ]
  Days (The major cardio-hepatic event composite endpoint consists of: MACE, liver-related death, histological progression to cirrhosis, liver-induced MELD score above or equal to 15, liver transplant or hepatic decompensation event)
• Change in liver stiffness assessed by FibroScan® [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline (FibroScan® will only be assessed at sites that has the equipment available)
• Change in ELF (Enhanced Liver Fibrosis) score [ Time Frame: From randomisation (week 0) to week 72 ]
  Logarithm

Original Secondary Outcome Measures (submitted: March 26, 2021)

• Progression of liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Change in body weight [ Time Frame: From randomisation (week 0) to week 72 ]
  Percentage
• Change in SF-36 (Short Form 36) Bodily Pain [ Time Frame: From randomisation (week 0) to week 72 ]
  Score points
• Change in body weight [ Time Frame: From randomisation (week 0) to week 240 ]
  Percentage
• Improvement in steatohepatitis with at least a 2-point reduction in NAS and no worsening of fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects (The 2-point reduction needs to include at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning)
• Change in histology-assessed liver collagen proportionate area [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Worsening in steatohepatitis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects (Defined as increase in NAS for ballooning, inflammation, or steatosis)
• Improvement in histology-assessed ballooning (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Improvement in histology-assessed inflammation (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Improvement in histology-assessed steatosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
  Count of subjects
• Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 240 ]
  Count of subjects
• Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) [ Time Frame: From randomisation (week 0) to week 240 ]
  Count of subjects
• Change in ALT (alanine aminotransferase) [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in AST (aspartate aminotransferase) [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in inflammation assessed by HsCRP (High Sensitive C-Reactive Protein) [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in HbA1c (glycated haemoglobin) [ Time Frame: From randomisation (week 0) to week 72 ]
  Percentage-points (absolute change) (For subjects with type 2 diabetes)
• Change in triglyceride [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in free fatty acids [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in LDL (low-density lipoprotein) cholesterol [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Change in HDL (High density lipoprotein ) cholesterol [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline
• Changes in SF-36 (Short Form 36 v2.0 acute ) Physical Component Summary [ Time Frame: From randomisation (week 0) to week 72 ]
  Score points
• Changes in SF-36 Mental Component Summary [ Time Frame: From randomisation (week 0) to week 72 ]
  Score points
• Changes in NASH-CHECK Pain [ Time Frame: From randomisation (week 0) to week 72 ]
  Score points
• Time to first MACE(Major Adverse Cardiovascular event ) (composite endpoint) [ Time Frame: From randomisation (week 0) to week 240 ]
  Days (The MACE composite endpoint consists of: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke)
• Time to first major cardio-hepatic event (composite endpoint) [ Time Frame: From randomisation (week 0) to week 240 ]
  Days (The major cardio-hepatic event composite endpoint consists of: MACE, liver-related death, histological progression to cirrhosis, liver-induced MELD score above or equal to 15, liver transplant or hepatic decompensation event)
• Change in liver stiffness assessed by FibroScan® [ Time Frame: From randomisation (week 0) to week 72 ]
  Ratio to baseline (FibroScan® will only be assessed at sites that has the equipment available)
• Change in ELF (Enhanced Liver Fibrosis) score [ Time Frame: From randomisation (week 0) to week 72 ]
  Logarithm

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH)
• Official Title: The Effect of Semaglutide in Subjects With Non-cirrhotic Non-alcoholic Steatohepatitis

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, 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

Primary Purpose: Treatment

• Condition: Non-alcoholic Steatohepatitis

Intervention

• Drug: Semaglutide
  Semaglutide administrated subcutaneously (under the skin) once weekly there will be a period of dose escalation before reaching the target dose.
• Drug: Placebo
  Placebo administrated subcutaneously (under the skin) once weekly.

Study Arms

• Experimental: Semaglutide OW (once weekly )
  Semaglutide administrated subcutaneously once weekly
  Intervention: Drug: Semaglutide
• Placebo Comparator: Placebo
  Placebo administrated subcutaneously once weekly
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 26, 2021): 1200
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 20, 2029
• Estimated Primary Completion Date: April 7, 2028 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 in 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novo Nordisk; (+1) 866-867-7178; clinicaltrials@novonordisk.com

• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Croatia, Czechia, Denmark, France, Germany, Greece, India, Ireland, Israel, Italy, Japan, Korea, Republic of, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Puerto Rico, Romania, Russian Federation, Serbia, Singapore, Slovakia, South Africa, Spain, Switzerland, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04822181
• Other Study ID Numbers: NN9931-4553; U1111-1244-3678 ( Other Identifier: World Health Organization (WHO) ); 2019-004594-44 ( Registry Identifier: European Medicines Agency (EudraCT) ); jRCT2031210033 ( Registry Identifier: JAPIC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com
• URL: http://novonordisk-trials.com

• Current Responsible Party: Novo Nordisk A/S
• Original Responsible Party: Same as current
• Current Study Sponsor: Novo Nordisk A/S
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Transparency (dept. 1452); Novo Nordisk A/S

• PRS Account: Novo Nordisk A/S
• Verification Date: May 2023