A Phase 3 Study to Evaluate the Effect of Resmetirom on Clinical Outcomes in Patients With Well-compensated NASH Cirrhosis (MAESTRO-NASH-OUTCOMES)

Study Overview
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Brief Summary
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This study will determine the effect of oral 80 mg resmetirom administered once daily on participants with well-compensated non-alcoholic steatohepatitis (NASH) cirrhosis by measuring the time to experiencing a Composite Clinical Outcome event.

Detailed Description
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This is a multi-national, multicenter, double-blind, randomized, placebo-controlled study in participants with well-compensated NASH cirrhosis. Participants will be randomized 3:1 in a blinded manner to receive 80 mg resmetirom or matching placebo given orally once daily in the morning for the duration of the study and until the required number of Composite Clinical Outcome events are achieved. Composite Clinical Outcome events are defined as any of the following: all-cause mortality, liver transplant, and significant hepatic events, including potential hepatic decompensation events (ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage), and confirmed increase of Model for End-stage Liver Disease (MELD) score from <12 to ≥15. The study comprises an up to 60-day screening period and an approximately 3-year treatment period.

Official Title
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A Randomized Double-blind Placebo-controlled Phase 3 Study to Evaluate the Effect of Resmetirom on Liver-related Outcomes in Patients With Well-compensated (Child-Pugh A) Non-alcoholic Steatohepatitis (NASH) Cirrhosis (MAESTRO-NASH-OUTCOMES)

Conditions
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NASH, Cirrhosis, Liver

Intervention / Treatment
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* Drug: Resmetirom
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Definitive (by histologic documentation) or probable NASH as causative agent for cirrhosis, following a modified version of the NASH Cirrhosis: Liver Forum Consensus Definitions for Clinical Trials. a. Most recent biopsy (within last 5 years) shows cirrhosis with a NAS of ≥ 2, and at least two components: one being steatosis and at least one other component; OR NAS of ≥ 2, if steatosis = 0 or is ungraded with inflammation and/or ballooning, eligible with an MRI-PDFF >5%. If steatosis and ballooning and/or steatosis and inflammation are noted by the local pathologist, then the biopsy qualifies even if a NAS is not provided (Approximately 70% of the study patient population) b. Historical biopsy (within last 5 years) showed NASH with significant fibrosis with pathology report documenting F2 or F3, with at least steatosis either by biopsy with no minimal percentage required or by MRI-PDFF >5%, AND inflammation or ballooning. Now with cirrhosis, either by clinical history or current features, imaging, noninvasive tests, or biopsy (see Appendix 7) (Up to approximately 20% of study patient population) c. Historical biopsy (within last 5 years) shows steatosis. Pathology report documents steatosis with no minimal percentage required. Now with cirrhosis, either by clinical history or current features, imaging, noninvasive tests, or biopsy (see Appendix 7). Prescreening metabolic risk factors must include obesity and/or T2D. (Up to approximately 10% of study patient population.) Well-compensated NASH cirrhosis at screening and baseline with Child-Pugh A (score of 5-6) (no history of hepatic decompensation event). At least 3 metabolic risk factors Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) that is obtained during the Screening period or a historic MRI-PDFF at ≤8 weeks old at the time of randomization with no weight change ≥5% weight change in that interval. MRE ≥4.2 where MRE is available. Enhanced liver function (ELF) ≥9.8, only if MRE is unavailable or contraindicated. Exclusion Criteria: Participants with a chronic liver diseases other than NASH cirrhosis, such as primary biliary cholangitis, primary sclerosing cholangitis, Hepatitis B positive, Hepatitis C, history or evidence of current active autoimmune hepatitis, history or evidence of Wilson's disease, history or evidence of alpha-1-antitrypsin deficiency, history or evidence of genetic hemochromatosis (hereditary, primary), evidence of drug-induced liver disease, as defined on the basis of typical exposure and history, known bile duct obstruction, or suspected or confirmed liver cancer, are excluded. Participants with MELD score ≥12 due to liver disease are excluded. Participants with a history of hepatic decompensation or impairment are excluded.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Resmetirom<br>80 mg daily | Drug: Resmetirom<br>* Randomized 80 mg<br>* Other names: MGL-3196;|
| Placebo Comparator: Placebo<br>matching placebo daily | Drug: Placebo<br>* randomized matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Of adjudicated Composite Clinical Outcome event | Any event of all-cause mortality, liver transplant, ascites, hepatic encephalopathy, gastroesophageal variceal hemorrhage, and confirmed increase of MELD score from <12 to .>/= 15 due to liver disease | Baseline up to Month 36 |