Exclusion criteria
vitiligo, Hashimoto’s thyroiditis, Wilson’s disease, rheumatoid arthritis, stroke, cirrhosis, autoimmune diseases, fibrosis, NASH, HCV antibody, liver diseases, autoimmune disease, ascites, α-1-antitrypsin deficiency, chronic kidney disease, cancer, HCV antibody and positive HCV, HCV infection, NASH/NAFLD, diabetic medication(s, hypothyroidism, diabetes, hepatitis B, bundle branch block, DB, end-stage liver disease, Gilbert’s syndrome, hyperthyroidism, infection, lupus, rheumatoid arthritis, hereditary or primary).Evidence of drug-induced, Hepatitis B, Weight gain, heart failure, NAFLD, renal impairment, hemochromatosis, autoimmune liver disease, liver disease
BILE DUCT OBSTRUCTION, VITILIGO, RHEUMATOID ARTHRITIS, INFLAMMATORY BOWEL DISEASE, LIVER CANCER, STROKE, CIRRHOSIS, AUTOIMMUNE DISEASES, FIBROSIS, UNSTABLE ANGINA, CARDIAC ARRHYTHMIA, HYPERSENSITIVITY, HEPATOCELLULAR CARCINOMA, LIVER DISEASES, HEART, AUTOIMMUNE DISEASE, ASCITES, CANCER, SYNDROME, PCP, ESOPHAGEAL VARICES, PRIMARY SCLEROSING CHOLANGITIS, HYPOTHYROIDISM, DISEASES, DIABETES, HEPATITIS B, HEPATITIS C, AUTOIMMUNE HEPATITIS, BUNDLE BRANCH BLOCK, HYPERTHYROIDISM, HEPATIC ENCEPHALOPATHY, HEPATITIS C, CAVITY, HEPATITIS B, HEART FAILURE, VIRUS, RENAL IMPAIRMENT, UNCONTROLLED HYPERTENSION, HEMOCHROMATOSIS, PRIMARY BILIARY CHOLANGITIS, DISEASE, AUTOIMMUNE LIVER DISEASE, LIVER DISEASE, SUBCLINICAL HYPOTHYROIDISM, HEPATIC DECOMPENSATION, MYOCARDIAL INFARCTION, SECONDARY, PROTOZOAL INFECTION
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 whether they qualify to participate.History of significant alcohol consumption for a period of more than three consecutive months within 1 year before screening. Note: significant alcohol consumption is defined as equal to or greater than approximately two alcoholic drinks per day for males and approximately 1.5 alcoholic drinks per day for females. One alcoholic drink is equal to 12 ounces (355 ml) of 5% alcohol by volume (ABV) beer, 5 ounces (148 ml) of 12% ABV wine or 1.5 ounces (44.4 ml) of 40% ABV distilled spirits. Note: Cabohydrate-deficient transferrin (CDT) will be measured at screening and if elevated by ≥3.0%, patients will be excluded unless another reason for CDT elevation is provided. If CDT is elevated >2.47 and <3.0, additional patient history should be obtained to rule out alcohol consumption inconsistent with the protocol exclusion limit. Significant alcohol consumption is not allowed for the duration of the study.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 dThyroid diseases:Active hyperthyroidism. Note: patients with a history of hyperthyroidism are eligible to participate.Untreated clinical hypothyroidism defined by TSH > 7 IU lSubclinical hypothyroidism and patients on stable thyroxine therapy are eligible to participate. During screening and after randomization, small adjustments of the thyroxine dose (12.5–25 μg every 4 weeks) are allowed as per the usual care.Note: investigators are asked to review TSH levels, particularly in OL and DB patients on thyroxine, at screening, baseline and throughout the study to determine whether to make dose adjustments in thyroxine (or recommend thyroxine dose adjustments to the patient’s primary care physician (PCP)). Small dose adjustments in thyroxine (12.5 to 25 μg every 4 weeks) are expected and are consistent with ‘stable’ thyroxine therapy. Patients with Hashimoto’s thyroiditis may have residual thyroid function and typically require a dose that is lower than patients with a complete thyroidectomy. Target TSH level may be >1 in patients at high CV risk or established CV disease.Note: NASH/NAFLD is associated with reduced conversion of prohormone T4 to the active hormone T3 in the liver and decreased plasma free T3/reverse T3 ratio. Most patients on thyroxine enrolled in the study will not require a reduction in thyroxine dose. Some patients with NAFLD may require a small reduction in thyroxine dose during screening or after randomization to maintain TSH at target due at least in part to more efficient conversion of T4 to T3 in the liver (and reduced reverse T3) that occurs with resmetirom treatment and/or increased diet/exercise.History of bariatric surgery or intestinal bypass surgery within the 5 years before randomization or planned during the conduct of the study.Weight gain or loss ≥5% total body weight within 12 weeks before randomization. Note: this includes the screening period.HbA1c > 9.0%. Note: patients with HbA1c > 8.0% and ≤10.0% should have documented efforts to control HbA1c to ≤8.0%. If there is no previous documentation of efforts to control HbA1c, patients may be treated with new or higher doses of existing diabetic medication(s) and are eligible for rescreening 6 weeks after initiating a new antidiabetic therapy if the repeated HbA1c is ≤9.0%. Patients must be on stable treatment for all diabetes medications, including any new doses or medications, for ≥30 d before randomization.Note: stable diabetes therapy is expected at the time of randomization, but may be modified after randomization, including increases in dose, switching or adding an additional antidiabetic if medically indicated (with the exception of adding GLP-1 agonists) to maintain good HbA1c control during the study. Investigators should enforce diet and exercise as described in the protocol.Note: insulin doses may be altered by up to 10% during the screening period.GLP-1 agonist therapy (for example, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide and albiglutide) unless stable dose for 24 weeks before screening. GLP-1 therapeutics may not be initiated, or doses increased during the study. A switch within class from a GLP-1 agonist to a different GLP-1 agonist at a dose assessed as equivalent would be allowed during the study.Use of high-dose vitamin E (>400 IU dPresence of cirrhosis on liver biopsy defined as stage 4 fibrosis is excluded from randomized arms.Diagnosis of hepatocellular carcinoma.Model for end-stage liver disease score ≥12 due to liver disease. Note: score of ≥12 must be the result of liver disease to be exclusionary, not isolated laboratory abnormalities such as elevated creatinine due to chronic kidney disease, international normalized ratio (INR) abnormality secondary to anticoagulants or laboratory error and bilirubin elevation due to Gilbert’s syndrome.Hepatic decompensation or impairment defined as presence of any of the following:History of esophageal varices, ascites or hepatic encephalopathy.Serum albumin <3.5 g dlINR > 1.4 unless due to therapeutic anticoagulants or laboratory error. Note: INR may be repeated once to reassess eligibility.Total bilirubin > 1.5 × ULN = 1.2 mg dlChronic liver diseases:Primary biliary cholangitis.Primary sclerosing cholangitis.Hepatitis B positive: as defined by the subject testing positive for Hepatitis B surface antigen, core antibody and positive for hepatitis B virus infection. A patient could also be excluded if hepatitis B DNA is detected.Hepatitis C as defined by presence of hepatitis C virus (HCV), HCV antibody and positive HCV RNA (tested for known cured HCV infection or positive HCV antibody 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 previous treatment for HCV was given and they have a documented sustained virologic response of at least 2 years before anticipated randomization.History or evidence of current active autoimmune hepatitis.History or evidence of Wilson’s disease.History or evidence of α-1-antitrypsin deficiency.History or evidence of genetic hemochromatosis (hereditary or primary).Evidence of drug-induced liver disease, as defined on the basis of typical exposure and history.Known bile duct obstruction.Suspected or proven liver cancer.Has an active autoimmune disease, including actively treated lupus, rheumatoid arthritis, inflammatory bowel disease or autoimmune hepatitis, requiring 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 who require intermittent use of bronchodilators, topical, inhaled or intranasal corticosteroids, or local steroid injections are not excluded from the study.Note: as evaluation of safety, not efficacy, is the major objective being evaluated in patients with moderate renal impairment (eGFR ≥ 30 and <45) enrolled in the OL arm, 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.Serum ALT > 250 U lNote: given the intrinsic variability in ALT and AST in patients with NASH, 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 before study entry) ALT and AST levels consistent with the screening ALT and AST values may help establish a stable baseline. This consistency may be established based on the following:If the historical and screening ALT and AST values are both ≤1.5 × ULN, there is no limit to the difference between the values.Patients who do not have historical ALT and AST evaluations available will have their ALT and AST repeated during the screening period to help to establish no worsening of >30% (both assessments during screening period) with >2 weeks between assessments. The second ALT, AST assessment may take place after the screening MRI-PDFF.If the historic ALT/AST are >1.5× elevated and screening ALT and AST are markedly improved (>50% decreased or normalized) relative to historic data, then a third ALT/AST determination will be made during screening to help establish a stable baseline.If at least one 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 help establish a lack of worsening trend in ALT/AST. If a worsening trend is confirmed (three consecutive worsening values with difference from first value and second value >30% and difference between second and third value >30%), the patient will be deemed a screen failure, but may be rescreened if ALT and AST stabilize.Use of pioglitazone >15 mg dPlatelet count <140,000 mmHistory of biliary diversion.Uncontrolled hypertension (either treated or untreated) defined as systolic blood pressure ˃170 mm Hg or a diastolic blood pressure ˃100 mm Hg at screening.New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction <30%.Uncontrolled cardiac arrhythmia.At screening, confirmed QT interval corrected using Fridericia’s formula (QTcF) > 450 ms for males and >470 ms for females based on triplicate ECG assessment. At least two of the three ECGs must show a prolongation and the average of the three ECGs must be prolonged to meet criteria for exclusion. Prolonged QTcF may be repeated and confirmed following machine calibration if needed. Note: patients with bundle branch block or other conditions in which a QTcF cannot be calculated are allowed.Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft or stroke within 12 weeks before randomization.Use of illicit intravenous drugs within 5 years before randomization or a urine drug screen result positive for amphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates or phencyclidine at screening, unless a prescribed drug accounts for the positive test.Active, serious medical disease with a likely life expectancy <2 years.Participation in an investigational new drug trial in the 60 d or five half-lives, whichever is longer, before randomization. Patients previously treated with NASH therapeutics in an investigational trial are allowed if follow-up liver biopsy at the end of trial continued to show active NASH fibrosis meeting eligibility criteria and they have been off the NASH therapeutic for at least 24 weeks before expected randomization. If a potential NASH therapeutic studied revealed no safety issues, and in fact was not a NASH therapeutic (no effect on liver biopsy compared to placebo), participation may occur 60 d or five half-lives, whichever is longer, after discontinuation of the therapy.History of major surgery (surgery involving a risk to the life of the patient; specifically, an operation upon an organ within the cranium, chest, abdomen or pelvic cavity) within 6 weeks before randomization.History of cancer within the last 5 years (other than treated and believed to be cured basal or squamous cell carcinoma of the skin or resected carcinoma of the cervix).Any other 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.Known immunocompromised status, including but not limited to individuals who have undergone organ transplantation, who are known to be positive for HIV or who have recurrent or chronic systemic bacterial, fungal, viral or protozoal infections.Hypersensitivity to resmetirom or to any of the excipients or to placebo.MAESTRO-NAFLD-1 was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with the International Conference on Harmonization Good Clinical Practice and applicable regulatory requirements. An institutional review board (IRB) or independent ethics committee at each site approved the protocol and all amendments (central IRB WCG, tracking no. 20192651; local IRB Duke University Health System tracking no. Pro00104842; local IRB Cedars-Sinai Office of Research Compliance and Quality Assurance tracking no. STUDY00001571). All patients provided written informed consent before enrollment.