A Phase 3 Study to Evaluate Safety and Biomarkers of Resmetirom (MGL-3196) in Non Alcoholic Fatty Liver Disease Patients (MAESTRO-NAFLD1)

A 52-Week, Phase 3 Study to Evaluate Safety and Biomarkers of Resmetirom (MGL-3196) in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) (MAESTRO-NAFLD-1)

A double-blind placebo controlled randomized Phase 3 study to evaluate the safety and tolerability of once-daily, oral administration of 80 or 100 mg resmetirom versus matching placebo. At least 100 patients will be enrolled in a 100 mg open-label arm and will include a special safety population (eg, patients with compensated NASH cirrhosis).

Study Overview

• Status: Completed
• Conditions: Non-Alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Resmetirom; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 1343
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico
    • Fundacion de Investigacion de Diego
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Central Research Associates
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Arizona Liver Health - Chandler
    • Chandler, Arizona, United States, 85224
      • East Valley Family Physicians
    • Glendale, Arizona, United States, 85306
      • The Institute for Liver Health - Glendale
    • Mesa, Arizona, United States, 85213
      • Arizona - Desert Clinical Research
    • Tucson, Arizona, United States, 85711
      • The Institute for Liver Health - Tucson
    • Tucson, Arizona, United States, 85712
      • Adobe Gastroenterology
  • Arkansas
    • North Little Rock, Arkansas, United States, 72117
      • Arkansas Gastroenterology
  • California
    • Fresno, California, United States, 93720
      • Fresno Clinical Research Center
    • Huntington Park, California, United States, 90255
      • National Research Institute - Huntington Park
    • Los Angeles, California, United States, 90036
      • Ruane Clinical Research Group
    • Los Angeles, California, United States, 90057
      • National Research Institute - Los Angeles
    • Montclair, California, United States, 91763
      • Catalina Research Institute
    • Panorama City, California, United States, 91402
      • National Research Institute - Panorama City
    • Poway, California, United States, 92064
      • Alliance Clinical Research
    • West Hills, California, United States, 91307
      • San Fernando Valley Health Institute
  • Colorado
    • Englewood, Colorado, United States, 80113
      • South Denver Gastroenterology - Swedish Medical Center Office
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Excel Medical Clinical Trials
    • Hallandale Beach, Florida, United States, 33009
      • Velocity Clinical Research, Hallandale Beach (MD Clinical)
    • Hialeah, Florida, United States, 33016
      • Floridian Clinical Research
    • Inverness, Florida, United States, 34452
      • Nature Coast Clinical Research - Inverness
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Research Institute
    • Miami, Florida, United States, 33176
      • Miami Dade Medical Research Institute
    • Orlando, Florida, United States, 32806
      • Orlando Research Center
    • Port Orange, Florida, United States, 32127
      • Progressive Medical Research
    • Sarasota, Florida, United States, 34240
      • Covenant Research
    • The Villages, Florida, United States, 32162
      • The Villages Research Center
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Gastrointestinal Specialists of Georgia
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • East-West Medical Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60602
      • Chicago Research Center
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Physicians Group
  • Iowa
    • West Des Moines, Iowa, United States, 50265
      • Iowa Diabetes Research
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Kansas Medical Clinic - Gastroenterology
  • Kentucky
    • Louisville, Kentucky, United States, 40213
      • L-MARC Research Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Digestive Health Center of Louisiana
    • Marrero, Louisiana, United States, 70072
      • Tandem Clinical Research - New Orleans Area Site
    • West Monroe, Louisiana, United States, 71291
      • Clinical Trials Of America
  • Michigan
    • Ypsilanti, Michigan, United States, 48197
      • Huron Gastroenterology
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Gastrointestinal Associates & Endoscopy Center - Flowood
    • Jackson, Mississippi, United States, 39216
      • Southern Therapy and Advanced Research
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Research Institute
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Henderson Research Center
  • New York
    • East Syracuse, New York, United States, 13057
      • Clarity Clinical Research
    • New York, New York, United States, 10029
      • Mount Sinai Health System
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Fayetteville, North Carolina, United States, 28304
      • Cumberland Research Associates
    • Morehead City, North Carolina, United States, 28557
      • Diabetes and Endocrinology Consultants
    • Wilmington, North Carolina, United States, 28403
      • TMA - Wilmington Gastroenterology Accociates
  • Ohio
    • Cincinnati, Ohio, United States, 45246
      • Platinum - Sterling Research Group - Springdale
    • Columbus, Ohio, United States, 43213
      • Aventiv Research Columbus
    • Marion, Ohio, United States, 43302
      • Awasty Research Network
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Northeast Clinical Research Center
  • Tennessee
    • Clarksville, Tennessee, United States, 37040
      • Premier Medical Group - Clarksville - Dunlop Lane
    • Germantown, Tennessee, United States, 38138
      • Gastro One - Germantown Office - Wolf Park Drive
  • Texas
    • Austin, Texas, United States, 78746
      • Pinnacle Clinical Research - Austin
    • Dallas, Texas, United States, 75203
      • The Liver Institute at Methodist Dallas
    • Dallas, Texas, United States, 75234
      • Dallas Research Center
    • Dallas, Texas, United States, 75234
      • Liver Center of Texas
    • Dallas, Texas, United States, 75246
      • Texas Digestive Disease Consultants - Dallas - Baylor University Medical Center Gaston Ave
    • Edinburg, Texas, United States, 78539
      • South Texas Research Institute
    • Fort Worth, Texas, United States, 76104
      • Texas Digestive Disease Consultants - Forth Worth - Downtown
    • Houston, Texas, United States, 77030
      • Liver Associates of Texas
    • McAllen, Texas, United States, 78504
      • Doctor's Hospital at Renaissance
    • Plano, Texas, United States, 75093
      • Plano Research Center
    • San Antonio, Texas, United States, 78215
      • Texas Liver Institute/American Research Corporation
    • San Antonio, Texas, United States, 78229
      • Pinnacle Clinical Research - San Antonio
    • San Antonio, Texas, United States, 78229
      • San Antonio Research Center
    • San Marcos, Texas, United States, 78666
      • Texas Digestive Disease Consultants - San Marcos
    • Webster, Texas, United States, 77598
      • Texas Digestive Disease Consultants - Bay Area Houston Endoscopy Center
  • Utah
    • Layton, Utah, United States, 84041
      • Wasatch Peak Family Practice
    • Murray, Utah, United States, 84123
      • Salt Lake City Research Center
  • Virginia
    • Richmond, Virginia, United States, 23226
      • Bon Secours Liver Institute of Richmond
    • Richmond, Virginia, United States, 23294
      • National Clinical Research - Richmond
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University School of Medicine
  • Washington
    • Seattle, Washington, United States, 98105
      • Liver Institute Northwest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 or NAFLD (presumed NASH):

