Evaluation of Non-Invasive Tests for Metabolic Liver Disease

Summary

The Non-Invasive Biomarkers for Metabolic Liver Disease (NIMBLE) study is a comprehensive, multi-year collaborative effort to standardize, validate and advance the regulatory qualification of blood- and imaging-based biomarkers to diagnose and stage Metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH). MASH is characterized by liver inflammation accompanied by simultaneous fat accumulation in the liver.

Eligibility

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged \> 18 years and \< 75 years
4. Participants must exhibit some manifestations of metabolic dysregulation. Either:

A. Physician-diagnosed T2DM for at least 90 days with HbA1c \> 6.5 and antidiabetic therapy, if any, stable for at least 90 days prior to screening or B. At least any one of the following six metabolic syndrome criteria \[6\]

1\. body mass index (BMI) of \> 25 kg/m2 2. waist circumference: i. \> 102 cm for men ii. \> 88.9 cm for women 3. fasting triglyceride concentration \> 150 mg/dL i. or ongoing treatment with triglyceride lowering medication 4. HDL-cholesterol concentration: i. \< 40 mg/dL for men ii. \< 50 mg/dL for women iii. or ongoing treatment with cholesterol lowering medication. 5. fasting glucose concentration \> 100 mg/dL 6. either semi-recumbent or supine blood pressure systolic \> 130 mmHg and/ or diastolic \> 85 mmHg i. or ongoing treatment with antihypertensive medication. 5. FIB-4 \> 1.3 (age \< 65 years) and \> 2.0 (age \> 65 years) 6. Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration

Exclusion Criteria:

1. Known history or evidence of other forms of chronic liver disease other than MASLD/MASH including but not limited to viral hepatitis B or C, autoimmune liver disease, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, hemochromatosis, drug-induced liver disease, conditions involving bile duct obstructions, liver cancer, past history of HCC or HCC treatment, listed for or history of liver transplantation, prior resection of liver, etc.
2. Current or past evidence of decompensated liver disease defined by overt ascites that is clinically obvious and requires diuretic therapy, overt encephalopathy requiring therapy or history of variceal hemorrhage
3. Circulating Alanine aminotransferase (ALT)\> 5xULN
4. Ongoing or recent (within the last two years prior to screening) consumption of significantly greater than moderate amounts of alcohol.

   * A standard alcoholic drink is any drink that contains about 14 g of pure alcohol, such as 12 fluid ounces of regular beer 8-10 fluid ounces of malt liquor or flavored malt beverages such as hard seltzer 5 fluid ounces of table wine 3-4 fluid ounces of fortified wine such as sherry or port 2-3 fluid ounces of cordial liqueur or aperitif 1.5 fluid ounces (a single jigger or shot) of brandy, cognac, or distilled spirits such as gin, rum, tequila, vodka, whiskey, etc.
   * Significantly greater than moderate alcohol consumption is defined as on average over a 2-year period prior to screening:

   Women
   * \>1 standard drink per day and/or
   * \>14 standard drinks per week Men
   * \>2 standard drinks per day and/or
   * \>21 standard drinks per week in men

     * An Alcohol Use Disorders Identification Test (AUDIT) score of 7 or higher
     * A PEth test score of ≥ 20ng/ml.
5. In the opinion of the investigator, any contraindications to liver biopsy including but not limited to having significant uncorrected coagulopathy or thrombocytopenia, on chronic anticoagulation with Direct Oral Anticoagulants (DOACs), or on low dose heparin or Warfarin.
6. Uncontrolled systolic blood pressure \> 180 mmHg and diastolic blood pressure \> 120 mmHg at screening. Blood pressure will be obtained after at least 10 minutes of resting in a semi-recumbent or supine position.
7. Any systemic disease that in the opinion of the investigator precludes inclusion of the patient in the trial
8. Unable or unwilling to provide informed consent
9. Unwilling to undergo liver biopsy procedure
10. Unable or unwilling to comply with requirements for study procedures (such as fasting)
11. Unable to perform study procedures in the opinion of the investigator
12. Participants who are unwilling or unable (e.g. due active implants such as pacemaker or having a waist diameter (calculated as: diameter = circumference / π) 70cm, unless a wide-bore MRI machine is available) to undergo MRI procedures.
13. Pregnancy or planned pregnancy within 4 months of screening.
14. Participation in another clinical trial within 30 days, or dosing with an investigational agent within 90 days prior to signing the ICF for this study.

Conditions9

Locations4 sites

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