Phase 3 Multinational Study of Resmetirom in Non-Alcoholic Steatohepatitis Patients to Assess NASH Resolution and Fibrosis Progression Prevention
- Trial ID
- 2024-510626-89-00
- Protocol
- MGL-3196-11
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, multinational, double-blind, randomized, placebo-controlled study is to evaluate the efficacy of once-daily oral administration of **MGL-3196** (resmetirom) at doses of 80 mg or 100 mg in patients with **Non-Alcoholic Steatohepatitis (NASH)**. The study aims to assess the resolution of NASH, characterized by at least a 2-point reduction in the NAFLD activity score (NAS) without worsening of fibrosis, as determined by liver biopsy after 52 weeks of treatment. Additionally, the study seeks to demonstrate histological improvement from baseline, indicated by at least a 1-point improvement in fibrosis without worsening of NAS at Week 52. These objectives are clinically relevant as they address the potential of MGL-3196 to halt or reverse liver damage in NASH, a condition that can progress to cirrhosis and hepatic decompensation.
The secondary objective focuses on determining the effect of MGL-3196 on the percent change from baseline in directly measured low-density lipoprotein cholesterol (LDL-C) at 24 weeks, compared to placebo. This objective is crucial for understanding the broader metabolic effects of MGL-3196, which may contribute to cardiovascular risk reduction in patients with NASH.
Participants
The clinical trial involves a total of **1315 participants** diagnosed with **Non-Alcoholic Steatohepatitis (NASH)**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on a suspected or confirmed diagnosis of NASH fibrosis, supported by historical biochemical tests, FibroScan results, or liver biopsy data. The trial includes individuals who are considered part of a vulnerable population. Participants' general health status is characterized by the presence of NASH, and they must meet specific criteria related to liver fibrosis and fat fraction as determined by MRI-PDFF. Lifestyle considerations such as diet and physical activity are not explicitly detailed in the trial data. Key inclusion criteria require participants to provide written informed consent and, for females of reproductive potential, to adhere to specific birth control measures. The trial does not specify any exclusion criteria in the provided data.
Plans and Procedures
The clinical trial is a **Phase 3**, multinational, double-blind, randomized, placebo-controlled study designed to evaluate the safety and effectiveness of **resmetirom** in patients with **Non-Alcoholic Steatohepatitis (NASH)** and fibrosis. The primary objective is to assess the effect of once-daily oral administration of 80 mg or 100 mg MGL-3196 compared to a matching placebo on the resolution of NASH and reduction in fibrosis progression over a 52-week period. The trial also aims to evaluate the time to experiencing a composite clinical outcome event by Month 54. The study is expected to conclude by January 30, 2029, with recruitment having commenced on September 30, 2019.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, willingness to provide informed consent, and a suspected or confirmed diagnosis of NASH fibrosis. The screening process includes a **MRI-PDFF** fat fraction assessment and, if necessary, a liver biopsy. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy endpoints, including a liver biopsy at Week 52 to assess NASH resolution and fibrosis improvement. The end-of-study visit will occur at Month 54, where the primary endpoint of time to composite clinical outcome event will be evaluated.
The expected duration of participant involvement is up to 54 months, with the possibility of early termination if participants experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial includes an open-label extension (OLE) phase for participants who complete all protocol-specified visits and the scheduled second liver biopsy at Month 54, allowing for the collection of long-term safety data and response measures for resmetirom. Participants in the OLE phase must provide additional informed consent to continue their involvement in the study.
Treatment
The clinical trial involves the administration of **MGL-3196**, known as **resmetirom**, which is a chemical compound provided in the form of a **film-coated tablet**. The trial includes three different dosages of resmetirom: 60 mg, 80 mg, and 100 mg. Each dosage is administered orally once daily. The maximum daily dose for each participant is 100 mg, with a total maximum dose of 97.20 g for the 60 mg tablet, 129.60 g for the 80 mg tablet, and 162 g for the 100 mg tablet over the course of the trial. The treatment period extends up to 104 weeks. Resmetirom is designed to target patients with **Non-Alcoholic Steatohepatitis (NASH)** and fibrosis, aiming to resolve NASH and reduce progression to cirrhosis and/or hepatic decompensation.
In addition to the experimental medication, the study employs a **matching placebo** for each dosage of resmetirom. The placebo is also provided in the form of a film-coated tablet, matching the 60 mg, 80 mg, and 100 mg dosages of the active drug. The placebo is administered orally once daily, following the same schedule as the active treatment. The use of a placebo allows for a double-blind, randomized, placebo-controlled study design, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thus maintaining the integrity of the trial results.
Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. This monitoring is crucial for the accurate assessment of the drug's efficacy and safety. The trial's primary objectives include evaluating the resolution of NASH and histological improvement in fibrosis after 52 weeks of treatment, as well as assessing long-term safety and response measures beyond 54 months.
Efficacy
The efficacy of the clinical trial will be assessed through a series of predefined endpoints aimed at evaluating the impact of MGL-3196 (resmetirom) on patients with Non-Alcoholic Steatohepatitis (NASH) and fibrosis. The primary endpoints include the resolution of NASH, characterized by an at least 2-point reduction in the NAFLD activity score (NAS) without worsening of fibrosis, as determined by liver biopsy after 52 weeks of treatment. This resolution is defined by the absence of ballooning (score = 0) and absent or mild lobular inflammation (score 0 to 1), along with no progression of fibrosis by at least one stage. Additionally, histological improvement from baseline will be assessed by at least a 1-point improvement in fibrosis without worsening of NAS at Week 52.
Secondary endpoints will focus on the percent change from baseline in directly measured LDL-C at Week 24 and Week 52. The trial will also evaluate the time to experiencing an adjudicated Composite Clinical Outcome event by Month 54. Efficacy assessments will be conducted using liver biopsies and laboratory tests at specified timepoints, including Week 52 and Month 54, to ensure comprehensive evaluation of the treatment's impact. The study aims to provide insights into the long-term safety and efficacy of resmetirom, with data collection extending beyond 54 months to align with real-world practice.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Must be willing to participate in the study and provide written informed consent
- Male and female adults ≥18 years of age.
- Female patients are eligible if they are of reproductive potential and have a negative serum pregnancy test, are not breastfeeding, and do not plan to become pregnant during the study and agree to use 2 highly effective birth control methods (HEBCM) during the study and for at least 30 days after study drug administration OR if they are not of child bearing potential. A woman is considered of childbearing potential (WOCP) i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal (PM) state is defined as no menses for 12 months without an alternative medical cause. A high folicle stimulating hormone (FSH) level in the PM range may be used to confirm PM state in women not using hormonal contraception (HC) or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. HEBCM include: Combined (and progestogen containing HC associated with inhibition of ovulation: oral, intravaginal, transdermal; Progestogen-only HC associated with inhibition of ovulation: oral, injectable, implantable; Intrauterine device); Intrauterine hormone-releasing system; Bilateral tubal occlusion; Vasectomized partner provided that the partner is the sole sexual partner of the trial participant, and that the partner has received medical assessment of the surgical process; Sexual abstinence
- Male subjects who are sexually active with a partner of child-bearing potential must either be sterile; 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 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.
- 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: • Historical biochemical test for fibrosis: PRO-C3 >14 ng/mL; or ELF ≥ 9 • FibroScan with transient elastography ≥8.5 kPa; and controlled attenuation parameter ≥280 dB.m-1. • 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. NOTE: A biopsy that was obtained >6 months before the time of anticipated randomization is not eligible for study entry; a biopsy ≤6 months is potentially eligible for study entry as a baseline biopsy only after confirmation of eligibility based on Inclusion #7 by the central pathology reviewer. NOTE: Eligibility based on meeting Inclusion #5 should be determined based on historic medical and laboratory (PRO-C3/ELF, FibroScan, liver biopsy) data and should be determined prior to informed consent and screening visit.
- 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. An eligible MRI-PDFF with fat fraction ≥8% must be obtained prior to performing the baseline liver biopsy (Criterion #7).
- Inclusion criteria for OLE phase: 1. Patients must be willing to participate in the OLE phase and provide written informed consent.
- Inclusion criteria for OLE phase: 2. Completed all protocol-specified visits in the Main Study and had the scheduled second liver biopsy at Month 54
Exclusion Criteria
- Regular use of drugs historically associated with NAFLD, which include but are not limited to the following: amiodarone, methotrexate, systemic oral glucocorticoids, 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
- Pioglitazone >15 mg per day, stable treatment for ≥24 weeks prior to the eligible liver biopsy.
- Platelet count <140,000/mm3. Patients with platelets <140,000 and ≥120,000 /mm3 are eligible if Fib-4<3.5
- Uncontrolled cardiac arrhythmia.
- 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
- Glucagon-like peptide 1 [GLP-1] agonist therapy (eg, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide and albiglutide) unless stable dose for 24 weeks prior to biopsy. NOTE: GLP-1 therapeutics may not be initiated or doses increased during the first 52 weeks of the study
- Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis
- Diagnosis of hepatocellular carcinoma (HCC)
- Chronic liver diseases: a.Primary biliary cholangitis b.Primary sclerosing cholangitis c.Hepatitis B positive d.Hepatitis C as defined by presence of hepatitis C virus (HCV) antibody (HCV Ab) and positive HCV RNA (tested for known cured HCV infection, or positive HCV Ab at Screening). NOTE: Patients who are HCV antibody positive and HCV RNA negative who have a history of clearly documented HCV infection (history of positive HCV RNA) are eligible to participate if prior treatment for HCV was given, and they have a documented sustained virologic response (SVR) of at least two years prior to the baseline liver biopsy e.History or evidence of current active autoimmune hepatitis f.History or evidence of Wilson's disease g.History or evidence of alpha-1-antitrypsin deficiency h.Evidence of genetic hemochromatosis (hereditary, primary) i.Evidence of drug-induced liver disease, as defined on the basis of typical exposure and history j.Known bile duct obstruction k.Suspected or proven liver cancer.
- Serum ALT >250 U/L NOTE:Given the intrinsic variability in ALT and AST in NASH patients, investigators should use the following guide in an attempt to establish a relatively stable baseline for ALT and AST. Investigator discretion is allowed. Documented historical (3 weeks to ≤ 6 months prior to study entry) ALT and AST levels consistent with the Screening ALT and AST values may help establish a stable baseline
- Statins and/or other lipid-lowering therapies unless dose(s) is stable for ≥30 days prior to anticipated randomization. Statins must be taken in the evening for at least 2 weeks prior to randomization, and permitted statins include rosuvastatin up to 20 mg/day, atorvastatin up to 40 mg/day, pravastatin up to 40 mg/day, simvastatin up to 20 mg/day, pitavastatin up to 2 mg/day and lovastatin up to 40 mg/day. Other stable dyslipidemia therapies not specifically listed as excluded or dose-restricted such as PCSK9 inhibitors are allowed. Higher doses and other statins are excluded. Stable doses of bile acid sequestrants are permitted only if taken 4 h after or 4 h before the study drug dose.
- Exclusion criterion for the OLE: 1. Any 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 Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 30 Sept 2019 | 6 |
 Belgium | Not Recruiting | 30 Sept 2019 | 43 |
 France | Not Recruiting | 30 Sept 2019 | 113 |
 Germany | Not Recruiting | 30 Sept 2019 | 69 |
 Hungary | Not Recruiting | 30 Sept 2019 | 44 |
 Italy | Not Recruiting | 30 Sept 2019 | 39 |
 Poland | Not Recruiting | 30 Sept 2019 | 92 |
 Spain | Not Recruiting | 30 Sept 2019 | 38 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Matching placebo MGL-3196 60 mg film-coated tablet, Matching placebo MGL-3196 80 mg film-coated tablet, Matching placebo MGL-3196 100 mg film-coated tablet. | Placebo | N/A | — | — | — | N/A |
MGL-3196 80 mg oral | Test | FILM-COATED TABLET | ORAL USE | 100 | 104 | PRD10931294 |
MGL-3196 60 mg oral | Test | FILM-COATED TABLET | ORAL USE | 100 | 104 | PRD4683991 |
MGL-3196 100 mg oral | Test | FILM-COATED TABLET | ORAL USE | 100 | 104 | PRD10931295 |