Phase 2 Study of MGL-3196 in Patients With Non-Alcoholic Steatohepatitis (NASH)

A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-controlled Study of MGL-3196 in Patients With Non-alcoholic Steatohepatitis

The primary objective of this study is to determine the effect of once-daily oral MGL-3196 on the percent change in hepatic fat fraction from baseline in participants with biopsy-proven Non-alcoholic Steatohepatitis (NASH).

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Steatohepatitis
• Intervention / Treatment: Drug: Placebo; Drug: MGL-3196

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Dothan, Alabama, United States
      • Madrigal Research Site
  • Arizona
    • Tucson, Arizona, United States
      • Madrigal Research Site
  • California
    • Coronado, California, United States
      • Madrigal Research Site
    • Los Angeles, California, United States, 90057
      • Madrigal Research Site
    • Rialto, California, United States
      • Madrigal Research Site
    • San Diego, California, United States
      • Madrigal Research Site
    • Ventura, California, United States
      • Madrigal Research Site
  • Colorado
    • Englewood, Colorado, United States
      • Madrigal Research Site
  • Florida
    • Boca Raton, Florida, United States
      • Madrigal Research Site
    • Lakewood Rch, Florida, United States
      • Madrigal Research Site
    • Lauderdale Lakes, Florida, United States
      • Madrigal Research Site
    • Miami, Florida, United States
      • Madrigal Research Site
    • New Port Richey, Florida, United States
      • Madrigal Research Site
  • Kansas
    • Kansas City, Kansas, United States
      • Madrigal Research Site
  • Louisiana
    • Monroe, Louisiana, United States
      • Madrigal Research Site
  • Maryland
    • Baltimore, Maryland, United States
      • Madrigal Research Site
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • Madrigal Research Site
  • Missouri
    • St Louis, Missouri, United States
      • Madrigal Research Site
  • New Mexico
    • Albuquerque, New Mexico, United States
      • Madrigal Research Site
  • New York
    • New York, New York, United States
      • Madrigal Research Site
  • North Carolina
    • Durham, North Carolina, United States
      • Madrigal Research Site
  • South Dakota
    • Rapid City, South Dakota, United States
      • Madrigal Research Site
  • Texas
    • Live Oak, Texas, United States, 78233
      • Madrigal Research Site
    • San Antonio, Texas, United States
      • Madrigal Research Site
  • Virginia
    • Charlottesville, Virginia, United States
      • Madrigal Research Site
  • Washington
    • Seattle, Washington, United States
      • Madrigal Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria. Participants who meet all of the following criteria will be eligible to participate in the study:

• Must be willing to participate in the study and provide written informed consent;
• Male and female adults ≥18 years of age;
• Female participants of child bearing potential with negative serum pregnancy (beta human chorionic gonadotropin) tests who are not breastfeeding, do not plan to become pregnant during the study, and agree to use effective birth control (that is, condoms, diaphragm, nonhormonal intrauterine device [IUD], or sexual abstinence [only if this is in line with the participant's current lifestyle]) throughout the study and for at least 1 month after study completion; hormonal contraception (estrogens stable ≥3 months) and hormonal IUDs are permitted if used with a secondary birth control measure (for example, condoms); or female participants of non-child bearing potential (that is, surgically [bilateral oophorectomy, hysterectomy, or tubal ligation] or naturally sterile [>12 consecutive months without menses]); Male participants who have sexual intercourse with a female partner of child bearing potential from the first dose of study drug until 1 month after study completion must be either surgically sterile (confirmed by documented azoospermia >90 days after the procedure) or agree to use a condom with spermicide. All male participants must agree not to donate sperm from the first dose of study drug until 1 month after study completion;
• Must have confirmation of ≥10% liver fat content on magnetic resonance imaging proton density fat fraction;

• Biopsy-proven NASH. Must have had prior liver biopsy within 180 days of randomization with fibrosis stage 1 to 3 and a non-alcoholic fatty liver disease activity score (NAS) of ≥4 with a score of 1 or more in each of the following NAS components:

  • Steatosis (scored 0 to 3),
  • Ballooning degeneration (scored 0 to 2), and
  • Lobular inflammation (scored 0 to 3);
• Must have documented historical (3 weeks to 6 months prior to the study entry) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels consistent with the screening ALT and AST values.

Exclusion Criteria. Participants who meet any of the following criteria will be excluded from participation in the study:

Note: Unless otherwise specified, repeat testing may be performed in consultation with the Medical Monitor.

