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

Madrigal Pharmaceuticals

Status and phase: Active, not recruiting; Phase 3

Conditions: NASH - Nonalcoholic Steatohepatitis

Treatments: Procedure: Liver Biopsy; Drug: MGL-3196; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT03900429

MGL-3196-11

Details and patient eligibility

About

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

Full 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.

Enrollment: 1,759 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1,759 participants in 3 patient groups, including a placebo group

Matching Placebo

Placebo Comparator group

Description:

Placebo Daily

Treatment:

Drug: Placebo

Procedure: Liver Biopsy

80 mg MGL-3196

Active Comparator group

Description:

80 mg daily

Treatment:

Drug: MGL-3196

Procedure: Liver Biopsy

100 mg MGL-3196

Active Comparator group

Description:

100 mg daily

Treatment:

Drug: MGL-3196

Procedure: Liver Biopsy