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

Phase 3

Recruiting

• Conditions: NASH; Cirrhosis, Liver
• Interventions: Drug: Placebo; Drug: Resmetirom

• Registration Number: NCT05500222
• Lead Sponsor: Madrigal Pharmaceuticals, Inc.

Brief Summary

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

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 (until the required number of Composite Clinical Outcome events are achieved). Composite Clinical Outcome events are defined as any of the following: liver-related and CV 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.

Study Timeline

• Study First Submitted: 2022-08-11
• Study First Submitted QC: 2022-08-11
• Study First Posted: 2022-08-15
• Study Start: 2022-08-26
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-21
• Last Update Posted: 2024-03-25
• Primary Completion: 2026-12
• Study Completion: 2027-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 700

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	matching placebo daily
Resmetirom	Resmetirom	80 mg daily

Primary Outcome Measures

Name	Time	Method
Incidence Of adjudicated Composite Clinical Outcome event	Baseline up to Month 36	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

Trial Locations

Locations (55)

Covenant Research - Fort Myers; 🇺🇸 Fort Myers, Florida, United States

Gastrointestinal Specialists of Georgia; 🇺🇸 Marietta, Georgia, United States

The Liver Institute at Methodist Dallas Medical Center; 🇺🇸 Dallas, Texas, United States

Liver Center of Texas; 🇺🇸 Dallas, Texas, United States

Houston Research Institute; 🇺🇸 Houston, Texas, United States

Liver Institute Northwest; 🇺🇸 Seattle, Washington, United States

Arizona Liver Health - Chandler; 🇺🇸 Chandler, Arizona, United States

Adobe Clinical Research; 🇺🇸 Tucson, Arizona, United States

Mercy Medical Center; 🇺🇸 Baltimore, Maryland, United States

Florida Research Institute; 🇺🇸 Lakewood Ranch, Florida, United States

University of California, San Francisco-Fresno; 🇺🇸 Fresno, California, United States

Latin Clinical Trials Center; 🇵🇷 San Juan, Puerto Rico

FDI Clinical Research (Fundacion de Investigacion de Diego); 🇵🇷 San Juan, Puerto Rico

Summit Clinical Research; 🇺🇸 Athens, Georgia, United States

Covenant Research; 🇺🇸 Sarasota, Florida, United States

Louisiana Research Center; 🇺🇸 Shreveport, Louisiana, United States

Southern California Research Center; 🇺🇸 Coronado, California, United States

St Johns Center for Clinical Research; 🇺🇸 Saint Augustine, Florida, United States

Florida Medical Clinic; 🇺🇸 Zephyrhills, Florida, United States

Keck School of Medicine of USC; 🇺🇸 Los Angeles, California, United States

Sanchez Clinical Research; 🇺🇸 Miami, Florida, United States

Texas Clinical Research Institute; 🇺🇸 Arlington, Texas, United States

Univ. of California San Diego School of Medicine; 🇺🇸 La Jolla, California, United States

Gastro One; 🇺🇸 Cordova, Tennessee, United States

Pinnacle Clinical Research - Georgetown; 🇺🇸 Georgetown, Texas, United States

Pinnacle Clinical Research - San Antonio; 🇺🇸 San Antonio, Texas, United States

University of Alabama at Birmingham (UAB); 🇺🇸 Birmingham, Alabama, United States

International Center for Research; 🇺🇸 Tampa, Florida, United States

Lucas Research; 🇺🇸 Morehead City, North Carolina, United States

South Texas Research Institute - Edinburg; 🇺🇸 Edinburg, Texas, United States

Impact Research Institute; 🇺🇸 Waco, Texas, United States

Digestive Health Research of Central Texas; 🇺🇸 Waco, Texas, United States

Arizona Liver Health - Tucson; 🇺🇸 Tucson, Arizona, United States

Arizona Liver Health - Peoria; 🇺🇸 Peoria, Arizona, United States

Arkansas Gastroenterology; 🇺🇸 North Little Rock, Arkansas, United States

Arkansas Diagnostic Center/Liver Wellness Center; 🇺🇸 Little Rock, Arkansas, United States

South Denver Gastroenterology; 🇺🇸 Englewood, Colorado, United States

California Liver Research Institute; 🇺🇸 Pasadena, California, United States

Hi Tech and Global Research; 🇺🇸 Coral Gables, Florida, United States

Ocala GI Research DBA Lake Center for Clinical Research; 🇺🇸 Lady Lake, Florida, United States

Top Medical Research Inc; 🇺🇸 Cutler Bay, Florida, United States

Jacksonville Center for Clinical Research; 🇺🇸 Jacksonville, Florida, United States

Ocala GI Research; 🇺🇸 Ocala, Florida, United States

Kansas Medical Clinic - Gastroenterology; 🇺🇸 Topeka, Kansas, United States

Delta Research Partners - Bastrop; 🇺🇸 Bastrop, Louisiana, United States

Premier Health Research; 🇺🇸 Sparta, New Jersey, United States

Regional Gastroenterology Associates of Lancaster; 🇺🇸 Flourtown, Pennsylvania, United States

Premier Medical Group; 🇺🇸 Clarksville, Tennessee, United States

Rapid City Medical Center; 🇺🇸 Rapid City, South Dakota, United States

South Texas Research Institute - Brownsville; 🇺🇸 Brownsville, Texas, United States

Pinnacle Clinical Research - Austin; 🇺🇸 Austin, Texas, United States

Hunter Holmes McGuire VA Medical Center; 🇺🇸 Richmond, Virginia, United States

Kansas City Research Institute; 🇺🇸 Kansas City, Missouri, United States

GI Select Health Research; 🇺🇸 Richmond, Virginia, United States

Nature Coast Clinical Research - Inverness; 🇺🇸 Inverness, Florida, United States