• History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening;
• Hyperthyroidism;
• Participants on thyroid replacement therapy (with exceptions);
• Prior or planned (during the study period) bariatric surgery (for example, gastroplasty, roux-en-Y gastric bypass);
• Type 1 diabetes;
• Uncontrolled Type 2 diabetes defined as Hemoglobin A1c (HbA1c) ≥ 9.5% at screening (participants with HbA1c ≥ 9.5% may be rescreened);
• Use of obeticholic acid, ursodeoxycholic acid (Ursodiol® and Urso®), high dose vitamin E (>400 IU/day) unless on stable dose of vitamin E >400 IU/day for at least 6 months at the time of liver biopsy, or pioglitazone within 90 days prior to enrollment or since screening biopsy, whichever is longer;
• Presence of cirrhosis on liver biopsy (stage 4 fibrosis);
• Platelet count < 140,000/mm^3;
• Clinical evidence of hepatic decompensation;
• Evidence of other forms of chronic liver disease;
• Active, serious medical disease with likely life expectancy <2 years;
• Participation in an investigational new drug trial in the 30 days prior to randomization; or
• Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, compromise the well-being of the participant, or interfere with the study outcomes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching Placebo	Drug: Placebo
Experimental: MGL-3196; Study Drug	Drug: MGL-3196

