Inclusion criteria (DB and OL noncirrhotic arms)
inflammation, fibrosis, NASH/NAFLD, weight gain, renal disease, steatosis, claustrophobia, dyslipidemia
INFLAMMATION, EVENT, FIBROSIS, STERILE, SECONDARY, RENAL DISEASE, -11, STEATOSIS, DYSLIPIDEMIA
We only evaluated patients for study participation if they met the prescreening criteria. Patients who did not initially meet the eligibility criteria may be retested, based on investigator judgment, to determine whether they qualify to participate. Patients who met all of the following criteria were eligible to participate in the study: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 (β-human chorionic gonadotropin), are not breastfeeding and do not plan to become pregnant during the study and agree to use two highly effective birth-control methods during the study OR if they are not of childbearing potential (surgically (bilateral oophorectomy, hysterectomy or tubal ligation) or are 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 the time of screening throughout the study and for at least 30 d 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.Male patients who are sexually active with a partner of childbearing potential must either be sterile (vasectomy with history of a negative sperm count at least 90 d following the procedure); 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 (such as one of the methods identified above for female patients of childbearing potential) from the time of screening until 30 d after the last dose of study drug administration. Male patients must agree not to donate sperm for a period of 30 d after the last dose of study drug administration.For suspected or confirmed diagnosis of NASH/NAFLD suggested by the historical data, they must meet one of the following criteria:FibroScan with kPa ≥ 5.5 and <8.5; CAP ≥ 280 dB mRecent liver biopsy (within past 2 years) documenting NASH/NAFLD with steatosis showing one of the following:NAS ≥ 4, steatosis ≥ 1, with fibrosis stage 0 (F0) OR with F1A/1C and PRO-C3 < 14.NAS < 4, steatosis ≥ 1, with fibrosis stage ≤3.NAS ≥ 4, steatosis ≥ 1, fibrosis stage ≤3 without ballooning.Note: following the completion of enrollment of the DB arms, patients meeting all other criteria who have a liver biopsy result from MGL-3196-11 with the following may be enrolled in the OL active treatment arm of MGL-3196-14 (100 mg dose):NAS = 3, steatosis 1, ballooning 1, inflammation 1 with F2 or F3.NAS = 3, ballooning 0 with F2 or F3.Note: if patient is F0, they must also, within the last 6 months, have a FibroScan with kPa ≥ 5.5 OR MRE ≥ 2.0 (no upper limit).Note: in patients on thyroxine >75 μg, a FibroScan with kPa ≥ 5.5 is eligible (no upper limit).Note: in patients with glomerular filtration rate (GFR) ≥ 30 and <45 (OL treatment arm). a FibroScan with kPa ≥ 5.5 is eligible (no upper limit).Note: eligibility based on meeting inclusion criterion 5 should be determined based on historic medical and laboratory (FibroScan, liver biopsy) data and should be determined before informed consent is provided and the screening visit.Note: FibroScan does not need to be repeated at screening if conducted at prescreening and/or a historical FibroScan was conducted in the previous 3 months (including study MGL-3196-11). A historic liver biopsy must not be accompanied by a significant decrease in body weight ≥5% since the biopsy or treatment with a new concomitant medication that might affect steatosis.Patients must meet inclusion criterion 0 before obtaining an MRI-PDFF (unless a patient has an existing qualifying MRI-PDFF). MRI-PDFF fat fraction ≥8% obtained during the screening period (baseline MRI-PDFF) or a historic MRI-PDFF ≤ 8 weeks (+3 d) old at the time of randomization.Note: an eligible MRI-PDFF with fat fraction ≥8% must be obtained for the baseline value (does not need to be repeated if conducted in the ≤8 weeks (+3 d) before anticipated randomization and there has not been >5% weight change in that interval). Patients with contraindications to an MRI-PDFF (for example, metal prosthetics, uncontrolled documented claustrophobia or where body weight exceeds the limit of the machine) examination or who are screened at an investigative site where MRI-PDFF is not available are eligible for this study if they have a FibroScan with CAP ≥ 300 dB mNote: if a historic liver biopsy shows steatosis of 0 and there has been no recent change in metabolic status such as weight gain, the patient is not eligible to participate unless the current MRI-PDFF is ≥8%.Must be on stable, standard care dyslipidemia therapy for ≥30 d before randomization that can be maintained for the entire study except for noted exceptions. Statins should be taken in the evening for at least 2 weeks before randomization and continue to be taken in the evening for the duration of the study. Patients recommended for dyslipidemia therapy but who are intolerant of statins or other dyslipidemia therapy are allowed. Permitted dyslipidemia therapy includes:Rosuvastatin ≤20 mg daily.Atorvastatin ≤40 mg daily.Simvastatin ≤20 mg daily.Pravastatin ≤40 mg daily.Lovastatin ≤40 mg daily.Pitavastatin ≤2 mg daily.Ezetimibe alone or in combination with any of the above statins.Omega III fatty acids.Bile acid sequestrants (for example, cholestyramine (Questran or Prevalite), colestipol (Colestid or Flavored Colestid) and colesevelam (Welchol)) are permitted if taken at least 4 h after or 4 h before the dose of study drug.The fenofibrate dose must be stable for at least 6 weeks before randomization and is allowed for patients with a history of and/or ongoing very high TGs (>500 mg dlNote: because lipid end points are assessed during the study, lipid therapies must be stable for the duration of the 52-week study. Lipids are blinded during the study and monitoring lipid levels at local laboratories outside the clinical trial is discouraged. Safety reasons that may result in an increase/modification in lipid therapy during the study include the occurrence of a laboratory alert for TGs > 1,000 or another acute indication for modifying lipid therapy such as a CV event. Statins and other lipid therapy may be reduced, switched to an alternative statin or cholesterol-lowering medication or discontinued secondary to AEs during the study.Note: patients already enrolled who are taking fenofibrate even if not for very high TGs may remain in the study, because there are no safety concerns in most patients taking fenofibrate.Note: other stable dyslipidemia therapies not specifically listed, such as PCSK9 inhibitors, are allowed.Note: patients with dyslipidemia therapy that was initiated <30 d before expected randomization may be rescreened after the dyslipidemia therapy is stabilized. In the case that a lipid-lowering medication is discontinued before randomization, the patient would be able to randomize 1 week after the discontinuation.Estimated GFR ≥ 45 (DB treatment arms) or ≥30 and <45 (OL treatment arm) by the modification of diet in renal disease 6-variable (MDRD-6) formula.