Metabolic Surgery for Non-Alcoholic Fatty Liver Disease

(FLAMES Trial)

Recruiting at 21 trial locations

Overseen By Chytaine Hall

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Ali Aminian

Must not be taking: Semaglutide, Tirzepatide, Liraglutide, others

Disqualifiers: Chronic liver diseases, Type 1 diabetes, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 104 weeks

120 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot have taken certain medications like semaglutide, tirzepatide, or liraglutide within 90 days before the study. If you have type 2 diabetes, you should have been on a stable dose of your anti-diabetic medication for at least 3 months before joining.

What data supports the effectiveness of this treatment for non-alcoholic fatty liver disease?

Research shows that bariatric surgery, a type of weight loss surgery, can significantly improve or even resolve non-alcoholic fatty liver disease (NAFLD) by helping with weight loss and improving insulin resistance (how the body uses insulin). This suggests that metabolic surgery is an effective treatment for NAFLD. ^{1 2 3 4 5}

Is bariatric surgery safe for treating non-alcoholic fatty liver disease?

Bariatric surgery, which is a type of weight loss surgery, is generally considered safe for people with non-alcoholic fatty liver disease (NAFLD), although there may be a higher risk of complications in patients with liver cirrhosis. It's important for patients to discuss potential risks with their doctors before surgery. ^{6 7 8 9 10}

How does metabolic surgery differ from other treatments for non-alcoholic fatty liver disease?

Metabolic surgery, also known as bariatric surgery, is unique because it not only helps with weight loss but also directly improves insulin resistance and reduces inflammation, which can significantly improve or even resolve non-alcoholic fatty liver disease, including severe cases. ^{1 2 5 11 12}

What is the purpose of this trial?

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), a major global public health concern, is commonly associated with obesity, diabetes, and dyslipidemia. MASLD is currently the most common cause of chronic liver disease affecting about 80% of people with obesity, ranging from simple fat deposits in the liver to Metabolic Dysfunction-Associated Steatohepatitis (MASH), cellular injury, advanced fibrosis, cirrhosis, or hepatocellular carcinoma. Patients with MASH are also at risk for cardiovascular disease and mortality. There is no universally approved medication for MASH. Weight loss remains the cornerstone of MASH treatment. Patients meeting the inclusion and exclusion criteria and who give informed consent will be enrolled in the trial and undergo the baseline liver biopsy (if none available). Approximately 120 patients with MASH and liver fibrosis (F1-F4 in baseline liver biopsy) will be randomized in a 1:1 ratio to metabolic surgery or medical treatment (incretin-based therapies ± other medical therapies for MASH) and followed for 2 years at which time a repeat liver biopsy will be performed for the assessment of the primary end point.

Research Team

Ali Aminian, MD

Principal Investigator

The Cleveland Clinic

Eligibility Criteria

This trial is for individuals with MASLD, a liver condition linked to obesity and diabetes. It's open to those who have evidence of liver fibrosis (stages F1-F4). Participants must consent to a liver biopsy if they haven't had one recently.

Inclusion Criteria

Has a negative urine pregnancy test at the first and at the randomization visits for women of childbearing potential

Self-reported stable weight in 3 months before the first study visit (no weight change >5% within 3 months prior to the first study visit)

I am willing and able to join the study and follow its procedures.

Exclusion Criteria

Anemia defined as hemoglobin less than 9 g/dL

Previous participation in this trial and got randomized to one of the study groups but did not proceed

Platelet count <100,000

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Participants undergo baseline liver biopsy and other assessments

1-2 weeks

1 visit (in-person)

Treatment

Participants are randomized to either metabolic surgery or incretin-based therapies for 2 years

104 weeks

Regular visits as per treatment protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a repeat liver biopsy

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Incretin-Based Therapy
• Metabolic Surgery

Trial Overview The study compares metabolic surgery against medical treatments using incretin-based therapies for MASH. About 120 patients will be randomly assigned to either the surgery or medication group and tracked over two years, including repeat liver biopsies.

Participant Groups

Group I: Metabolic Surgery Active Control 1 Intervention

FLAMES will examine the class effect (not the specific procedure effect) of metabolic surgery. The study is not intended to compare Roux-en-Y Gastric Bypass (RYGB) vs Sleeve Gastrectomy (SG) head-to-head. RYGB and SG constitute one group as a metabolic surgery group. Assignment of RYGB or SG is not based on a randomized design. Each patient and surgical team will make a shared decision about the most appropriate surgical procedure.

Group II: Incretin-Based Therapy Active Control 1 Intervention

Three incretin-based medications that have been approved for treatment of obesity including liraglutide, semaglutide, or tirzepatide will be used in the nonsurgical group. The FLAMES will examine the class effect (not the specific drug effect) of incretin-based therapies. The study is not intended to compare semaglutide vs tirzepatide vs liraglutide head-to-head.

Metabolic Surgery is already approved in European Union, United States for the following indications:

Approved in European Union as Metabolic Surgery for:

• Metabolic Dysfunction-Associated Steatohepatitis (MASH)
• Non-Alcoholic Fatty Liver Disease (NAFLD)
• Liver Fibrosis

Approved in United States as Metabolic Surgery for:

• Metabolic Dysfunction-Associated Steatohepatitis (MASH)
• Non-Alcoholic Fatty Liver Disease (NAFLD)
• Liver Fibrosis

Who Is Running the Clinical Trial?

Ali Aminian

Lead Sponsor

Trials

4

Recruited

4,500+

Findings from Research

The term non-alcoholic fatty liver disease (NAFLD) has been updated to metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect its connection with metabolic syndrome, particularly in obese individuals.

Bariatric and metabolic surgery is emerging as a key treatment strategy for MAFLD, showing promising outcomes in improving liver health from early stages like hepatic steatosis to more severe conditions such as cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bariatric Surgery and Metabolic Dysfunction-Associated Fatty Liver Disease: a 2022 Update. Lazaridis, II., Delko, T.[2023]

Bariatric surgery can significantly improve or even resolve nonalcoholic fatty liver disease (NAFLD), which is a serious condition linked to metabolic syndrome.

The benefits of bariatric surgery for NAFLD are attributed not only to weight loss but also to improvements in insulin resistance and reductions in inflammatory proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effects of Metabolic Surgery on Fatty Liver Disease and Nonalcoholic Steatohepatitis. Clanton, J., Subichin, M.[2022]

In a randomized trial involving 288 participants with non-alcoholic steatohepatitis (NASH), bariatric-metabolic surgery (Roux-en-Y gastric bypass and sleeve gastrectomy) resulted in significantly higher rates of NASH resolution compared to lifestyle modifications, with 56% and 57% of participants achieving resolution respectively, versus only 16% in the lifestyle group.

The study reported no deaths or life-threatening complications, indicating that bariatric surgery is a safe option for treating NASH, although 6% of participants experienced severe adverse events that were manageable without re-operations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Verrastro, O., Panunzi, S., Castagneto-Gissey, L., et al.[2023]

Bariatric surgery in 196 patients with advanced NASH led to significant histological improvements, with 29% achieving normal liver histology and 74% experiencing NASH resolution without fibrosis progression after an average follow-up of 6 years.

Despite these improvements, advanced fibrosis persisted in 47% of patients, indicating that while weight loss and metabolic improvements are beneficial, they may not be enough to fully reverse advanced fibrosis, especially in older patients or those undergoing sleeve gastrectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery. Pais, R., Aron-Wisnewsky, J., Bedossa, P., et al.[2022]

Bariatric surgery, particularly Roux-en-Y gastric bypass (RYGB), significantly improves non-alcoholic fatty liver disease (NAFLD) as evidenced by reduced liver stiffness and improved fibrosis scores in a study of 100 patients over a median follow-up of 12.5 months.

The study found that improvements in liver health were not directly correlated with weight loss, suggesting that bariatric surgery may have specific benefits for liver health beyond just reducing body weight.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bariatric Surgery as an Efficient Treatment for Non-Alcoholic Fatty Liver Disease in a Prospective Study with 1-Year Follow-up : BariScan Study. Nickel, F., Tapking, C., Benner, L., et al.[2019]

In a study of 60 obese patients after mini gastric bypass surgery, a tailored probiotic and micronutrient mixture significantly improved liver health markers, including serum aspartate aminotransferase (ASAT) and NAFLD fibrosis score, compared to a basic micronutrient supplement.

While there was no significant change in serum alanine aminotransferase (ALAT) levels between the two groups, the probiotic and micronutrient combination also reduced serum triglycerides and visceral fat, suggesting a beneficial effect on overall metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Specifically Tailored Multistrain Probiotic and Micronutrient Mixture Affects Nonalcoholic Fatty Liver Disease-Related Markers in Patients with Obesity after Mini Gastric Bypass Surgery. Crommen, S., Rheinwalt, KP., Plamper, A., et al.[2023]

In a study of 90 morbidly obese patients with a BMI between 35 and 40 kg/m2, high levels of parathyroid hormone (PTH) were significantly associated with the presence of hepatic fibrosis, steatosis, and NASH/NAFLD, indicating that PTH could be a useful biomarker for liver health in this population.

The research suggests that measuring PTH levels before and after bariatric surgery may help in assessing liver conditions, but further randomized controlled trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The predictive role of parathyroid hormone for non-alcoholic fatty liver disease based on invasive and non-invasive findings in candidates of bariatric surgery. Jamialahmadi, T., Nematy, M., Jangjoo, A., et al.[2022]

Patients with nonalcoholic fatty liver disease (NAFLD) who underwent bariatric surgery (BS) experienced 35% lower inpatient mortality and shorter hospital stays compared to those without NAFLD, indicating that BS is safe and effective for this group.

Bariatric surgery not only reduces mortality and complications for NAFLD patients but also has the potential to improve liver health by significantly reducing liver inflammation and fibrosis through substantial weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonalcoholic fatty liver disease does not predict worse perioperative outcomes in bariatric surgery. Mavilia, MG., Wakefield, D., Karagozian, R.[2020]

Bariatric surgery, specifically sleeve gastrectomy, not only aids in weight loss but also increases plasma levels of genistein, a metabolite linked to reduced severity of non-alcoholic fatty liver disease (NAFLD), as shown in a study involving 5 patients and rodent models.

The study found that the changes in gut microbiota after surgery play a crucial role in elevating plasma genistein levels, suggesting that bariatric surgery can have beneficial effects on liver health through mechanisms beyond just weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased plasma genistein after bariatric surgery could promote remission of NAFLD in patients with obesity. Wang, G., Wang, Y., Bai, J., et al.[2023]

Bariatric surgery in patients with liver cirrhosis is associated with a higher risk of complications and perioperative mortality, based on a review of 11 studies.

Surgeons should proactively discuss the potential for undiagnosed cirrhosis in bariatric surgery patients and establish a plan for management if cirrhosis is discovered during surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of Bariatric Surgery in Patients with Liver Cirrhosis. Jan, A., Narwaria, M., Mahawar, KK.[2018]

Bariatric surgery may be an effective treatment option for nonalcoholic fatty liver disease, particularly in patients with liver fibrosis and compensated cirrhosis, as suggested by a review of existing outcomes.

Despite the promising potential of bariatric surgery for improving liver health, more research is needed to fully understand its effects on liver fibrosis and cirrhosis in patients with nonalcoholic fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Bariatric Surgery on the Spectrum of Fatty Liver Disease. Nostedt, JJ., Switzer, NJ., Gill, RS., et al.[2018]

Bariatric surgery significantly reduces various histological features of non-alcoholic fatty liver disease (NAFLD) in obese patients, including steatosis, fibrosis, hepatocyte ballooning, and lobular inflammation, indicating a strong therapeutic effect on liver health.

Post-surgery, patients also experience significant reductions in liver enzyme levels (ALT, AST, ALP, and gamma-GT), which are important markers of liver injury, further supporting the efficacy of bariatric surgery in improving NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bariatric Surgery and Non-Alcoholic Fatty Liver Disease: a Systematic Review of Liver Biochemistry and Histology. Bower, G., Toma, T., Harling, L., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Bariatric Surgery and Metabolic Dysfunction-Associated Fatty Liver Disease: a 2022 Update. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

The Effects of Metabolic Surgery on Fatty Liver Disease and Nonalcoholic Steatohepatitis. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Bariatric Surgery as an Efficient Treatment for Non-Alcoholic Fatty Liver Disease in a Prospective Study with 1-Year Follow-up : BariScan Study. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

A Specifically Tailored Multistrain Probiotic and Micronutrient Mixture Affects Nonalcoholic Fatty Liver Disease-Related Markers in Patients with Obesity after Mini Gastric Bypass Surgery. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

The predictive role of parathyroid hormone for non-alcoholic fatty liver disease based on invasive and non-invasive findings in candidates of bariatric surgery. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Nonalcoholic fatty liver disease does not predict worse perioperative outcomes in bariatric surgery. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Increased plasma genistein after bariatric surgery could promote remission of NAFLD in patients with obesity. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

A Systematic Review of Bariatric Surgery in Patients with Liver Cirrhosis. [2018]

11. Egypt pubmed.ncbi.nlm.nih.gov

The Effect of Bariatric Surgery on the Spectrum of Fatty Liver Disease. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

Bariatric Surgery and Non-Alcoholic Fatty Liver Disease: a Systematic Review of Liver Biochemistry and Histology. [2022]