Statistical analysis
nonadherence, ASCVD
EVENTS, SECONDARY, TYPE 2 DIABETES, ASCVD
Sample size was based on safety and regulatory considerations to facilitate the evaluation of the treatment effect within subgroups of interest. For evaluation of the key secondary end points, randomizing ≥200 patients to each of the three DB arms was expected to provide >90% power to demonstrate a statistically significant difference between each resmetirom dose and placebo at the two-sided 0.025 significance level in the %CFB in LDL-C at week 24, assuming a ≥13.5% difference between the resmetirom arm and placebo arm with a within-treatment s.d. of 16%. Other key secondary lipid end points and percent change in hepatic fat between the resmetirom and placebo arms had ≥90% power. This trial was designed to maintain an overall study-wise type I error rate of α = 0.05 for the key secondary end points only. The error rate was controlled by first splitting the overall two-sided α = 0.05 into two partitions via the Bonferroni method and then the key secondary end points were tested in a prespecified hierarchical order (Extended Data Fig. The primary analyses were conducted after all patients in the DB arms completed the 52-week treatment period and 4-week follow-up period (or discontinued from the trial with a 4-week follow-up period). TEAEs were analyzed descriptively for each treatment arm. For the primary analysis of key secondary lipid end points, an ANCOVA model was used to analyze each set of ten imputed datasets. The ANCOVA models for each lipid outcome included %CFB to week 24 (and all other end point visits) as the dependent variable; treatment and stratification factors (presence of type 2 diabetes and ASCVD) as independent variables; and baseline lipid values as a covariable. The statistical method of estimating the treatment effect and testing for apoB and TGs was similar to the LDL-C end point; a similar ANCOVA model was used whereby the baseline value of the dependent variable was included as covariate instead of LDL-C.This study was impacted by COVID-19 and the estimand in the statistical analysis plan reflected the statistical approach taken to address COVID-19-related missing data. The strategy was used to evaluate the effect of resmetirom as though the blister pack kit shortage due to the COVID-19 pandemic or other missing receipt of study drug (due to site closures or other COVID-19-related missed visits) had not happened. To address the COVID-19 impact, the week-24 lipid assessment and lipid assessment at any visit in which fasting lipids were measured (weeks 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) that was impacted by the blister pack kit shortage at the previous visit (unavailability of study drug during the 4 weeks preceding the visit), was considered missing. Per protocol and of note, all post-baseline lipids/lipoproteins and MRI-PDFF measurements were blinded during the study, as was the treatment code.The analysis of lipids was performed after imputation was performed for missing results. The imputation was conducted in two stages, where stage 1 utilized a single imputation using a patient’s own data and stage 2 used a multiple imputation approach. In stage 1, invalid and missing data caused by the COVID-19 pandemic were imputed using the ‘valid visit’ lipid measurement (if available) obtained just before the missing visit. If the previous visit was missing or invalid, the lipid value obtained immediately after the missing visit was imputed for the missing visit. For lipid data that were still missing after the single imputation approach described above, those missing data were imputed using the non-missing lipid values (including the singly imputed data from above) based on missing-at-random-based multiple imputation. When applying the missing-at-random-based multiple imputation, data were imputed separately by randomized treatment group and randomization stratification factors. Lipid assessments impacted by other COVID-19-related factors including drop-out from the study due to COVID-19 (including drop outs caused by blister pack kit shortages) and nonadherence to dosing due to COVID-19 were not considered for single imputation given that they were either infrequent (missed visits) or difficult to track. The values for lipid end points affected by all other intercurrent events (COVID-19-related and non-COVID-19-related) were multiply imputed as described in the statistical analysis plan.In this trial, few patients had a baseline FibroScan VCTE LSM that met criteria for analysis. As such, a responder analysis was performed to evaluate the percent of patients whose FibroScan VCTE LSM improved or worsened by either ≥2 kPa or ≥30% from baseline at week 52. A similar responder analysis was performed for MRE as well to evaluate the percent of patients whose LSM by MRE improved or worsened by ≥19% from baseline at week 52. For analysis of the OL resmetirom arm, end points were summarized descriptively and analyzed by a within-group CFB. For descriptive statistical summaries, the number of non-missing observations, mean, s.d., median, minimum and maximum were calculated for continuous variables. For categorical variables, the frequency and percentage of each category were provided. All statistical analyses were performed with SAS v.9.4 or above.Safety end points were evaluated in the safety population, which included all randomized patients who received ≥1 dose of the DB study drug. Efficacy end points were evaluated in the mITT population, which included all randomized patients who received ≥1 dose of the DB study drug and had a baseline and ≥1 post-baseline measurement. The ITT population, which included all DB randomized patients, could be used for sensitivity analysis if it differed substantially from the mITT population.