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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.

Study Description
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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

Condition or disease Intervention/treatment Phase
NASH - Nonalcoholic Steatohepatitis Drug: MGL-3196 Drug: Placebo Procedure: Liver Biopsy Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1759 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : March 28, 2019
Estimated Primary Completion Date : January 2028
Estimated Study Completion Date : January 2028

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Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Matching Placebo
Placebo Daily
 Drug: Placebo
Matching Tablets

Procedure: Liver Biopsy
A procedure in which a needle is inserted into the liver to collect a tissue sample
Active Comparator: 80 mg MGL-3196
80 mg daily
 Drug: MGL-3196
Tablet
Other Name: Resmetirom

Procedure: Liver Biopsy
A procedure in which a needle is inserted into the liver to collect a tissue sample
Active Comparator: 100 mg MGL-3196
100 mg daily
 Drug: MGL-3196
Tablet
Other Name: Resmetirom

Procedure: Liver Biopsy
A procedure in which a needle is inserted into the liver to collect a tissue sample


Outcome Measures
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Primary Outcome Measures :
  1. 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

  2. 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).


Secondary Outcome Measures :
  1. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03900429


Locations
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Sponsors and Collaborators
Madrigal Pharmaceuticals, Inc.
Investigators
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Study Director: Rebecca Taub, MD Madrigal Pharmaceuticals, Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Madrigal Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03900429    
Other Study ID Numbers: MGL-3196-11
First Posted: April 3, 2019    Key Record Dates
Last Update Posted: February 20, 2024
Last Verified: February 2024

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases