Clinical trial NCT05500222: A Phase 3 Study to Evaluate the Effect of Resmetirom on Clinical Outcomes in Patients With Well-compensated NASH Cirrhosis (MAESTRO-NASH-OUTCOMES)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: NASH
Cirrhosis, Liver
Lead sponsor: Madrigal Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2022-08-15
Enrollment: 700
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence Of adjudicated Composite Clinical Outcome event
timeFrame: Baseline up to Month 36
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham (UAB)
state: Alabama
city: Chandler
country: United States
facility: Arizona Liver Health - Chandler
state: Arizona
city: Peoria
country: United States
facility: Arizona Liver Health - Peoria
state: Arizona
city: Tucson
country: United States
facility: Adobe Clinical Research
state: Arizona
city: Tucson
country: United States
facility: Arizona Liver Health - Tucson
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Diagnostic Center/Liver Wellness Center
state: Arkansas
city: North Little Rock
country: United States
facility: Arkansas Gastroenterology
state: Arkansas
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Fresno
country: United States
facility: University of California, San Francisco-Fresno
state: California
city: La Jolla
country: United States
facility: Univ. of California San Diego School of Medicine
state: California
city: Los Angeles
country: United States
facility: Keck School of Medicine of USC
state: California
city: Pasadena
country: United States
facility: California Liver Research Institute
state: California
city: Englewood
country: United States
facility: South Denver Gastroenterology
state: Colorado
city: Coral Gables
country: United States
facility: Hi Tech and Global Research
state: Florida
city: Cutler Bay
country: United States
facility: Top Medical Research Inc
state: Florida
city: Fort Myers
country: United States
facility: Covenant Research - Fort Myers
state: Florida
city: Inverness
country: United States
facility: Nature Coast Clinical Research - Inverness
state: Florida
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Lady Lake
country: United States
facility: Ocala GI Research DBA Lake Center for Clinical Research
state: Florida
city: Lakewood Ranch
country: United States
facility: Florida Research Institute
state: Florida
city: Miami
country: United States
facility: Sanchez Clinical Research
state: Florida
city: Ocala
country: United States
facility: Ocala GI Research
state: Florida
city: Saint Augustine
country: United States
facility: St Johns Center for Clinical Research
state: Florida
city: Sarasota
country: United States
facility: Covenant Research
state: Florida
city: Tampa
country: United States
facility: International Center for Research
state: Florida
city: Zephyrhills
country: United States
facility: Florida Medical Clinic
state: Florida
city: Athens
country: United States
facility: Summit Clinical Research
state: Georgia
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: Topeka
country: United States
facility: Kansas Medical Clinic - Gastroenterology
state: Kansas
city: Bastrop
country: United States
facility: Delta Research Partners - Bastrop
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana Research Center
state: Louisiana
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Kansas City
country: United States
facility: Kansas City Research Institute
state: Missouri
city: Sparta
country: United States
facility: Premier Health Research
state: New Jersey
city: Morehead City
country: United States
facility: Lucas Research
state: North Carolina
city: Flourtown
country: United States
facility: Regional Gastroenterology Associates of Lancaster
state: Pennsylvania
city: Rapid City
country: United States
facility: Rapid City Medical Center
state: South Dakota
city: Clarksville
country: United States
facility: Premier Medical Group
state: Tennessee
city: Cordova
country: United States
facility: Gastro One
state: Tennessee
city: Arlington
country: United States
facility: Texas Clinical Research Institute
state: Texas
city: Austin
country: United States
facility: Pinnacle Clinical Research - Austin
state: Texas
city: Brownsville
country: United States
facility: South Texas Research Institute - Brownsville
state: Texas
city: Dallas
country: United States
facility: The Liver Institute at Methodist Dallas Medical Center
state: Texas
city: Dallas
country: United States
facility: Liver Center of Texas
state: Texas
city: Edinburg
country: United States
facility: South Texas Research Institute - Edinburg
state: Texas
city: Georgetown
country: United States
facility: Pinnacle Clinical Research - Georgetown
state: Texas
city: Houston
country: United States
facility: Houston Research Institute
state: Texas
city: San Antonio
country: United States
facility: Pinnacle Clinical Research - San Antonio
state: Texas
city: Waco
country: United States
facility: Impact Research Institute
state: Texas
city: Waco
country: United States
facility: Digestive Health Research of Central Texas
state: Texas
city: Richmond
country: United States
facility: GI Select Health Research
state: Virginia
city: Richmond
country: United States
facility: Hunter Holmes McGuire VA Medical Center
state: Virginia
city: Seattle
country: United States
facility: Liver Institute Northwest
state: Washington
city: San Juan
country: Puerto Rico
facility: Latin Clinical Trials Center
city: San Juan
country: Puerto Rico
facility: FDI Clinical Research (Fundacion de Investigacion de Diego)
Study officials:
affiliation: VP, Clinical Research
name: Thomas Hare
role: STUDY_DIRECTOR
References: