A Study to Evaluate the Effect of Resmetirom on Clinical Outcomes in Patients With Well-compensated NASH Cirrhosis
- Conditions
- on-alcoholic Steatohepatitis (NASH) CirrhosisMedDRA version: 20.0Level: LLTClassification code 10009214Term: Cirrhosis of liver without mention of alcoholSystem Organ Class: 100000004871Therapeutic area: Diseases [C] - Digestive System Diseases [C06]
- Registration Number
- EUCTR2022-002279-13-FR
- Lead Sponsor
- Madrigal Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 700
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 who:
a. 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
b. OR are not of child bearing potential (ie, 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 male partner, or sexual abstinence (defined as refraining from heterosexual intercourse), from Screening, throughout the study, and for at least 30 days after the last dose of study drug administration. Reliance on abstinence from heterosexual intercourse is acceptable only if it is the patient’s habitual practice.
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 use a male condom with any sexual activity;
d. 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 patients of childbearing potential) 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 (Table 4); and as described in the Prescreening Criteria and Exclusion Criteria #1.
a. Most recent biopsy (within last 5 years) shows cirrhosis with a NAS of = 2, and at least two components: one being steatosis and at least one other component; OR NAS of = 2, if steatosis = 0 or is ungraded with inflammation and/or ballooning, eligible with an MRI-PDFF >5%. If steatosis and ballooning and/or steatosis and inflammation are noted by the local pathologist, then the biopsy qualifies even if a NAS is not provided (Approximately 70% of the study patient population)
b. Historical biopsy (within last 5 years) showed NASH with significant fibrosis with pathology report documenting F2” or F3”, with at least steatosis either by biopsy with no minimal percentage required or by MRI-PDFF >5%, AND inflammation or ballooning. Now with cirrhosis, either by clinical history or current features, imaging, noninvasive tests, or biopsy (see Appendix 7) (Up to approximately 20% of study patient population)
c. Historical biopsy (within last 5 years) shows steatosis. Pathology report documents steatosis with no minimal percentage required. Now with cirrhosis, either by clinical history or current features, imaging, noninvasive tests, or biopsy (see Appendix 7).
Prescreening metabolic risk factors must include obesity and/or T2D. (Up to approximately 10% of study patient population.)
- NOT
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
2. MELD score =12, due to liver disease.
- NOTE: MELD of =12 must be the result of liver disease to be exclusionary, NOT 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, defined as presence of any of the following:
a. History of variceal bleeding (NOTE: small non-bleeding 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.
c. Overt hepatic encephalopathy, lactulose treatment, or other treatment for hepatic encephalopathy
d. Serum albumin <3.2 g/dL, except as explained by non-hepatic causes
e. INR >1.4 unless due to therapeutic anticoagulants or laboratory error (retest is required)
- NOTE: INR may be repeated once to reassess eligibility
f. Total bilirubin =2 mg/dL
- NOTE: Patients with genetically confirmed Gilbert’s syndrome are eligible with a total bilirubin above 1.5 × upper limit of normal (ULN) (ULN = 1.2) 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 =3 at Screening
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, and if still does not meet entry criteria, patients will be considered screen failures. Patients with untreated clinical hypothyroidism may be stabilized on thyroxine replacement therapy and rescreened for eligibility.
- NOTE: During Screening, patients receiving thyroxine must be on a stable dose for at least 2 weeks prior to randomization, with screening TSH =1 and <5 IU/L. Thyroxine dose may be adjusted once during Screening and TSH retested at least 2 weeks prior to randomization (See Section 7.3.3 for details on thyroxine dose adjustment and stabilization).
7. 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 immuno
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method