  • Fibroscan with kPa ≥5.5 and <8.5; CAP ≥280 dB.m-1 OR
  • MRE ≥2 and <4.0; MRI-PDFF ≥8% liver fat consistent with steatosis and fibrosis stage ≥1 and <4. OR

  • Recent liver biopsy (within past 2 years) documenting NASH/NAFLD with steatosis showing one of the following:

    • NAS ≥4, steatosis ≥1, fibrosis stage 0 or F1A/1C with PRO-C3 <14
    • NAS <4, steatosis ≥1, with fibrosis stage ≤3

    • NAS ≥4, steatosis ≥1, fibrosis stage ≤3 without ballooning

      • NOTE: Since the completion of enrollment of the double-blind arms, patients meeting all other criteria who have a liver biopsy result from MGL-3196-11 with the following may be enrolled in the open-label active treatment arm of MGL-3196-14 (100 mg dose):

        • NAS = 3, steatosis 1, ballooning 1, inflammation 1 with F2 or F3
        • NAS = 3, ballooning 0 with F2 or F3
      • For the compensated NASH cirrhosis arm, eligible patients must have compensated NASH cirrhosis diagnosed by liver biopsy showing NASH with F4 stage fibrosis (either historic or recent biopsy) or a historic biopsy with NASH F2-F3 fibrosis with subsequent progression to NASH cirrhosis as diagnosed by an expert hepatologist/gastroenterologist.

  • Compensated NASH cirrhosis at screening and baseline includes

    • Child Pugh-A (score 5-6) ( may have either mild hepatic encephalopathy OR mild diuretic responsive ascites OR albumin < 3.5 and ≥ 3.2 (not any two of these, unless explained by Gilbert's Syndrome or non-hepatic causes)).
    • MELD < 12 at screening/baseline unless MELD ≥ 12 based on non-cirrhotic parameters (e.g., elevated INR due to anticoagulation, bilirubin elevation due to documented Gilbert's Syndrome, elevated creatine due to renal disease (non-hepatic)).
    • Albumin ≥ 3.2.
    • Bilirubin < 2 (unless documented Gilbert's Syndrome).
• MRI-PDFF fat fraction ≥8% obtained during the Screening Period (baseline MRI-PDFF) or a historic MRI-PDFF ≤8 weeks old at the time of randomization.
• Stable dyslipidemia therapy for ≥30 days prior to randomization.

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.
• History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.
• Weight gain or loss ≥5% total body weight within 12 weeks prior to randomization.
• HbA1c >9.0%.
• Glucagon-like peptide 1 [GLP-1] agonist therapy or high dose vitamin E (>400 IU/day) unless stable for 24 weeks prior to biopsy.
• Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis.
• Diagnosis of hepatocellular carcinoma (HCC).
• Model for End-stage Liver Disease (MELD) score ≥12, as determined at Screening, unless due to therapeutic anti coagulation or Gilbert syndrome.
• Hepatic decompensation.
• Chronic liver diseases.
• Has an active autoimmune disease.
• Serum ALT >250 U/L.
• History of biliary diversion.
• Uncontrolled hypertension (either treated or untreated).
• 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, prior to randomization.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open label: resmetirom; 100 mg daily	Drug: Resmetirom; Tablet; Other Names: MGL-3196
Placebo Comparator: Double blinded: matching placebo; Placebo daily	Drug: Placebo; Matching tablets
Experimental: Double blinded: resmetirom 80 mg; 80 mg daily	Drug: Resmetirom; Tablet; Other Names: MGL-3196
Experimental: Double blinded: resmetirom 100 mg; 100 mg daily	Drug: Resmetirom; Tablet; Other Names: MGL-3196

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the incidence of adverse events.	The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the incidence of adverse events.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in low density lipoprotein C (LDL-C) from baseline to Week 24	The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in low density lipoprotein C (LDL-C) from baseline to Week 24	24 weeks
The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in apolipoprotein B (ApoB) from baseline to Week 24	The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in apolipoprotein B (ApoB) from baseline to Week 24	24 weeks
The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in hepatic fat fraction as determined by MRI-PDFF from baseline to Week 16.	The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in hepatic fat fraction as determined by MRI-PDFF from baseline to Week 16.	16 weeks
The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in triglycerides (TGs) from baseline to Week 24 in patients with baseline TG > 150 mg/dL.	The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in triglycerides (TGs) from baseline to Week 24 in patients with baseline TG > 150 mg/dL.	24 weeks
The change from baseline to Week 52 in FibroScan vibration controlled transient elastography (kPa)	The change from baseline to Week 52 in FibroScan vibration controlled transient elastography (VCTE) (kPa) in patients with baseline kPa >/=7.2 and a Week 52 or end of treatment FibroScan (VCTE)	52 weeks
The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo after 52 weeks on FibroScan controlled attenuation parameter (CAP)	The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo after 52 weeks on FibroScan controlled attenuation parameter (CAP)	52 weeks

Collaborators and Investigators

• Sponsor: Madrigal Pharmaceuticals, Inc.
• Investigators: Study Director: Rebecca Taub, MD, Madrigal Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2019
• Primary Completion (Actual): January 6, 2023
• Study Completion (Actual): January 6, 2023

Study Registration Dates

• First Submitted: December 11, 2019
• First Submitted That Met QC Criteria: December 11, 2019
• First Posted (Actual): December 13, 2019

Study Record Updates

• Last Update Posted (Actual): September 5, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Fibrosis; Dyslipidemia; Cardiovascular; NAFLD; NASH; Hyperlipidemia; Nonalcoholic steatohepatitis; Cirrhosis; Hepatic; Resmetirom; Thyroid hormone receptor beta; NASH resolution; Thyroid hormone receptor agonist; Fatty liver disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: MGL-3196-14

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No