Statistical analysis
DARLING
The primary end point was prespecified as the least squares mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure (combination of DBTP and SBTP) in cohort 3. This was assessed in cohort 3 using asynchronous study periods that were dependent upon treatment group to assess changes in triglycerides after 12 weeks of evinacumab treatment; for patients randomized to evinacumab, the primary analysis included the 12-week DBTP, whereas for patients randomized to placebo the primary analysis included the subsequent 12-week SBTP of active treatment with evinacumab. Point estimates of mean percent changes in triglycerides between the placebo run-in period and each observation were calculated using a mixed-effect model for repeated measures (MMRM) approach.Before MMRM analysis of the primary end point, fasting serum triglycerides were log-transformed with the aim to provide a normal data distribution. A log-scale s.d. of 0.5 was used based on available evinacumab phase 1 data. To reduce variability of baseline triglyceride measurements, baseline was the mean of the three log-transformed measurements (day –28, day –14 and week 0 (DBTP); weeks 6, 8 and 12 (SBTP)).The primary end point analysis was based on the percent change in triglycerides from baseline following 12 weeks of treatment with evinacumab in cohort 3. Point estimates of mean percent changes in triglycerides between the placebo run-in period and each observation were calculated using an MMRM approach. The MMRM model assessed within-patient treatment comparisons using an unstructured covariance matrix while accounting for baseline triglyceride values, study visit and baseline triglyceride values by study visit interaction, but not trough levels of evinacumab, which varied and were often below the targeted threshold of 100 mg lSecondary end points included the percent triglyceride lowering from baseline following 2–24 weeks repeated i.v. doses of evinacumab; the proportion of patients who achieved at least a 40%, 50%, 60%, 70%, 80% or 90% reduction in triglycerides from baseline and the proportion of patients who achieved a reduction in triglycerides below 500 mg dlPost hoc analyses were undertaken to evaluate whether (1) mean triglyceride values at baseline and week 12; (2) percent change in mean triglyceride values at week 12; (3) mean log-transformed triglyceride values from baseline and week 12; and (4) change in mean log-transformed triglyceride values from baseline at week 12 achieved normal distribution using the MMRM model. It was essential to determine whether triglyceride values that do not follow a normal distribution are log-normal, as applying MMRM analysis without confirming the data obey a log-normal distribution, could lead to misinterpretation of data. Accordingly, tests of normality, including Anderson–Darling, Cramer–von Mises, Kolmogorov–Smirnov and Shapiro–Wilk, were performed. These tests demonstrated that log-transformed triglyceride values were not normally distributed, thus median percent changes were additionally determined and analyzed.For the DBTP and SBTP, both percent change and absolute triglyceride values, as well as safety and other efficacy end points, were summarized descriptively. For the DBTP, post hoc nominal 