A Phase 3 Study to Evaluate Safety and Biomarkers of Resmetirom (MGL-3196) in Non Alcoholic Fatty Liver Disease Patients

Study Overview
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Brief Summary
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A double-blind placebo controlled randomized Phase 3 study to evaluate the safety and tolerability of once-daily, oral administration of 80 or 100 mg resmetirom versus matching placebo. At least 100 patients will be enrolled in a 100 mg open-label arm and will include a special safety population (eg, patients with compensated NASH cirrhosis).

Official Title
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A 52-Week, Phase 3 Study to Evaluate Safety and Biomarkers of Resmetirom (MGL-3196) in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) (MAESTRO-NAFLD-1)

Conditions
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Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: Resmetirom


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be willing to participate in the study and provide written informed consent. Male and female adults ≥18 years of age. Suspected or confirmed diagnosis of NASH or NAFLD (presumed NASH): Fibroscan with kPa ≥5.5 and <8.5; CAP ≥280 dB.m-1 OR MRE ≥2 and <4.0; MRI-PDFF ≥8% liver fat consistent with steatosis and fibrosis stage ≥1 and <4. OR Recent liver biopsy (within past 2 years) documenting NASH/NAFLD with steatosis showing one of the following: NAS ≥4, steatosis ≥1, fibrosis stage 0 or F1A/1C with PRO-C3 <14 NAS <4, steatosis ≥1, with fibrosis stage ≤3 NAS ≥4, steatosis ≥1, fibrosis stage ≤3 without ballooning NOTE: Since the completion of enrollment of the double-blind arms, patients meeting all other criteria who have a liver biopsy result from MGL-3196-11 with the following may be enrolled in the open-label active treatment arm of MGL-3196-14 (100 mg dose): NAS = 3, steatosis 1, ballooning 1, inflammation 1 with F2 or F3 NAS = 3, ballooning 0 with F2 or F3 For the compensated NASH cirrhosis arm, eligible patients must have compensated NASH cirrhosis diagnosed by liver biopsy showing NASH with F4 stage fibrosis (either historic or recent biopsy) or a historic biopsy with NASH F2-F3 fibrosis with subsequent progression to NASH cirrhosis as diagnosed by an expert hepatologist/gastroenterologist. Compensated NASH cirrhosis at screening and baseline includes Child Pugh-A (score 5-6) ( may have either mild hepatic encephalopathy OR mild diuretic responsive ascites OR albumin < 3.5 and ≥ 3.2 (not any two of these, unless explained by Gilbert's Syndrome or non-hepatic causes)). MELD < 12 at screening/baseline unless MELD ≥ 12 based on non-cirrhotic parameters (e.g., elevated INR due to anticoagulation, bilirubin elevation due to documented Gilbert's Syndrome, elevated creatine due to renal disease (non-hepatic)). Albumin ≥ 3.2. Bilirubin < 2 (unless documented Gilbert's Syndrome). MRI-PDFF fat fraction ≥8% obtained during the Screening Period (baseline MRI-PDFF) or a historic MRI-PDFF ≤8 weeks old at the time of randomization. Stable dyslipidemia therapy for ≥30 days prior to randomization. Exclusion Criteria: History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening. Regular use of drugs historically associated with NAFLD. History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study. Weight gain or loss ≥5% total body weight within 12 weeks prior to randomization. HbA1c >9.0%. Glucagon-like peptide 1 [GLP-1] agonist therapy or high dose vitamin E (>400 IU/day) unless stable for 24 weeks prior to biopsy. Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis. Diagnosis of hepatocellular carcinoma (HCC). Model for End-stage Liver Disease (MELD) score ≥12, as determined at Screening, unless due to therapeutic anti coagulation or Gilbert syndrome. Hepatic decompensation. Chronic liver diseases. Has an active autoimmune disease. Serum ALT >250 U/L. History of biliary diversion. Uncontrolled hypertension (either treated or untreated). Active, serious medical disease with a likely life expectancy <2 years. Participation in an investigational new drug trial in the 60 days or 5 half-lives, whichever is longer, prior to randomization. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open label: resmetirom<br>100 mg daily | Drug: Resmetirom<br>* Tablet<br>* Other names: MGL-3196;|
| Placebo Comparator: Double blinded: matching placebo<br>Placebo daily | Drug: Placebo<br>* Matching tablets<br>|
| Experimental: Double blinded: resmetirom 80 mg<br>80 mg daily | Drug: Resmetirom<br>* Tablet<br>* Other names: MGL-3196;|
| Experimental: Double blinded: resmetirom 100 mg<br>100 mg daily | Drug: Resmetirom<br>* Tablet<br>* Other names: MGL-3196;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the incidence of adverse events. | The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the incidence of adverse events. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in low density lipoprotein C (LDL-C) from baseline to Week 24 | The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in low density lipoprotein C (LDL-C) from baseline to Week 24 | 24 weeks | 
| The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in apolipoprotein B (ApoB) from baseline to Week 24 | The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in apolipoprotein B (ApoB) from baseline to Week 24 | 24 weeks | 
| The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in hepatic fat fraction as determined by MRI-PDFF from baseline to Week 16. | The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in hepatic fat fraction as determined by MRI-PDFF from baseline to Week 16. | 16 weeks | 
| The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in triglycerides (TGs) from baseline to Week 24 in patients with baseline TG > 150 mg/dL. | The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo on the percent change in triglycerides (TGs) from baseline to Week 24 in patients with baseline TG > 150 mg/dL. | 24 weeks | 
| The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo after 52 weeks on FibroScan controlled attenuation parameter (CAP) | The effect of once daily, oral administration of 80 or 100 mg resmetirom versus placebo after 52 weeks on FibroScan controlled attenuation parameter (CAP) | 52 weeks | 
| The change from baseline to Week 52 in FibroScan vibration controlled transient elastography (kPa) | The change from baseline to Week 52 in FibroScan vibration controlled transient elastography (VCTE) (kPa) in patients with baseline kPa >/=7.2 and a Week 52 or end of treatment FibroScan (VCTE) | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, NASH, Hyperlipidemia, Resmetirom, Thyroid hormone receptor beta, Hepatic, Fibrosis, NASH resolution, Thyroid hormone receptor agonist, Cardiovascular, Dyslipidemia, Fatty liver disease, Nonalcoholic steatohepatitis, Cirrhosis