A Study to Evaluate the Effect of Resmetirom on Clinical Outcomes in Patients With Well-compensated NASH Cirrhosis

Phase 1

• Conditions: on-alcoholic Steatohepatitis (NASH) Cirrhosis; MedDRA version: 20.0Level: LLTClassification code: 10009214Term: Cirrhosis of liver without mention of alcohol Class: 10019805; Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

• Registration Number: CTIS2024-510627-20-00
• Lead Sponsor: Madrigal Pharmaceuticals Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2024-06-25
• Last Update Posted: 21 August 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 700

Inclusion Criteria

1. 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), 2. Male and female adults =18 years of age, 3. 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), 4. 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., 5. 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 ii) If screening FibroScan = 15 kPa, must also have one of the following screening results: (1) MRE =4.2 kPa (2) ELF =10.25 (3) Fib-4 =3 (4) Platelet count <140,000 mm3 iii) If screening FibroScan < 15 kPa, must also have two of the following screening results: (1) MRE =4.2 kPa (2) ELF =10.25 (3) Fib-4 =3 (4) Platelet count <140,000 mm3 • 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 ii) If screening FibroScan = 15 kPa, must also have one of the following screening results: (1) MRE =4.2 kPa (2) ELF =10.25 (3) Fib-4 =3 (4) Platelet count <140,000 mm3 iii) If screening FibroScan < 15 kPa, must also have two of the following screening results: (1) MRE =4.2 kPa (2) ELF =10.25 (3) Fib-4 =3 (4) Platelet count <140,000 per mL • No Biopsy – subject must be presenting

Exclusion Criteria

1. 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, 10. History of biliary diversion, 11. Uncontrolled hypertension (either treated or untreated), defined as systolic blood pressure >170 mmHg or diastolic blood pressure >100 mmHg at Screening, 12. New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction <30%, 13. Uncontrolled cardiac arrhythmia, 14. Screening ECG shows uncontrolled cardiac arrythmia, or not previously diagnosed., 2. 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)., 3. 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., 4. Diagnosis of hepatocellular carcinoma (HCC) at Screening or historically, 5. 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., 6. 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 d

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified