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

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ClinicalTrials.gov Identifier: NCT04822181
Recruitment Status : Recruiting
First Posted : March 30, 2021
Last Update Posted : May 24, 2023
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Description
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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.


Condition or disease Intervention/treatment Phase
Non-alcoholic Steatohepatitis Drug: Semaglutide Drug: Placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1200 participants
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
Official Title: The Effect of Semaglutide in Subjects With Non-cirrhotic Non-alcoholic Steatohepatitis
Actual Study Start Date : April 1, 2021
Estimated Primary Completion Date : April 7, 2028
Estimated Study Completion Date : July 20, 2029

Resource links provided by the National Library of Medicine

Drug Information available for: Semaglutide

Arms and Interventions
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Arm Intervention/treatment
Experimental: Semaglutide OW (once weekly )
Semaglutide administrated subcutaneously once weekly
 Drug: Semaglutide
Semaglutide administrated subcutaneously (under the skin) once weekly there will be a period of dose escalation before reaching the target dose.
Placebo Comparator: Placebo
Placebo administrated subcutaneously once weekly
 Drug: Placebo
Placebo administrated subcutaneously (under the skin) once weekly.


Outcome Measures
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Primary Outcome Measures :
  1. 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. )

  2. 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. )

  3. 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).


Secondary Outcome Measures :
  1. Progression of liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
    Count of subjects

  2. Change in body weight [ Time Frame: From randomisation (week 0) to week 72 ]
    Percentage

  3. Change in SF-36 (Short Form 36) Bodily Pain [ Time Frame: From randomisation (week 0) to week 72 ]
    Score points

  4. Change in body weight [ Time Frame: From randomisation (week 0) to week 240 ]
    Percentage

  5. 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)

  6. Change in histology-assessed liver collagen proportionate area [ Time Frame: From randomisation (week 0) to week 72 ]
    Ratio to baseline

  7. Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
    Count of subjects

  8. 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)

  9. Improvement in histology-assessed ballooning (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
    Count of subjects

  10. Improvement in histology-assessed inflammation (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
    Count of subjects

  11. Improvement in histology-assessed steatosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 72 ]
    Count of subjects

  12. Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) [ Time Frame: From randomisation (week 0) to week 240 ]
    Count of subjects

  13. Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) [ Time Frame: From randomisation (week 0) to week 240 ]
    Count of subjects

  14. Change in ALT (alanine aminotransferase) [ Time Frame: From randomisation (week 0) to week 72 ]
    Ratio to baseline

  15. Change in AST (aspartate aminotransferase) [ Time Frame: From randomisation (week 0) to week 72 ]
    Ratio to baseline

  16. Change in inflammation assessed by hsCRP (High Sensitive C-Reactive Protein) [ Time Frame: From randomisation (week 0) to week 72 ]
    Ratio to baseline

  17. Change in HbA1c (glycated haemoglobin) [ Time Frame: From randomisation (week 0) to week 72 ]
    Percentage-points (absolute change) (For subjects with type 2 diabetes)

  18. Change in triglyceride [ Time Frame: From randomisation (week 0) to week 72 ]
    Ratio to baseline

  19. Change in free fatty acids [ Time Frame: From randomisation (week 0) to week 72 ]
    Ratio to baseline

  20. Change in LDL (low-density lipoprotein) cholesterol [ Time Frame: From randomisation (week 0) to week 72 ]
    Ratio to baseline

  21. Change in HDL (High density lipoprotein ) cholesterol [ Time Frame: From randomisation (week 0) to week 72 ]
    Ratio to baseline

  22. Changes in SF-36 (Short Form 36 v2.0 acute ) Physical Component Summary [ Time Frame: From randomisation (week 0) to week 72 ]
    Score points

  23. Changes in SF-36 Mental Component Summary [ Time Frame: From randomisation (week 0) to week 72 ]
    Score points

  24. Changes in NASH-CHECK Pain [ Time Frame: From randomisation (week 0) to week 72 ]
    Score points

  25. 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)

  26. 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)

  27. 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)

  28. Change in ELF (Enhanced Liver Fibrosis) score [ Time Frame: From randomisation (week 0) to week 72 ]
    Logarithm


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04822181


Contacts
Layout table for location contacts
Contact: Novo Nordisk (+1) 866-867-7178 clinicaltrials@novonordisk.com

Locations
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Sponsors and Collaborators
Novo Nordisk A/S
Investigators
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Study Director: Clinical Transparency (dept. 1452) Novo Nordisk A/S
More Information
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Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: 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 )
First Posted: March 30, 2021    Key Record Dates
Last Update Posted: May 24, 2023
Last Verified: May 2023
Individual Participant Data (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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases