Evaluation of Resmetirom on Liver-Related Outcomes in Patients with Well-Compensated Non-Alcoholic Steatohepatitis Cirrhosis: A Phase 3 Randomized Study
- Trial ID
- 2024-510627-20-00
- Protocol
- MGL-3196-19
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **resmetirom** administered orally at a dose of 80 mg daily, compared to a matching placebo, on the time to the first adjudicated Composite Clinical Outcome event in patients with well-compensated Non-alcoholic Steatohepatitis (NASH) Cirrhosis. This outcome is defined by the occurrence of liver-related or cardiovascular mortality, liver transplant, and significant hepatic events, including hepatic decompensation events such as ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage, as well as a confirmed increase in the Model for End-stage Liver Disease (MELD) score from less than 12 to 15 or greater. The clinical relevance of this objective lies in its potential to provide insights into the efficacy of resmetirom in delaying or preventing critical liver-related outcomes in this patient population.
Secondary objectives include:
- Percent change from baseline to week 28 in low-density lipoprotein cholesterol (LDL-C).
- Percent change from baseline to week 52 in hepatic fat fraction, as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF), in patients with a baseline MRI-PDFF greater than 5%.
Participants
The clinical trial involves a total of **697 participants** diagnosed with **Non-alcoholic Steatohepatitis (NASH) Cirrhosis**. The study population includes both male and female adults aged **18 years and older**. Participants were selected based on specific inclusion criteria, including a definitive or probable diagnosis of NASH as the causative agent for cirrhosis, and a well-compensated Child-Pugh A cirrhosis status. The trial population is characterized by a diverse range of individuals, including those considered vulnerable. Participants are required to adhere to specific lifestyle considerations, such as the use of effective birth control methods for those of reproductive potential. The selection process ensures that participants have no history of hepatic decompensation events, maintaining a focus on individuals with stable health conditions related to their liver disease. The trial does not provide additional information regarding specific lifestyle habits such as diet or physical activity.
Plans and Procedures
The clinical trial is designed to evaluate the effect of **resmetirom** on liver-related outcomes in patients with well-compensated non-alcoholic steatohepatitis (NASH) cirrhosis. This is a randomized, double-blind, placebo-controlled Phase 3 study. Participants will be randomly assigned to receive either 80 mg of resmetirom or a matching placebo, administered orally once daily. The primary endpoint is the time to a confirmed adjudicated composite clinical outcome event, which includes liver-related or cardiovascular mortality, liver transplant, significant hepatic events, and a confirmed increase in the Model for End-stage Liver Disease (MELD) score from less than 12 to 15 or more.
The trial is expected to last until June 2026, with participant involvement spanning up to 36 months. The study will commence with an inclusion (screening) visit to assess eligibility based on criteria such as age, reproductive status, and definitive or probable NASH as the causative agent for cirrhosis. Participants must have well-compensated Child-Pugh A cirrhosis and no history of hepatic decompensation events. Follow-up visits will occur at regular intervals to monitor the participants' health status and adherence to the study protocol. The end-of-study visit will conclude the trial for each participant, assessing the final outcomes and any adverse events.
Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial will also include secondary endpoints, such as the percent change from baseline in LDL-C at Week 28 and the percent change in hepatic fat fraction by MRI-PDFF at Week 52 in patients with a baseline MRI-PDFF of 5% or more. The study aims to provide comprehensive data on the efficacy and safety of resmetirom in treating NASH cirrhosis, contributing to the understanding and management of this condition.
Treatment
The clinical trial involves the administration of **MGL-3196**, also known as **resmetirom**, which is a chemical compound provided in the form of a film-coated tablet. The experimental medication is available in three dosages: 60 mg, 80 mg, and 100 mg. Each dosage is administered orally once daily. The maximum daily dose for each variant corresponds to its respective dosage, with a treatment period extending up to 36 months. The active substance, resmetirom, is chemically synthesized and is intended to evaluate its effect on liver-related outcomes in patients with well-compensated non-alcoholic steatohepatitis (NASH) cirrhosis.
In addition to the experimental medication, the study includes the use of matching placebos for each dosage level of MGL-3196. These placebos are also provided as film-coated tablets and are designed to be indistinguishable from the active medication in appearance and administration. The placebo tablets are administered orally once daily, mirroring the dosing schedule of the active treatment. The inclusion of placebos allows for a double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias and enhancing the reliability of the study outcomes.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the effect of once-daily, oral administration of **resmetirom** versus a matching placebo in patients with Non-Alcoholic Steatohepatitis (NASH) cirrhosis. The primary endpoint is the time to a confirmed adjudicated Composite Clinical Outcome event. This composite event includes liver-related or cardiovascular mortality, liver transplant, significant hepatic events such as hepatic decompensation events, and a confirmed increase in the Model for End-stage Liver Disease (MELD) score from less than 12 to 15 or greater.
Secondary endpoints include the percent change from baseline in LDL-C at Week 28 and the percent change from baseline to Week 52 in hepatic fat fraction as measured by MRI-PDFF in patients with a baseline MRI-PDFF of 5% or greater. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, ensuring a comprehensive analysis of the treatment's impact on the disease progression and related outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Must be willing to participate in the study and provide written informed consent NOTE: Subjects must be affiliated to the social security regime or be a beneficiary of such a regime. (France only)
- Male and female adults ≥18 years of age
- Female patients who: a. are of reproductive potential and have a negative serum pregnancy test (beta human chorionic gonadotropin), are not parturient, not breastfeeding, and do not plan to become pregnant during the study and agree to use highly effective birth control methods during the study from Screening, throughout the study, and for at least 30 days after the last dose of study drug administration. b. OR are not of child bearing potential (ie, surgically [permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy] or naturally sterile [no menses for > 12 months without an alternative medical cause]) - Female patients must agree not to donate ovocytes for a period of 30 days after the last dose of study drug administration (France only)
- Male patients who are sexually active with a partner of child-bearing potential and: a. are sterile (vasectomy with history of a negative sperm count at least 90 days following the procedure) b. OR practice total abstinence from sexual intercourse as the preferred lifestyle (periodic abstinence is not acceptable) OR c. OR agree to use a birth control method during the study from the time of Screening until 30 days after the last dose of study drug administration. - Male patients must agree not to donate sperm for a period of 30 days after the last dose of study drug administration.
- Definitive (by histologic documentation) or probable NASH as causative agent for cirrhosis, following a modified version of the NASH Cirrhosis: Liver Forum Consensus Definitions for Clinical Trials, Noureddin 2020; Historic Biopsy, Tissue available A. On study centrally read as F4, historic biopsy is consistent with NASH cirrhosis i) Continue in screening B. On study centrally read as consistent with NASH with significant fibrosis i) Biopsy must have been obtained six months or greater prior to prescreening date (to allow time for clinical progression to occur) and patient must now be presenting with clinical cirrhosis • Historic Biopsy, Tissue not available A. Historical read as F4. If steatosis and ballooning and/or steatosis and inflammation are noted by the local pathologist, then the biopsy qualifies even if an NAS is not provided. i) Continue in screening B. Historical read as consistent with NASH with significant fibrosis i) Biopsy must have been obtained six months or greater prior to prescreening date (to allow time for clinical progression to occur) and patient must now be presenting with clinical cirrhosis • No Biopsy – subject must be presenting with clinical cirrhosis • On study (not historic) biopsy (only obtained in rare instances and with preapproval from the Sponsor), or the biopsy was obtained less than six months prior to the screening date A. On study (not historic) centrally read as F4, biopsy is consistent with NASH cirrhosis i) Continue in screening B. On study centrally read as consistent with NASH with significant fibrosis NOTE: When possible, historical biopsies that are used for eligibility will be reviewed and confirmed as consistent with NASH cirrhosis by a central pathologist − In the event of a conflicting read between historical biopsy report and central biopsy read, the central report will be used.
- Well-compensated Child-Pugh A (score of 5–6) cirrhosis at Screening and Baseline AND no history of a hepatic decompensation event.
Exclusion Criteria
- Chronic liver diseases other than NASH cirrhosis: a. Primary biliary cholangitis b. Primary sclerosing cholangitis c. Hepatitis B positive (as defined in Appendix 2) d. Hepatitis C (as defined in Appendix 3) 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. History or 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 confirmed liver cancer
- MELD score ≥12, due to liver disease at either screening OR baseline. - NOTE: MELD of ≥12 as the result of liver disease is exclusionary, NOT including isolated lab abnormalities such as elevated creatinine due to chronic kidney disease, INR abnormality secondary to anticoagulants or lab error, or bilirubin elevation due to Gilbert's syndrome. UGT1A1 allele testing to be performed at Screening on all patients (where permitted).
- History of hepatic decompensation or impairment at either screening or baseline, defined as presence of any of the following: a. History of variceal bleeding (NOTE: small to medium (Grade I-II) nonbleeding varices are allowed) b. Ascites due to cirrhosis. Screening MRI or CT shows at least a 2 cm pocket of fluid in at least 2 of 5 abdominal stations, including the four abdominal quadrants and pelvis. NOTE: in situations where both MRI and CT are contraindicated, ultrasound is acceptable for evaluation of ascites. c. Overt hepatic encephalopathy, lactulose treatment, or other treatment for hepatic encephalopathy d. Serum albumin <3.5 g/dL, except as explained by non-hepatic causes e. INR >1.4 unless due to therapeutic anticoagulants or laboratory error (NOTE: If laboratory error is suspected, retest to confirm INR ≤1.4 is required) f. Total bilirubin ≥2 mg/dL - NOTE: Patients with genetically confirmed Gilbert's syndrome are eligible with a total bilirubin ≥2 mg/dL if reticulocyte count is within normal limits, hemoglobin is within normal limits unless due to chronic anemia and unrelated to hemolysis, and direct bilirubin is <20% of total bilirubin.
- Diagnosis of HCC at Screening or historically
- Liver Imaging Reporting and Data System (LI-RADS) score ≥4 at Screening. NOTE: in situations where both MRI and CT are contraindicated, ultrasound is acceptable for evaluation of hepatocellular cancer.
- Thyroid diseases, as defined by the following conditions: a. Active hyperthyroidism. - NOTE: Patients with a history of hyperthyroidism are eligible to participate. b. Untreated clinical hypothyroidism defined by: - Thyroid stimulating hormone (TSH) ≥7 IU/L with symptoms of hypothyroidism, or - TSH ≥10 IU/L without symptoms • NOTE: TSH may be repeated once during Screening, and if still does not meet entry criteria, patients will be considered screen failures. Patients with clinical hypothyroidism newly treated with thyroxine may be rescreened once thyroxine dose is stabilized.
- Has an active autoimmune disease, including actively treated lupus, rheumatoid arthritis, inflammatory bowel disease, or autoimmune hepatitis that requires systemic treatment within the past 12 weeks or a documented history of clinically severe autoimmune disease, including autoimmune liver disease, or a syndrome that requires systemic steroids or immunosuppressive agents. • NOTE: Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators, topical, inhaled, or intranasal corticosteroids, or local steroid injections are not excluded from the study. • NOTE: Patients with autoimmune diseases such as rheumatoid arthritis who are on systemic therapies may be eligible on a case-by-case basis as long as the systemic therapy for the autoimmune disease is not specifically excluded (ie, steroids or immunosuppressive agents).
- Alcohol consumption of any type, frequency or amount is not allowed during the Screening or Treatment phase of the study
- History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study
- History of biliary diversion
- Uncontrolled hypertension (either treated or untreated), defined as systolic blood pressure >170 mmHg or diastolic blood pressure >100 mmHg at Screening
- New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction <30%
- Uncontrolled cardiac arrhythmia
- Screening ECG shows uncontrolled cardiac arrythmia, or not previously diagnosed.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 28 Jul 2023 | 12 |
 France | Not Recruiting | 28 Jul 2023 | 62 |
 Germany | Not Recruiting | 28 Jul 2023 | 12 |
 Italy | Not Recruiting | 28 Jul 2023 | 29 |
 Spain | Not Recruiting | 28 Jul 2023 | 33 |
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 100 mg film-coated tablet | Placebo | N/A | — | — | — | N/A |
MGL-3196 80 mg oral | Test | FILM-COATED TABLET | ORAL USE | 80 | 36 | PRD10931294 |
MGL-3196 100 mg oral | Test | FILM-COATED TABLET | ORAL USE | 100 | 36 | PRD10931295 |
MGL-3196 60 mg oral | Test | FILM-COATED TABLET | ORAL USE | 60 | 36 | PRD4683991 |
Matching placebo MGL-3196 80 mg film-coated tablet | Placebo | N/A | — | — | — | N/A |
Matching placebo MGL-3196 60 mg film-coated tablet | Placebo | N/A | — | — | — | N/A |