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

Study Overview
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Brief Summary
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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 patients with biopsy-proven Non-alcoholic Steatohepatitis (NASH).

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

Conditions
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Non-alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: MGL-3196
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria. Patients 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 with a BMI <45 kg/m^2; Female patients 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 (ie, condoms, diaphragm, non hormonal intrauterine device [IUD], or sexual abstinence [only if this is in line with the patient'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 (eg, condoms); OR female patients of non-child bearing potential (ie, surgically [bilateral oophorectomy, hysterectomy, or tubal ligation] or naturally sterile [>12 consecutive months without menses]); Male patients 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 patients 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 PDFF-MRI; Biopsy-proven NASH. Must have had prior liver biopsy within 180 days of randomization with fibrosis stage 1 to 3 and a NAS of ≥4 with at least a score of 1 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) ALT and AST levels consistent with the screening ALT and AST values. Exclusion Criteria. Patients 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; Weight gain or loss >5% in the 6 months prior to randomization or >10% in the 12 months prior to screening; Hyperthyroidism; Patients on thyroid replacement therapy; Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y gastric bypass); Type 1 diabetes; Uncontrolled Type 2 diabetes defined as Hemoglobin A1c ≥ 9.5% at screening (patients 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 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: MGL-3196<br>Study Drug | Drug: MGL-3196<br> <br> |
| Placebo Comparator: Placebo<br>Matching Placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in hepatic fat fraction assessed by MRI-PDFF |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two-point reduction in Non-alcoholic fatty liver disease NASH CRN (NAFLD) activity score (NAS) |  | 36 weeks | 
| Resolution of Non-alcoholic steatohepatitis (NASH) (ballooning = 0; inflammation = 0 to 1) as determined by the NASH CRN NAS score |  | 36 weeks | 
| Improvement in fibrosis by at least 1 stage with no worsening of steatohepatitis |  | 36 weeks | 
| Change from baseline in hepatic fat fraction |  | 36 weeks | 
| Safety and tolerability of MGL-3196 based on Adverse Events and Changes in Laboratory Values |  | 12 and 36 weeks | 
| Effect on high-sensitivity C-reactive protein (hsCRP) |  | 12 and 36 weeks | 
| Effect on serum alanine aminotransferase (ALT) |  | 12 and 36 weeks | 
| Effect on aspartate aminotransferase (AST) |  | 12 and 36 weeks | 
| Effect on lipid parameters | Determine the effect on lipid parameters including low-density lipoprotein cholesterol (LDL-C), non- LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol, triglycerides, apolipoprotein B (ApoB), and lipoprotein(a) (Lp[a]) particles. | 12 and 36 weeks | 
| Effect on NASH and fibrosis biomarkers | Determine the effect on NASH and fibrosis biomarkers including cytokeratin-18 (CK-18), fibrosis-4 (FIB-4), and enhanced liver function (ELF) test. | 12 and 36 weeks |