Non-Alcoholic Steatohepatitis (NASH) MedDRA version: 20.1 Level: PT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Name: resmetirom
Product Code: MGL-3196
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Resmetirom
CAS Number: 920509-32-6
Current Sponsor code: MGL-3196
Concentration unit: mg mi
Sponsors
Madrigal Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Only evaluate patients for study participation if they meet the Prescreening Criteria. Patients who do not initially meet eligibility criteria may be retested, based on Investigator judgment, to determine if they qualify to participate. Patients who meet all of the following criteria will be eligible to participate in the study: 1. Must be willing to participate in the study and provide written informed consent. 2. Male and female adults =18 years of age. 3. Female patients are eligible if they are of reproductive potential and have a negative serum pregnancy test (beta human chorionic gonadotropin), are not breastfeeding, and do not plan to become pregnant during the study and agree to use 2 highly effective birth control methods during the study OR if they are not of child bearing potential (i.e., surgically [bilateral oophorectomy, hysterectomy, or tubal ligation] or naturally sterile [>12 consecutive months without menses]). Highly effective birth control methods include condoms with spermicide, diaphragm with spermicide, hormonal and non-hormonal intrauterine device, hormonal contraception (estrogens stable =3 months), a vasectomized partner, or sexual abstinence (defined as refraining from heterosexual intercourse), throughout the study and for at least 30 days after study drug administration. Reliance on abstinence from heterosexual intercourse is acceptable only if it is the subject’s habitual practice. 4. Male subjects who are sexually active with a partner of child-bearing potential must either be sterile (vasectomy with history of a negative sperm count at least 90 days following the procedure); practice total abstinence from sexual intercourse as the preferred lifestyle (periodic abstinence is not acceptable); use a male condom with any sexual activity; or agree to use a birth control method considered to be appropriate by the Investigator (such as one of the methods identified above for female subjects of childbearing potential) from the time of Screening until 30 days after the last dose of study drug administration. Male subjects must agree not to donate sperm for a period of 30 days after the last dose of study drug administration. 5. Suspected or confirmed diagnosis of NASH suggested by the historical data assessed in the following order. Subjects MUST meet both criterion 5 (a) and (b) BEFORE obtaining an MRI-PDFF (criterion 6) or liver biopsy (criterion 7). a. First: Meet metabolic risk factors and elevated liver enzyme (AST) as part of Prescreening criteria. b. Second: Meet one of the following that is consistent with liver fibrosis: ? Biochemical test for fibrosis: PRO-C3 >14 ng/mL; or ELF =9. ? Fibroscan with transient elastography =8.5 kPa; and controlled attenuation parameter =300 dB.m-1 ? Historical liver biopsy obtained >24 weeks and 5% or medication that might affect NAS or fibrosis stage. NOTE: This biopsy is not eligible for study entry because it was obtained > 24 weeks before expected randomization; however the biopsy is evidence of existing NASH fibrosis. MRI-PDFF fat fraction =8% obtained during the screening period (Baseline MRI-PDFF). NOTE: To be eligible to perform the screening MRI-PDFF (Baseline MRI-PDFF) a patient must first meet Criterion #5, a and b. An eligible MRI-PDFF with fat fraction =8% must be obtained prior to performing the baseline liver biopsy (Criterion #7)
Exclusion criteria
Exclusion criteria: Patients who meet any of the following criteria will be excluded from participation in the study. Patients who do not initially meet eligibility criteria may be retested or rescreened, based on Investigator judgment, to determine if they qualify to participate. 2. Regular use of drugs historically associated with NAFLD, which include but are not limited to the following: amiodarone, methotrexate, systemic glucocorticoids at greater than 5 mg/day, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement or contraception, anabolic steroids except testosterone replacement, valproic acid, and known hepatotoxins for more than 4 weeks within the last 8 weeks prior to the initial Screening. 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. Weight gain or loss =5% total body weight within 12 weeks prior to randomization. 7. Glucagon-like peptide 1 [GLP-1] agonist therapy (e.g., exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide and albiglutide) unless stable dose for 24 weeks prior to biopsy. GLP-1 therapeutics may not be initiated or doses increased during the first 52 weeks of the study. 9. Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis. 10. Diagnosis of hepatocellular carcinoma (HCC). 13. Chronic liver diseases: a. Primary biliary cholangitis b. Primary sclerosing cholangitis c. Hepatitis B positive (as defined in Appendix 3) d. Hepatitis C as defined by presence of hepatitis C virus (HCV) antibody (HCV Ab) or positive HCV RNA (tested for known cured HCV infection, or positive HCV Ab at Screening). NOTE: Patients with positive anti-HCV who test negative for HCV RNA at Screening will be allowed to participate in the study. If prior treatment for HCV, a documented sustained virologic response (SVR) must be available and the patient must have achieved this SVR at least 2 years prior to the qualifying liver biopsy. e. History or evidence of current active autoimmune hepatitis f. History or evidence of primary biliary cholangitis g. History or evidence of primary sclerosing cholangitis h. History or evidence of Wilson's disease i. History or evidence of alpha-1-antitrypsin deficiency j. Evidence of hemochromatosis k. History or evidence of drug-induced liver disease, as defined on the basis of typical exposure and history l. Known bile duct obstruction m. Suspected or proven liver cancer. 15. Serum ALT >250 U/L. NOTE: 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. This consistency is established based on the following: o If the historical and Screening ALT and AST values are both =1.5 × ULN, there is no limit to the difference between the values. o If the historic ALT/AST are >1.5 × elevated and Screening ALT and AST are markedly improved (>50% decreased or normalized) relative to historic, then a third ALT/AST determination will be made during Screening to assure a stable Baseline. o If at least 1 of the values is >1.5 × ULN and the second value is greater than the first value, the difference in the mean of ALT and AST values must be =30%. If the second value is greater than the first value by >30%, a third value assessed >2 weeks after the second value should be determined to confirm lack of worsening trend in ALT/AST. If
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the effect of once-daily, oral administration of 80 or 100 mg MGL 3196 versus matching placebo on NASH, as measured by: 1.The resolution of NASH associated with an at least 2-point reduction in non alcoholic fatty liver disease (NAFLD) activity score (NAS) and without worsening of fibrosis by liver biopsy after 52 weeks of treatment (Week 52 Primary Endpoint) in the Week 52 population (defined as the first 900 F2 and F3 patients randomized, containing at least 450 F3 patients). Resolution includes: •The total absence of ballooning (score = 0) and absent or mild inflammation (score 0 to 1) (associated with an at least 2-point reduction in NAS). •No worsening of fibrosis: worsening of fibrosis is defined as any progression =1 stage. 2.Time to experiencing an adjudicated Composite Clinical Outcome event in all F2 and F3 patients; Final Primary Endpoint, at 54 months. ;Secondary Objective: Key Secondary Objectives: 1.To determine the effect of once-daily, oral administration of 80 or 100 mg MGL-3196 versus matching placebo on the percent change from Baseline at 24 weeks in low-density lipoprotein cholesterol (LDL-C). 2.To determine the effect of once-daily, oral administration of 80 or 100 mg MGL-3196 versus placebo for 52 weeks in patients with biopsy-proven NASH on the histological improvement from Baseline demonstrated by at least a 1-point improvement in fibrosis by liver biopsy with no worsening of NAS (total of three NAS components, ballooning, inflammation and steatosis) (Fibrosis =1 Stage Responder).;Primary end point(s): NASH Resolution Response at Week 52 Time to Composite Clinical Outcome Event at Month 54;Timepoint(s) of evaluation of this end point: Week 52. Month 54 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Percent change from baseline in LDL-C Improvement in Fibrosis without Worsening of NAS Resolution of NASH ;Timepoint(s) of evaluation of this end point: Week 52. Month 54 | — |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Hungary, Israel, Italy, Spain, United Kingdom, United States
Contacts
Public ContactRebecca Taub, MD
Madrigal Pharmaceuticals, Inc.
Outcome results
None listed