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline To Week 12 In Hepatic Fat Fraction Assessed By Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF)	The primary endpoint was relative change in MRI-PDFF assessed hepatic fat fraction compared with placebo at Week 12 in participants who had both a baseline and Week 12 MRI-PDFF. Least squares (LS) mean was provided for the statistical comparison of MGL-3196 versus placebo.	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Of Participants With Adverse Events (AEs)	An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.	Week 12 and Week 36
Percent Change From Baseline To Week 36 In Hepatic Fat Fraction Assessed By MRI-PDFF	The endpoint was relative change assessed hepatic fat fraction compared with placebo at Week 36. LS mean was provided for the statistical comparison of MGL-3196 versus placebo.	Week 36
Change From Baseline To Week 12 In Absolute Hepatic Fat Fraction Assessed By MRI-PDFF	The endpoint was change in MRI-PDFF assessed absolute hepatic fat fraction compared with placebo at Week 12. LS mean was provided for the comparison of MGL-3196 versus placebo.	Week 12
Change From Baseline To Week 36 In Absolute Hepatic Fat Fraction Assessed By MRI-PDFF	The endpoint was change in assessed absolute hepatic fat fraction compared with placebo at Week 36. LS mean was provided for the comparison of MGL-3196 versus placebo.	Week 36
Percentage Of Participants With At Least 30% Relative Fat Reduction at Week 12	The endpoint presented the percentage of participants achieving a relative fat reduction of ≥30% at Week 12.	Week 12
Percentage Of Participants With At Least 30% Relative Fat Reduction At Week 36	The endpoint presented the percentage of participants achieving a relative fat reduction of ≥30% at Week 36.	Week 36
Percentage Of Participants Achieving A 1-Point Reduction In Non-alcoholic Fatty Liver Disease Activity Score (NAS) At Week 36	The NAS is a histologic scale for non-alcoholic steatohepatitis (NASH) activity, which combines into a single score steatosis (Grade 0 to 3), ballooning (Grade 0 to 2), and lobular inflammation (Grade 0 to 3). The endpoint presented the percentage of participants with a 1-point or greater reduction in NAS.	Week 36
Percentage Of Participants Achieving A 2-Point Reduction In NAS At Week 36	The NAS is a histologic scale for NASH activity, which combines into a single score steatosis (Grade 0 to 3), ballooning (Grade 0 to 2), and lobular inflammation (Grade 0 to 3). The endpoint presented the percentage of participants with a 2-point or greater reduction in NAS.	Week 36
Percentage Of Participants Achieving A 2-Point Reduction In NAS And Either A ≥1-Point Reduction In Lobular Inflammation Or Hepatocellular Ballooning At Week 36	The NAS is a histologic scale for NASH activity, which combines into a single score steatosis (Grade 0 to 3), ballooning (Grade 0 to 2), and lobular inflammation (Grade 0 to 3). The endpoint presented the percentage of participants with a 2-point or greater reduction in NAS and a 1-point or greater reduction in lobular inflammation or hepatocellular ballooning.	Week 36
Percentage Of Participants Achieving A 2-Point Reduction In NAS Without Fibrosis Worsening At Week 36	The NAS is a histologic scale for NASH activity, which combines into a single score steatosis (Grade 0 to 3), ballooning (Grade 0 to 2), and lobular inflammation (Grade 0 to 3). Fibrosis stage (0 to 3) was also included in the assessment. The endpoint presented the percentage of participants with a 2-point or greater reduction in NAS without worsening fibrosis.	Week 36
Percentage Of Participants With A Reduction In Hepatocellular Steatosis At Week 36	The NAS is a histologic scale for NASH activity, which combines into a single score steatosis (Grade 0 to 3), ballooning (Grade 0 to 2), and lobular inflammation (Grade 0 to 3). The endpoint presented the percentage of participants with a reduction in hepatocellular steatosis.	Week 36
Percentage Of Participants With A Reduction In Lobular Inflammation At Week 36	The NAS is a histologic scale for NASH activity, which combines into a single score steatosis (Grade 0 to 3), ballooning (Grade 0 to 2), and lobular inflammation (Grade 0 to 3). The endpoint presented the percentage of participants with a reduction in lobular inflammation.	Week 36
Percentage Of Participants With A Reduction In Hepatocellular Ballooning At Week 36	The NAS is a histologic scale for NASH activity, which combines into a single score steatosis (Grade 0 to 3), ballooning (Grade 0 to 2), and lobular inflammation (Grade 0 to 3). The endpoint presented the percentage of participants with a reduction in hepatocellular ballooning.	Week 36
Percentage Of Participants Achieving NASH Resolution With At Least 2-Point Reduction In NAS At Week 36	The endpoint presented the percentage of participants achieving NASH resolution with a 2-point reduction at Week 36.	Week 36
Percent Change From Baseline To Week 12 In High-sensitivity C-reactive Protein (hsCRP)	hsCRP was used as a non-invasive inflammation marker for this study. Blood samples were collected to determine the effect of MGL-3196 on hsCRP.	Week 12
Percent Change From Baseline To Week 36 In hsCRP	hsCRP was used as a non-invasive inflammation marker for this study. Blood samples were collected to determine the effect of MGL-3196 on hsCRP.	Week 36
Change From Baseline To Week 12 In Serum Alanine Aminotransferase (ALT)	Blood samples were collected to determine the effect of MGL-3196 on serum ALT.	Week 12
Change From Baseline To Week 36 In ALT	Blood samples were collected to determine the effect of MGL-3196 on serum ALT.	Week 36
Change From Baseline To Week 12 In Serum Aspartate Aminotransferase (AST)	Blood samples were collected to determine the effect of MGL-3196 on serum AST.	Week 12
Change From Baseline To Week 36 In AST	Blood samples were collected to determine the effect of MGL-3196 on serum AST.	Week 36
Percent Change From Baseline To Week 12 In Lipid Parameters	Blood samples were collected to determine the effect of MGL-3196 on lipid parameters including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), triglycerides (TG), apolipoprotein B (ApoB), and Apolipoprotein CIII (ApoCIII).	Week 12
Percent Change From Baseline To Week 36 In Lipid Parameters	Blood samples were collected to determine the effect of MGL-3196 on lipid parameters including LDL-C, HDL-C, non-HDL-C, TC, TG, ApoB, and ApoCIII.	Week 36
Percent Change From Baseline To Week 12 In Lipid Parameter Lipoprotein(a) (Lp[a])	Blood samples were collected to determine the effect of MGL-3196 on lipid parameter Lp(a).	Week 12
Percent Change From Baseline To Week 36 In Lipid Parameter Lp[a]	Blood samples were collected to determine the effect of MGL-3196 on lipid parameter Lp(a).	Week 36
Change From Baseline To Week 12 And Week 36 In Cytokeratin-18 (CK-18)	Serum CK-18 fragments, detected using the M30 antibody, is a non-invasive biomarker for NASH that may reflect hepatocyte apoptosis.	Week 12 and Week 36
Change From Baseline To Week 12 And Week 36 In Enhanced Liver Fibrosis (ELF) Test	The ELF Test is a non-invasive blood test that provides a simple, unitless numeric score that is used as a marker of collagen formation and fibrogenic activity and can be used to assess the risk of progression to cirrhosis. Scores below 9.8 indicate low risk of disease progression, and scores above 11.29 indicate high risk. The ELF score is derived from values of three serum biomarkers: hyaluronic acid (HA), procollagen III N-terminal peptide (PIIINP), and tissue inhibitor of metalloproteinase-1 (TIMP-1). The formula is 2.278 + 0.851 × ln(HA) + 0.751 × ln(PIIINP) + 0.394 × ln(TIMP-1); there are no minimum or maximum values.	Week 12 and Week 36
Change From Baseline To Week 12 And Week 36 In Fibrosis-4 (Fib-4) Score	The Fib-4 score is a scoring system used to estimate the amount of scarring in the liver. It is based on common clinical parameters (age, AST, ALT, and platelets) and has been shown to have the best diagnostic accuracy for advanced fibrosis when compared with other noninvasive clinical scores. Scores are categorized into low (<1.30), indeterminate (1.30-2.67), or high (>2.67) risk of fibrosis. The formula for Fib-4 is: (Age [yr] x AST [U/L]) / ((PLT [109/L]) x (ALT [U/L])½); there are no minimum or maximum values	Week 12 and Week 36
Change From Baseline of Thyrotropin at Week 12	Thyrotropin (TSH) was assessed at each study visit.	Baseline up to Week 12
Change From Baseline of Total Thyroxine at Week 12	Total thyroxine (FT4) was assessed at each study visit.	Baseline up to Week 12
Change From Baseline of Free Thyroxine at Week 12	Free thyroxine (FT4) was assessed at each study visit.	Baseline up to Week 12
Change From Baseline of Total Triiodothyronine at Week 12	Total Triiodothyronine (T3) was assessed at each study visit.	Baseline up to Week 12
Change From Baseline of Free Triiodothyronine at Week 12	Free triiodothyronine (T3) was assessed at each study visit.	Baseline up to Week 12
Change From Baseline of Thyroxine Binding Globulin at Week 12	Thyroxine Binding Globulin was assessed at each study visit.	Baseline up to Week 12
Change From Baseline of Reverse Triiodothyronine Globulin at Week 12	Reverse Triiodothyronine (T3) was assessed at each study visit.	Baseline up to Week 12
Change From Baseline of Thyrotropin at Week 36	Tyrotropin (TSH) was assessed at each study visit.	Baseline up to Week 36
Change From Baseline of Total Thyroxine at Week 36	Total thyroxine (FT4), thyrotropin (TSH) was assessed at each study visit.	Baseline up to Week 36
Change From Baseline of Free Thyroxine Week 36	Total free thyroxine (FT4) was assessed at each study visit.	Baseline up to Week 36
Change From Baseline of Total Triiodothyronine at Week 36	Total triiodothyronine (T3) was assessed at each study visit.	Baseline up to Week 36
Change From Baseline of Free Triiodothyronine at Week 36	Free triiodothyronine (T3) was assessed at each study visit.	Baseline up to Week 36
Change From Baseline of Thyroxine-Binding Globulin at Week 36	Thyroxine-binding globulin (TBG) was assessed at each study visit.	Baseline up to Week 36
Change From Baseline of Reverse Triiodothyronine at Week 36	Reverse triiodothyronine (T3) was assessed at each study visit.	Baseline up to Week 36

