Clinical trial NCT04197479: A Phase 3 Study to Evaluate Safety and Biomarkers of Resmetirom (MGL-3196) in Non Alcoholic Fatty Liver Disease Patients
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-Alcoholic Fatty Liver Disease
Keywords: NAFLD
NASH
Hyperlipidemia
Resmetirom
Thyroid hormone receptor beta
Hepatic
Fibrosis
NASH resolution
Thyroid hormone receptor agonist
Cardiovascular
Dyslipidemia
Fatty liver disease
Nonalcoholic steatohepatitis
Cirrhosis
Lead sponsor: Madrigal Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2019-12-13
Enrollment: 1343
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: 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).


Eligibility criteria: 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.

Primary outcomes:
measure: The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the incidence of adverse events.
timeFrame: 52 weeks
Secondary outcomes:
measure: 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
timeFrame: 24 weeks
measure: 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
timeFrame: 24 weeks
measure: 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.
timeFrame: 16 weeks
measure: 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.
timeFrame: 24 weeks
measure: The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo after 52 weeks on FibroScan controlled attenuation parameter (CAP)
timeFrame: 52 weeks
measure: The change from baseline to Week 52 in FibroScan vibration controlled transient elastography (kPa)
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Central Research Associates
state: Alabama
city: Chandler
country: United States
facility: Arizona Liver Health - Chandler
state: Arizona
city: Chandler
country: United States
facility: East Valley Family Physicians
state: Arizona
city: Glendale
country: United States
facility: The Institute For Liver Health - Glendale
state: Arizona
city: Mesa
country: United States
facility: Arizona - Desert Clinical Research
state: Arizona
city: Tucson
country: United States
facility: The Institute For Liver Health - Tucson
state: Arizona
city: Tucson
country: United States
facility: Adobe Gastroenterology
state: Arizona
city: North Little Rock
country: United States
facility: Arkansas Gastroenterology
state: Arkansas
city: Fresno
country: United States
facility: Fresno Clinical Research Center
state: California
city: Huntington Park
country: United States
facility: National Research Institute - Huntington Park
state: California
city: Los Angeles
country: United States
facility: Ruane Clinical Research Group
state: California
city: Los Angeles
country: United States
facility: National Research Institute - Los Angeles
state: California
city: Montclair
country: United States
facility: Catalina Research Institute
state: California
city: Panorama City
country: United States
facility: National Research Institute - Panorama City
state: California
city: Poway
country: United States
facility: Alliance Clinical Research
state: California
city: West Hills
country: United States
facility: San Fernando Valley Health Institute
state: California
city: Englewood
country: United States
facility: South Denver Gastroenterology - Swedish Medical Center Office
state: Colorado
city: Boca Raton
country: United States
facility: Excel Medical Clinical Trials
state: Florida
city: Hallandale Beach
country: United States
facility: Velocity Clinical Research, Hallandale Beach (MD Clinical)
state: Florida
city: Hialeah
country: United States
facility: Floridian Clinical Research
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: Lakewood Ranch
country: United States
facility: Florida Research Institute
state: Florida
city: Miami
country: United States
facility: Miami Dade Medical Research Institute
state: Florida
city: Orlando
country: United States
facility: Orlando Research Center
state: Florida
city: Port Orange
country: United States
facility: Progressive Medical Research
state: Florida
city: Sarasota
country: United States
facility: Covenant Research
state: Florida
city: The Villages
country: United States
facility: The Villages Research Center
state: Florida
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: Honolulu
country: United States
facility: East-West Medical Research Institute
state: Hawaii
city: Chicago
country: United States
facility: Chicago Research Center
state: Illinois
city: Chicago
country: United States
facility: Northwestern Memorial Physicians Group
state: Illinois
city: West Des Moines
country: United States
facility: Iowa Diabetes Research
state: Iowa
city: Topeka
country: United States
facility: Kansas Medical Clinic - Gastroenterology
state: Kansas
city: Louisville
country: United States
facility: L-MARC Research Center
state: Kentucky
city: Baton Rouge
country: United States
facility: Digestive Health Center of Louisiana
state: Louisiana
city: Marrero
country: United States
facility: Tandem Clinical Research - New Orleans Area Site
state: Louisiana
city: West Monroe
country: United States
facility: Clinical Trials of America
state: Louisiana
city: Ypsilanti
country: United States
facility: Huron Gastroenterology
state: Michigan
city: Flowood
country: United States
facility: Gastrointestinal Associates & Endoscopy Center - Flowood
state: Mississippi
city: Jackson
country: United States
facility: Southern Therapy and Advanced Research
state: Mississippi
city: Kansas City
country: United States
facility: Kansas City Research Institute
state: Missouri
city: Henderson
country: United States
facility: Henderson Research Center
state: Nevada
city: East Syracuse
country: United States
facility: Clarity Clinical Research
state: New York
city: New York
country: United States
facility: Mount Sinai Health System
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Fayetteville
country: United States
facility: Cumberland Research Associates
state: North Carolina
city: Morehead City
country: United States
facility: Diabetes and Endocrinology Consultants
state: North Carolina
city: Wilmington
country: United States
facility: TMA - Wilmington Gastroenterology Accociates
state: North Carolina
city: Cincinnati
country: United States
facility: Platinum - Sterling Research Group - Springdale
state: Ohio
city: Columbus
country: United States
facility: Aventiv Research Columbus
state: Ohio
city: Marion
country: United States
facility: Awasty Research Network
state: Ohio
city: Bethlehem
country: United States
facility: Northeast Clinical Research Center
state: Pennsylvania
city: Clarksville
country: United States
facility: Premier Medical Group - Clarksville - Dunlop Lane
state: Tennessee
city: Germantown
country: United States
facility: Gastro One - Germantown Office - Wolf Park Drive
state: Tennessee
city: Austin
country: United States
facility: Pinnacle Clinical Research - Austin
state: Texas
city: Dallas
country: United States
facility: The Liver Institute At Methodist Dallas
state: Texas
city: Dallas
country: United States
facility: Dallas Research Center
state: Texas
city: Dallas
country: United States
facility: Liver Center of Texas
state: Texas
city: Dallas
country: United States
facility: Texas Digestive Disease Consultants - Dallas - Baylor University Medical Center Gaston Ave
state: Texas
city: Edinburg
country: United States
facility: South Texas Research Institute
state: Texas
city: Fort Worth
country: United States
facility: Texas Digestive Disease Consultants - Forth Worth - Downtown
state: Texas
city: Houston
country: United States
facility: Liver Associates of Texas
state: Texas
city: McAllen
country: United States
facility: Doctor's Hospital at Renaissance
state: Texas
city: Plano
country: United States
facility: Plano Research Center
state: Texas
city: San Antonio
country: United States
facility: Texas Liver Institute/American Research Corporation
state: Texas
city: San Antonio
country: United States
facility: Pinnacle Clinical Research - San Antonio
state: Texas
city: San Antonio
country: United States
facility: San Antonio Research Center
state: Texas
city: San Marcos
country: United States
facility: Texas Digestive Disease Consultants - San Marcos
state: Texas
city: Webster
country: United States
facility: Texas Digestive Disease Consultants - Bay Area Houston Endoscopy Center
state: Texas
city: Layton
country: United States
facility: Wasatch Peak Family Practice
state: Utah
city: Murray
country: United States
facility: Salt Lake City Research Center
state: Utah
city: Richmond
country: United States
facility: Bon Secours Liver Institute of Richmond
state: Virginia
city: Richmond
country: United States
facility: National Clinical Research - Richmond
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University School of Medicine
state: Virginia
city: Seattle
country: United States
facility: Liver Institute Northwest
state: Washington
city: San Juan
country: Puerto Rico
facility: Fundacion de Investigacion de Diego
Study officials:
affiliation: Madrigal Pharmaceuticals, Inc.
name: Rebecca Taub, MD
role: STUDY_DIRECTOR
References: