SemAglutide treatMent in the reAl-woRld for fibrosis due to MASLD in obesity and T2DM (SAMARA)

Status: Currently recruiting subjects

Required visits: Seven on-site visits

Age of participants: Between the ages of 18-80

Gender of participants: Male and Female

Study Overview

Metabolic dysfunction-associated steatotic liver disease (MASLD) (previously NAFLD) affects approximately 25-30% of the global population and is projected to become the leading cause of liver transplantation in the United States by 2030. Development of efficient screening strategies for the identification and treatment of individuals who are at greatest risk for advanced disease in this population is an urgent and unmet medical need.

Type 2 diabetes mellitus (T2DM) and obesity are critical risk factors for advanced MASLD. In a prospective cross-sectional study of patients with type 2 diabetes, we screened 524 participants (50-80 years old) with type 2 diabetes mellitus for the presence of MASLD and observed relative prevalences of 70% for steatosis and 15% for advanced fibrosis. The presence of obesity in this population further increased the odds of advanced fibrosis. These findings suggest that screening populations of individuals with obesity or T2DM may be an effective strategy for identifying high-risk patients with MASLD.

Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) that is FDA-approved for the treatment of obesity (as Wegovy) or T2DM (as Ozempic), conditions that are considered major risk factors for advanced fibrosis in the MASLD population. It is unclear, however, whether semaglutide is effective for treatment of fibrosis due to MASLD in these populations. Here, we propose to conduct a community intervention study that will:

1. Validate a screening approach to identify patients at risk for advanced MASLD in the obese or T2DM population and,
2. Test whether semaglutide treatment is effective for the management of significant fibrosis due to MASLD in high-risk patients.

Study Design

Inclusion criteria:

1. Adult, age ≥ 18 and < 80 years
2. Participant must meet at least one of following sets of conditions:

 A) BMI ≥ 27 kg/m2

 OR

B) BMI ≥ 25 kg/m2 AND presence of i) pre-diabetes (HbA1C ≥ 5.7) or ii) type 2 diabetes mellitus (T2DM), as defined bythe American Diabetes Association (ADA) clinical practice The ADA definition of T2DM is applicable if one of the following criteria is met:

• Presence of  diabetes  symptoms  (polyuria,  polydipsia,  polyphagia,    increased fatigue, weight loss, blurred vision) and casual plasma glucose ≥ 200 mg/dL (11.1 mmol/L)
• Fasting plasma glucose (FPG) ≥ 126 mg/dl (7.0 mmol/L)
• Plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT)

OR

• Hemoglobin A1C (HbA1C) ≥ 6.5% 69.

Exclusion criteria:

1. Presence of regular and/or excessive use of alcohol, defined as > 30 g/day for males and > 20 g/day for females, for a period longer than 2 years at any time in the last 10 years
2. Evidence of cirrhosis or previously known cirrhosis, based on the results from previous liver biopsy or history of portalhypertension presented by ascites, hepatic encephalopathy or varices
3. VCTE ≥ 20 kPa
4. Platelet count ≤ 140,000 per Ml
5. Albumin < 3.6 g/dL
6. INR > 1.35, unless on coumadin for another indication
7. Serum creatinine > 2.0 mg/dL
8. eGFR < 30 mL/min/1.73 m² as defined according to the CKDEPI creatinine equation
9. Use of other weight loss medications, including GLP1RA within the last 90 days
10. Greater than 10% weight loss in the prior six months
11. Known or suspected hypersensitivity to GLP1RA medications including semaglutide
12. History of bariatric surgery within the past 5 years or expected bariatric surgery
13. History or Evidence of other causes of chronic liver disease including:
    1. Hepatitis B, as defined as presence of hepatitis B surface antigen (HBsAg)
    2. Previous or current infection with Hepatitis C, as defined by presence of hepatitis C virus Ab in serum (anti-HCV Ab)
    3. Autoimmune hepatitis, as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistentwith autoimmune hepatitis or previous response to immunosuppressive
    4. Autoimmune cholestatic liver disorders, as defined by elevation of alkaline phosphatase and anti- mitochondrial antibody of greater than 1:80 or liver histology consistent with primary biliary cirrhosis or elevation of alkaline phosphataseand liver histology consistent with sclerosing
    5. Wilson disease, as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilson
    6. Alpha-1-antitrypsin deficiency, as defined by alpha-1-antitrypsin phenotype and liver histology consistent with alpha-1-antitrypsin
    7. Hemochromatosis, as defined by  presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D
    8. Drug-induced liver disease, as defined on the basis of typical exposure and history
    9. Bile duct obstruction, as evidenced by imaging

14. History of known HIV infection
15. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using a highly effective contraceptive method
16. History or presence of acute pancreatitis within the past 180 days prior to screening
17. History or presence of chronic pancreatitis
18. History or presence of type 1 diabetes
19. Personal or first-degree relative(s) history of medullary thyroid carcinoma (MTC)
20. Personal or first-degree relative(s) history or presence of multiple endocrine neoplasia syndrome type 2 (MEN 2)
21. Life expectancy less than 5 years
22. Contraindications to computed tomography (CT) or magnetic resonance imaging (MRI):

• The subject has any contraindication to MR imaging, such as patients with cardiac pacemaker or defibrillator, neurostimulator, intravascular stents, coils, valves, surgical clips, implanted electronic infusion pump,ferromagnetic foreign body or other conditions that would preclude proximity to a strong magnetic
• The subject has a history of extreme

23. Any of the following: myocardial infarction, stroke, classification of heart failure New York Heart Association (NYHA) Class IV, hospitalization for unstable angina pectoris or transient ischemic attack within the past 90 days prior to the day ofscreening and between screening and
24. History or presence of hepatocellular carcinoma
25. Presence or history within the past 5 years prior to screening of malignant neoplasms other than hepatocellular
26. Treatment with vitamin E (at doses ≥800 IU/day) or pioglitazone or medications approved for treatment of NASH, which hasnot been at a stable dose, in the period from 90 days prior to
27. ALT > 150 IU/L.
28. AST > 150 IU/L.
29. Total bilirubin > 1.5 mg/dL at screening. Total bilirubin level > 1.5 mg/dL is allowed if conjugated bilirubin is within normal
30. Alkaline phosphatase levels > 2 x ULN at
31. MELD score >= 10 points at screening.
32. HbA1c > 9.5%
33. Any subject where a substantial weight loss in the investigator’s opinion might jeopardize subject’s safety
34. History of diabetic retinopathy or maculopathy
35. For subjects with T2D: Diabetic retinopathy or maculopathy. Verified by a fundus examination performed within 90 days prior to screening or in the period between screening and randomization. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated
36. History of suicidal attempts or active suicidal ideation
37. Any condition which, in the investigator’s opinion might jeopardize subject’s safety or compliance with the