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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03900429
Recruitment Status : Active, not recruiting
First Posted : April 3, 2019
Last Update Posted : February 20, 2024
Sponsor:
Information provided by (Responsible Party):
Madrigal Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE March 26, 2019
First Posted Date  ICMJE April 3, 2019
Last Update Posted Date February 20, 2024
Actual Study Start Date  ICMJE March 28, 2019
Estimated Primary Completion Date January 2028   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 11, 2023)
  • 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 gastroesophageal variceal hemorrhage], histological progression to cirrhosis, and a confirmed increase of MELD score from <12 to ≥15).
Original Primary Outcome Measures  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis
Official Title  ICMJE 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 fibrosis score 3 (F3), the remainder fibrosis score 2 (F2) and <10% fibrosis score F1B (F1B) based on final liver biopsy baseline fibrosis score.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE NASH - Nonalcoholic Steatohepatitis
Intervention  ICMJE
  • Drug: MGL-3196
    Tablet
    Other Name: Resmetirom
  • Drug: Placebo
    Matching Tablets
  • Procedure: Liver Biopsy
    A procedure in which a needle is inserted into the liver to collect a tissue sample
Study Arms  ICMJE
  • Placebo Comparator: Matching Placebo
    Placebo Daily
    Interventions:
    • Drug: Placebo
    • Procedure: Liver Biopsy
  • Active Comparator: 80 mg MGL-3196
    80 mg daily
    Interventions:
    • Drug: MGL-3196
    • Procedure: Liver Biopsy
  • Active Comparator: 100 mg MGL-3196
    100 mg daily
    Interventions:
    • Drug: MGL-3196
    • Procedure: Liver Biopsy
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 11, 2023)
1759
Original Estimated Enrollment  ICMJE
 (submitted: March 30, 2019)
2000
Estimated Study Completion Date  ICMJE January 2028
Estimated Primary Completion Date January 2028   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 fibrosis suggested by the historical data. Meet one of the following criteria that is consistent with NASH liver fibrosis:

    1. Historical biochemical test for fibrosis: PRO-C3 >14 ng/mL or ELF ≥9
    2. FibroScan with transient elastography ≥8.5 kPa and controlled attenuation parameter ≥280 dB.m-1
    3. Historical liver biopsy obtained <2 years before expected randomization showing Stage 1B, 2 or 3 fibrosis with NASH based on existing pathology review, with no significant change in body weight >5% or medication that might affect NAS or fibrosis stage.
  4. MRI-PDFF fat fraction ≥8% obtained during the screening period
  5. Biopsy-proven NASH (baseline liver biopsy) based on a liver biopsy obtained ≤6 months before anticipated date of randomization (if the biopsy is deemed acceptable for interpretation by the central reader) with fibrosis stage 1A/1C, 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. Thyroid diseases:

    1. Active hyperthyroidism.
    2. Untreated clinical hypothyroidism defined by thyroid stimulating hormone (TSH) >7 IU/L with symptoms of hypothyroidism or >10 IU/L without symptoms.
    3. Patients who have had a thyroidectomy and are on replacement thyroxine doses >75 µg per day are allowed.
  4. History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.
  5. Recent significant weight gain or loss
  6. HbA1c ≥ 9.0%.
  7. 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.
  8. Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis.
  9. Diagnosis of hepatocellular carcinoma (HCC).
  10. MELD score ≥12, as determined at Screening, unless due to therapeutic anti coagulation.
  11. Hepatic decompensation
  12. Chronic liver diseases other than NASH
  13. Active autoimmune disease
  14. Serum ALT > 250 U/L.
  15. Active, serious medical disease with a likely life expectancy < 2 years.
  16. Participation in an investigational new drug trial in the 60 days or 5 half-lives, whichever is longer.
  17. 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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   France,   Germany,   Hungary,   Israel,   Italy,   Mexico,   Poland,   Puerto Rico,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03900429
Other Study ID Numbers  ICMJE 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  ICMJE Not Provided
Current Responsible Party Madrigal Pharmaceuticals, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Madrigal Pharmaceuticals, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Rebecca Taub, MD Madrigal Pharmaceuticals, Inc.
PRS Account Madrigal Pharmaceuticals, Inc.
Verification Date February 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP