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

• ClinicalTrials.gov Identifier: NCT04197479
• Recruitment Status: Completed
• First Posted: December 13, 2019
• Last Update Posted: September 5, 2023
• Sponsor: Madrigal Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Madrigal Pharmaceuticals, Inc.

Tracking Information

• First Submitted Date: December 11, 2019
• First Posted Date: December 13, 2019
• Last Update Posted Date: September 5, 2023
• Actual Study Start Date: December 16, 2019
• Actual Primary Completion Date: January 6, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 28, 2023)

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

The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the incidence of adverse events.

• Original Primary Outcome Measures (submitted: December 11, 2019): The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the incidence of adverse events. [ Time Frame: 52 weeks ]

Current Secondary Outcome Measures (submitted: August 30, 2023)

• 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 [ Time Frame: 24 weeks ]
  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 apolipoprotein B (ApoB) from baseline to Week 24 [ Time Frame: 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 hepatic fat fraction as determined by MRI-PDFF from baseline to Week 16. [ Time Frame: 16 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 triglycerides (TGs) from baseline to Week 24 in patients with baseline TG > 150 mg/dL. [ Time Frame: 24 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 after 52 weeks on FibroScan controlled attenuation parameter (CAP) [ Time Frame: 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 change from baseline to Week 52 in FibroScan vibration controlled transient elastography (kPa) [ Time Frame: 52 weeks ]
  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)

Original Secondary Outcome Measures (submitted: December 11, 2019)

• 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 24 weeks ]
• The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo after 52 weeks on N-terminal type III collagen propeptide (PRO-C3) in patients with baseline PRO-C3 ≥10 ng/mL. [ Time Frame: 52 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Non-Alcoholic Fatty Liver Disease

Intervention

• Drug: Placebo
  Matching tablets
• Drug: Resmetirom
  Tablet
  Other Name: MGL-3196

Study Arms

• Experimental: Open label: resmetirom
  100 mg daily
  Intervention: Drug: Resmetirom
• Placebo Comparator: Double blinded: matching placebo
  Placebo daily
  Intervention: Drug: Placebo
• Experimental: Double blinded: resmetirom 80 mg
  80 mg daily
  Intervention: Drug: Resmetirom
• Experimental: Double blinded: resmetirom 100 mg
  100 mg daily
  Intervention: Drug: Resmetirom

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 28, 2023): 1343
• Original Estimated Enrollment (submitted: December 11, 2019): 700
• Actual Study Completion Date: January 6, 2023
• Actual Primary Completion Date: January 6, 2023 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT04197479
• Other Study ID Numbers: MGL-3196-14
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Madrigal Pharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Madrigal Pharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Madrigal Pharmaceuticals, Inc.
• Verification Date: August 2023