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

Madrigal Pharmaceuticals, Inc.125 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

125

Conditions

Non-alcoholic Steatohepatitis

Interventions

MGL-3196DRUG

PlaceboDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (26)

Madrigal Research Site

Dothan, Alabama, United States

Outcomes

Primary Outcomes

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.

Time frame: Week 12

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Week 36

Data from ClinicalTrials.gov

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Madrigal Research Site

Tucson, Arizona, United States

Madrigal Research Site

Coronado, California, United States

Madrigal Research Site

Los Angeles, California, United States

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

Englewood, Colorado, United States

Madrigal Research Site

Boca Raton, Florida, United States

Madrigal Research Site

Lakewood Rch, Florida, United States

...and 16 more locations

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: Week 36

Percentage Of Participants With A Reduction In Hepatocellular Steatosis At Week 36

Time frame: Week 36

Percentage Of Participants With A Reduction In Lobular Inflammation At Week 36

Time frame: Week 36

Percentage Of Participants With A Reduction In Hepatocellular Ballooning At Week 36

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Week 12

Change From Baseline To Week 36 In ALT

Blood samples were collected to determine the effect of MGL-3196 on serum ALT.

Time frame: 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.

Time frame: Week 12

Change From Baseline To Week 36 In AST

Blood samples were collected to determine the effect of MGL-3196 on serum AST.

Time frame: 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).

Time frame: 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.

Time frame: 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).

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: Week 12 and Week 36

Change From Baseline of Thyrotropin at Week 12

Thyrotropin (TSH) was assessed at each study visit.