A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis

Study Overview
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Brief Summary
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A double-blind placebo controlled randomized Phase 3 study to determine if 80 or 100 mg of MGL-3196 as compared with placebo resolves NASH and/or reduces fibrosis on liver biopsy and prevents progression to cirrhosis and/or advanced liver disease

Detailed Description
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Primary and secondary endpoint population at Week 52 will be at least 900 patients, more than half F3, the remainder F2 and <10% F1B based on final liver biopsy baseline fibrosis score.

Official Title
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A Phase 3, Multinational, Double-Blind, Randomized, Placebo-Controlled Study of MGL-3196 (Resmetirom) in Patients With Non-Alcoholic Steatohepatitis (NASH) and Fibrosis to Resolve NASH and Reduce Progression to Cirrhosis and/or Hepatic Decompensation

Conditions
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NASH - Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: MGL-3196
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be willing to participate in the study and provide written informed consent. Male and female adults ≥ 18 years of age. Suspected or confirmed diagnosis of NASH fibrosis suggested by the historical data. Meet one of the following criteria that is consistent with NASH liver fibrosis: Historical biochemical test for fibrosis: PRO-C3 >14 ng/mL or ELF ≥9 FibroScan with transient elastography ≥8.5 kPa and controlled attenuation parameter ≥280 dB.m-1 Historical liver biopsy obtained <2 years before expected randomization showing Stage 1B, 2 or 3 fibrosis with NASH based on existing pathology review, with no significant change in body weight >5% or medication that might affect NAS or fibrosis stage. MRI-PDFF fat fraction ≥8% obtained during the screening period Biopsy-proven NASH (baseline liver biopsy) based on a liver biopsy obtained ≤6 months before anticipated date of randomization (if the biopsy is deemed acceptable for interpretation by the central reader) with fibrosis stage 1A/1C, 1B, 2, or 3 on liver biopsy and NAS of ≥4 with a score of at least 1 in each of the following NAS components: Steatosis (scored 0 to 3) Ballooning degeneration (scored 0 to 2) Lobular inflammation (scored 0 to 3) Exclusion Criteria: History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening. Regular use of drugs historically associated with NAFLD Thyroid diseases: Active hyperthyroidism. Untreated clinical hypothyroidism defined by thyroid stimulating hormone (TSH) >7 IU/L with symptoms of hypothyroidism or >10 IU/L without symptoms. Patients who have had a thyroidectomy and are on replacement thyroxine doses >75 µg per day are allowed. History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study. Recent significant weight gain or loss HbA1c ≥ 9.0%. Glucagon-like peptide 1 [GLP-1] agonist, high dose Vitamin E (> 400 IU/day), or pioglitazone therapy unless stable dose for 24 weeks prior to biopsy. Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis. Diagnosis of hepatocellular carcinoma (HCC). MELD score ≥12, as determined at Screening, unless due to therapeutic anti coagulation. Hepatic decompensation Chronic liver diseases other than NASH Active autoimmune disease Serum ALT > 250 U/L. Active, serious medical disease with a likely life expectancy < 2 years. Participation in an investigational new drug trial in the 60 days or 5 half-lives, whichever is longer. Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, compromise the well-being of the patient, or interfere with the study outcomes.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Matching Placebo<br>Placebo Daily | Drug: Placebo<br>* Matching Tablets<br>|
| Active Comparator: 80 mg MGL-3196<br>80 mg daily | Drug: MGL-3196<br>* Tablet<br>* Other names: Resmetirom;|
| Active Comparator: 100 mg MGL-3196<br>100 mg daily | Drug: MGL-3196<br>* Tablet<br>* Other names: Resmetirom;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Week 52 Dual Primary Objectives: To determine the effect of 80 or 100 mg MGL-3196 vs matching placebo on liver biopsy (NASH CRN score) at Week 52 compared with Baseline | Proportion with resolution of NASH (ballooning 0, inflammation 0,1) associated with at least 2-point reduction in NAFLD Activity Score (NAS) without worsening of fibrosis stage OR Proportion with at least a 1-point improvement in fibrosis stage with no worsening of NAS | 52 weeks | 
| Month 54 Primary Objective: Time to experiencing an adjudicated Composite Clinical Outcome event (Final Primary Endpoint, at 54 months) | The Composite Clinical Outcome is composed of all-cause mortality, liver transplant, and significant hepatic events (including hepatic decompensation events [ascites, encephalopathy, or gastroesophageal variceal hemorrhage], histological progression to cirrhosis, and a confirmed increase of MELD score from <12 to ≥15). | up to 54 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Week 52 Key Secondary Objective: To determine the effect of once-daily, oral administration of MGL-3196 80 or 100 mg versus matching placebo on the percent change from Baseline at 24 weeks in directly measured low-density lipoprotein cholesterol (LDL-C) | Assess the effect of MGL-3196 80 mg or 100 mg compared to placebo on LDL-C measured by percent change from Baseline at 24 weeks. | 24 weeks |