Semaglutide for Non-alcoholic Steatohepatitis

(ESSENCE Trial)

Not currently recruiting at 949 trial locations

Overseen By Novo Nordisk

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novo Nordisk A/S

Must not be taking: Vitamin E, Pioglitazone, GLP-1 RAs, others

Disqualifiers: Chronic liver diseases, Alcohol use, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 24

Duration: 240 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if semaglutide, a medicine already used for type 2 diabetes, can treat non-alcoholic steatohepatitis (NASH), a liver condition. Participants will receive either semaglutide or a placebo (a dummy medicine) randomly and will need to inject themselves once a week. The trial seeks individuals diagnosed with NASH through a liver biopsy, which involves examining a small sample of liver tissue. Those with another chronic liver disease are not eligible for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that certain medications be at a stable dose for at least 90 days before the screening visit. If you are taking vitamin E, pioglitazone, GLP-1 RAs, glucose-lowering agents, lipid-lowering medications, or weight loss medications, they must be stable according to the investigator's opinion. You may need to adjust your medications to meet these criteria.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study showed that semaglutide reduced liver scarring in 36.8% of patients without worsening liver inflammation. This suggests semaglutide might be safe for individuals with liver issues. Additionally, semaglutide is already approved for treating type 2 diabetes, indicating it has undergone safety testing for that condition. While specific side effects in this trial aren't detailed, semaglutide's existing approval and previous study results suggest it is likely safe for many. As always, discussing potential risks and benefits with a healthcare provider is important before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for NASH?

Unlike the standard treatments for non-alcoholic steatohepatitis (NASH), which often focus on lifestyle changes and addressing associated conditions like diabetes, semaglutide offers a novel approach. Semaglutide is a GLP-1 receptor agonist that works by enhancing insulin secretion and reducing appetite. Administered once weekly via injection, it provides a convenient dosing schedule that can improve patient adherence. Researchers are particularly excited about its potential to not only address the metabolic aspects of NASH but also directly impact liver health, offering hope for more comprehensive management of the disease.

What evidence suggests that semaglutide might be an effective treatment for NASH?

Research has shown that semaglutide, which participants in this trial may receive, may help treat non-alcoholic steatohepatitis (NASH), a liver condition. One study found that 36.8% of patients taking semaglutide experienced a reduction in liver scarring without their condition worsening. However, some studies have found that semaglutide did not significantly improve liver scarring compared to a placebo, which is another treatment arm in this trial. On a positive note, semaglutide has improved liver enzyme levels and reduced liver stiffness, both positive indicators for liver health. While semaglutide is already used to treat type 2 diabetes, its potential benefits for NASH remain under investigation. ^{1 2 3 6 7}

Who Is on the Research Team?

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Are You a Good Fit for This Trial?

Adults with a specific liver condition called NASH and fibrosis stages 2 or 3 can join this study. They must have evidence of NASH from a recent biopsy, not be on certain unstable medications, and cannot have other chronic liver diseases or excessive alcohol use. Pregnant women or those planning pregnancy are excluded.

Inclusion Criteria

My liver disease score is 4 or higher, with signs of fat, inflammation, and cell damage.

My liver fibrosis is at stage 2 or 3 according to a specialist's review.

My liver fibrosis is at stage 2 or 3 according to a biopsy.

Exclusion Criteria

You drink too much alcohol or have an addiction to alcohol.

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).

I haven't changed my dose of vitamin E, pioglitazone, or NASH medication in the last 90 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive semaglutide or placebo administered subcutaneously once weekly

240 weeks

21 visits (in-person), 9 phone calls

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Semaglutide

Trial Overview The trial is testing Semaglutide, already used for type 2 diabetes, against a placebo to see if it helps with NASH. Participants will inject themselves weekly and the study spans about five years with regular clinic visits and phone check-ins.

How Is the Trial Designed?

Group I: Semaglutide OW (once weekly ) Experimental Treatment 1 Intervention

Semaglutide administrated subcutaneously once weekly

Group II: Placebo Placebo Group 1 Intervention

Placebo administrated subcutaneously once weekly

Who Is Running the Clinical Trial?

Novo Nordisk A/S

Lead Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Published Research Related to This Trial

Semaglutide and obeticholic acid (OCA) both show histological improvement in patients with non-alcoholic fatty liver disease (NAFLD), but only semaglutide leads to complete resolution of non-alcoholic steatohepatitis (NASH).

Semaglutide is considered the safer option, promoting significant weight loss and better outcomes for hepatic steatosis, while OCA can improve NASH-associated fibrosis but may cause side effects like dyslipidemia and severe itching, necessitating caution in certain patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing the Efficacy and Safety of Obeticholic Acid and Semaglutide in Patients With Non-Alcoholic Fatty Liver Disease: A Systematic Review. Ahmed, NR., Kulkarni, VV., Pokhrel, S., et al.[2022]

In a study using Ldlr-/-.Leiden mice, semaglutide significantly reduced liver fat and inflammation by 74% and 73% respectively, indicating its potential effectiveness in treating non-alcoholic steatohepatitis (NASH).

While semaglutide improved liver health by reversing certain gene expressions associated with NASH, it did not significantly affect liver fibrosis, suggesting that it may need to be combined with other treatments for advanced fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide Has Beneficial Effects on Non-Alcoholic Steatohepatitis in Ldlr-/-.Leiden Mice. Inia, JA., Stokman, G., Morrison, MC., et al.[2023]

In a phase 2 trial involving 71 patients with NASH-related cirrhosis, semaglutide did not significantly improve liver fibrosis or lead to NASH resolution compared to placebo after 48 weeks.

The safety profile of semaglutide was similar to that of the placebo, with no new safety concerns identified, and common side effects included nausea and diarrhea, but overall liver and kidney function remained stable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Loomba, R., Abdelmalek, MF., Armstrong, MJ., et al.[2023]

In a phase II trial involving 108 patients with non-alcoholic steatohepatitis (NASH), the combination of semaglutide with cilofexor and/or firsocostat was found to be safe and well tolerated, with similar rates of adverse events across treatment groups.

The combination therapies resulted in greater improvements in liver steatosis and liver biochemistry compared to semaglutide alone, suggesting that targeting multiple mechanisms may enhance treatment efficacy for NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. Alkhouri, N., Herring, R., Kabler, H., et al.[2022]

In a systematic review of 8 studies involving 2413 patients, 24 weeks of semaglutide treatment significantly reduced liver enzymes (alanine transaminase and aspartate transaminase) and improved liver fat content and stiffness, indicating its efficacy in treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Despite its benefits, semaglutide treatment was associated with a higher risk of serious gastrointestinal adverse events, such as nausea and vomiting, highlighting the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of semaglutide in the treatment of nonalcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. Bandyopadhyay, S., Das, S., Samajdar, SS., et al.[2023]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2413258

Phase 3 Trial of Semaglutide in Metabolic Dysfunction– ... A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8351017/

Semaglutide for nonalcoholic steatohepatitis - PubMed Central However, semaglutide did not show any improvement of at least one fibrosis stage without worsening of NASH in patients who received semaglutide 0.4 mg compared ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36934740/

Semaglutide 2·4 mg once weekly in patients with ... - PubMed In patients with NASH and compensated cirrhosis, semaglutide did not significantly improve fibrosis or achievement of NASH resolution versus placebo.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1871402123001455

Role of semaglutide in the treatment of nonalcoholic fatty ... Treatment with 24 weeks of semaglutide could significantly improve liver enzymes, reduce liver stiffness, and improve metabolic parameters in patients with ...

5. fda.gov fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash

FDA Approves Treatment for Serious Liver Disease Known ... At week 72, the primary efficacy endpoint was based on histology (liver biopsy results). Interim results showed 63% of participants receiving ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0168827822002355

Safety and efficacy of combination therapy with ... Despite similar weight loss (7–10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI- ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05016882

NCT05016882 | Research Study on Whether a ... 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 ...