Procedures
EVENTS, LIVER, DECAY
For all patients randomized to resmetirom treatment, dose adjustments could be triggered by an unblinded monitor. At week 12, the resmetirom dose was reduced by 20 mg if FT4 levels decreased from baseline by ≥30% (to <0.7 ng dlA DMC, which met at least quarterly throughout the MAESTRO-NAFLD-1 trial, evaluated the safety and key pharmacodynamic data to recommend whether the trial should continue, be modified or stopped. The DMC reviewed the unblinded safety data, including TEAEs, serious TEAEs and pharmacodynamic data. Blinded hepatic and CV adjudication committees evaluated potential liver or major adverse CV events.A TEAE was defined as any AE with onset or post-dose worsening of any pre-existing AE (existing before the first dose of study drug), either by severity or by study drug relationship, on or after the date of the first dose of study drug up to 30 d after the date of the last dose of study drug. Patients who discontinued treatment but remained in the trial could have their safety data defined by new AEs that occurred >30 d after last dose censored (considered not treatment-emergent). AEs were coded using MedDRA v.24.0.MRI-PDFF and MRE (at participating sites) were performed at baseline (before initiation of study drug), week 16 and week 52. MRI-PDFF was calculated using a proton density weighted two-dimensional multi-echo gradient echo pulse sequence, including six nominally in- and opposed-phase echoes. The reconstruction accounted for T2*-related signal decay and the spectral complexity of fat. MRE was obtained and reconstructed using vendor-supplied hardware and software. FibroScans were obtained at prescreening or during screening and at week 52. Both MRI and MRE image analyses were conducted using OsiriX 9 (Pixmeo Sarl). Vital signs, a 12-lead ECG and clinical laboratory testing (hematology, chemistry and urinalysis) and assessment of lipid parameters, thyroid hormone parameters and other biomarkers were conducted at specified visits.Liver volume was assessed at baseline and week 52 in the OL 100 mg resmetirom arm. Volumes were estimated based on motion-robust single-shot fast-spin echo MRI obtained as part of the MRI examinations for MRI-PDFF estimation. Images were obtained in the axial plane with a slice thickness of 6–8 mm and inter-slice gap of 0–2 mm, with maximum in-plane voxel dimensions of 1.9 × 1.9 mm. Initial two-dimensional contours were developed using a model based on the UNet architecture. Contours were visually assessed and adjusted by imaging core laboratory technologists with experience in liver volumetry and validated by a fellowship-trained abdominal radiologist with over 15 years’ experience in abdominal radiology. Liver volumes were estimated in ml based on the number of voxels segmented, in-plane voxel size and section spacing.