NASH - Nonalcoholic Steatohepatitis
Conditions
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.
Interventions
DRUGMGL-3196
Tablet
DRUGPlacebo
Matching Tablets
PROCEDURELiver Biopsy
A procedure in which a needle is inserted into the liver to collect a tissue sample
Sponsors
Madrigal Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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. |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Hungary, Israel, Italy, Mexico, Poland, Puerto Rico, Spain, Switzerland, United Kingdom, United States
Outcome results
None listed