A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis (MAESTRO-NASH)

• ClinicalTrials.gov Identifier: NCT03900429
• Recruitment Status: Recruiting
• First Posted: April 3, 2019
• Last Update Posted: December 6, 2022
• Sponsor: Madrigal Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Madrigal Pharmaceuticals, Inc.

Tracking Information

• First Submitted Date: March 26, 2019
• First Posted Date: April 3, 2019
• Last Update Posted Date: December 6, 2022
• Actual Study Start Date: March 28, 2019
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 4, 2022)

• Week 52 Dual Primary Objectives: To determine the effect of 80 or 100 mg MGL-3196 vs matching placebo on liver biopsy (NASH CRN score) at Week 52 compared with Baseline [ Time Frame: 52 weeks ]
  1. Proportion with resolution of NASH (ballooning 0, inflammation 0,1) associated with at least 2-point reduction in NAFLD Activity Score (NAS) without worsening of fibrosis stage OR
  2. Proportion with at least a 1-point improvement in fibrosis stage with no worsening of NAS
• Month 54 Primary Objective: Time to experiencing an adjudicated Composite Clinical Outcome event (Final Primary Endpoint, at 54 months) [ Time Frame: up to 54 months ]
  The Composite Clinical Outcome is composed of all-cause mortality, liver transplant, and significant hepatic events (including hepatic decompensation events [ascites, encephalopathy, or variceal hemorrhage], histological progression to cirrhosis, and a confirmed increase of MELD score from <12 to ≥15).

Original Primary Outcome Measures (submitted: March 30, 2019)

• To evaluate the effect of MGL-3196 80 mg or 100 mg compared to placebo to achieve NASH resolution on liver histology in non-cirrhotic NASH patients with stage 2 or 3 fibrosis [ Time Frame: Measurements at Baseline and 52 weeks ]
  Assessment will be in the first 900 patients, at least 450 F3, and be based on the proportion of MGL-3196 80 mg or 100 mg treated patients relative to placebo achieving NASH resolution (NASH Activity Score (NAS), ballooning =0; lobular inflammation =0,1) with at least a 2 point reduction in NAS and no worsening of fibrosis.
• Composite long-term outcome composed of all-cause mortality, cirrhosis, and liver-related clinical outcomes [ Time Frame: Time frame to acrue a prespecified number of adjudicated events, up to 54 months ]
  To evaluate the effect of MGL-3196 80 mg or 100 mg compared to placebo on composite long-term outcome measured by the number of patients with the onset of any of the adjudicated events, composed of cirrhosis, all-cause mortality, liver-related clinical outcomes.

Current Secondary Outcome Measures (submitted: November 4, 2022)

Week 52 Key Secondary Objective: To determine the effect of once-daily, oral administration of MGL-3196 80 or 100 mg versus matching placebo on the percent change from Baseline at 24 weeks in directly measured low-density lipoprotein cholesterol (LDL-C) [ Time Frame: 24 weeks ]

Assess the effect of MGL-3196 80 mg or 100 mg compared to placebo on LDL-C measured by percent change from Baseline at 24 weeks.

Original Secondary Outcome Measures (submitted: March 30, 2019)

• To determine the effect of once-daily, oral administration of MGL-3196 80 or 100 mg versus matching placebo on the percent change from Baseline at 24 weeks in low-density lipoprotein cholesterol (LDL-C) [ Time Frame: Baseline and 24 weeks ]
• To evaluate the effect of MGL-3196 80 mg or 100 mg compared to placebo to achieve improvement in fibrosis on liver histology in non-cirrhotic NASH patients with stage 2 or 3 fibrosis [ Time Frame: Baseline and 52 weeks ]
  Assessment will be in the first 900 patients, at least 450 F3, and be based on the proportion of MGL-3196 80 mg or 100 mg treated patients relative to placebo achieving at least a 1-point improvement in fibrosis (NASH Clinical Research Network system) by liver biopsy with no worsening of NAS.

• 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 the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis
• Official Title: A Phase 3, Multinational, Double-Blind, Randomized, Placebo-Controlled Study of MGL-3196 (Resmetirom) in Patients With Non-Alcoholic Steatohepatitis (NASH) and Fibrosis to Resolve NASH and Reduce Progression to Cirrhosis and/or Hepatic Decompensation
• Brief Summary: A double-blind placebo controlled randomized Phase 3 study to determine if 80 or 100 mg of MGL-3196 as compared with placebo resolves NASH and/or reduces fibrosis on liver biopsy and prevents progression to cirrhosis and/or advanced liver disease
• Detailed Description: Primary and secondary endpoint population at Week 52 will be at least 900 patients, more than half F3, the remainder F2 and <10% F1B based on final liver biopsy baseline fibrosis score.
• 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: NASH - Nonalcoholic Steatohepatitis

Intervention

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

Study Arms

• Placebo Comparator: Matching Placebo
  Placebo Daily
  Intervention: Drug: Placebo
• Active Comparator: 80 mg MGL-3196
  80 mg daily
  Intervention: Drug: MGL-3196
• Active Comparator: 100 mg MGL-3196
  100 mg daily
  Intervention: Drug: MGL-3196

• Publications *: Harrison SA, Bashir M, Moussa SE, McCarty K, Pablo Frias J, Taub R, Alkhouri N. Effects of Resmetirom on Noninvasive Endpoints in a 36-Week Phase 2 Active Treatment Extension Study in Patients With NASH. Hepatol Commun. 2021 Jan 4;5(4):573-588. doi: 10.1002/hep4.1657. eCollection 2021 Apr.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 30, 2019): 2000
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 2026
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Must be willing to participate in the study and provide written informed consent.
2. Male and female adults ≥ 18 years of age.

3. Suspected or confirmed diagnosis of NASH

   1. Metabolic risk factors and AST > 20 U/L

   2. Criteria consistent with liver fibrosis as defined as one of the following:

      • Biochemical test for fibrosis OR
      • Fibroscan test OR
      • Historical liver biopsy with diagnosis of NASH with fibrosis Stage 2 or 3
4. MRI-PDFF with increased fat fraction

5. Biopsy-proven NASH (Baseline liver biopsy) based on a liver biopsy obtained within 24 weeks before anticipated date of randomization (if the biopsy is deemed acceptable for interpretation by the central reader) with fibrosis stage 1A, 1B, 2, or 3 on liver biopsy and NAS of ≥ 4 with a score of at least 1 in each of the following NAS components:

   1. Steatosis (scored 0 to 3)
   2. Ballooning degeneration (scored 0 to 2)
   3. Lobular inflammation (scored 0 to 3)

Exclusion Criteria:

1. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening.
2. Regular use of drugs historically associated with NAFLD
3. History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.
4. Recent significant weight gain or loss
5. HbA1c ≥ 9.0%.
6. Glucagon-like peptide 1 [GLP-1] agonist, high dose Vitamin E (> 400 IU/day), or pioglitazone therapy unless stable dose for 24 weeks prior to biopsy.
7. Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis.
8. Diagnosis of hepatocellular carcinoma (HCC).
9. MELD score ≥12, as determined at Screening, unless due to therapeutic anti coagulation.
10. Hepatic decompensation
11. Chronic liver diseases other than NASH
12. Active autoimmune disease
13. Serum ALT > 250 U/L.
14. Active, serious medical disease with a likely life expectancy < 2 years.
15. Participation in an investigational new drug trial in the 60 days or 5 half-lives, whichever is longer.
16. 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: Kimberly Dorney, RN, MSN; 267-520-0252; info@madrigalpharma.com

• Listed Location Countries: Australia, Austria, Belgium, Canada, France, Germany, Hungary, Israel, Italy, Poland, Puerto Rico, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03900429
• Other Study ID Numbers: MGL-3196-11
• 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: November 2022