Collaborators and Investigators

• Sponsor: Madrigal Pharmaceuticals, Inc.

Publications and helpful links

General 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.
• Younossi ZM, Stepanova M, Taub RA, Barbone JM, Harrison SA. Hepatic Fat Reduction Due to Resmetirom in Patients With Nonalcoholic Steatohepatitis Is Associated With Improvement of Quality of Life. Clin Gastroenterol Hepatol. 2022 Jun;20(6):1354-1361.e7. doi: 10.1016/j.cgh.2021.07.039. Epub 2021 Jul 27.
• Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140-6736(19)32517-6. Epub 2019 Nov 11.
• Harrison SA, Ratziu V, Anstee QM, Noureddin M, Sanyal AJ, Schattenberg JM, Bedossa P, Bashir MR, Schneider D, Taub R, Bansal M, Kowdley KV, Younossi ZM, Loomba R. Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2024 Jan;59(1):51-63. doi: 10.1111/apt.17734. Epub 2023 Oct 2.

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2016
• Primary Completion (Actual): October 25, 2017
• Study Completion (Actual): November 23, 2021

Study Registration Dates

• First Submitted: September 19, 2016
• First Submitted That Met QC Criteria: September 20, 2016
• First Posted (Estimated): September 23, 2016

Study Record Updates

• Last Update Posted (Estimated): December 23, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; resmetirom
• Other Study ID Numbers: MGL-3196-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO