Statistical analysis
migraine, Migraine, CM
REGRESSION, EVENT, SECONDARY, MIGRAINE, MIGRAINE
In a prior study of eptinezumab, the subgroup of CM patients with MOH showed an improvement of 3.0 MMDs for the 100-mg dose compared to placebo, with a standard deviation of 6.0 [The estimand for the primary endpoint was described by the following attributes. The first attribute was the population of interest, which was patients with a dual diagnosis of migraine and MOH who fulfilled the inclusion and exclusion criteria of the study. The second attribute was the endpoint to be considered, which was the change from baseline in MMDs (Weeks 1–12). The third attribute was the treatment condition of interest, which was the comparison of eptinezumab 100 mg to placebo, with or without the use of preventive migraine medication. The fourth attribute was the other intercurrent event of interest, which was handled with a treatment policy strategy to assess the effect regardless of infusion interruption or termination before full dose is received. The last attribute was the population level summary, which was the mean difference in the primary endpoint across Weeks 1–12 comparing the effect of eptinezumab 100 mg to placebo.The main estimator for the primary estimand was based on the primary endpoint, change from baseline in the number of MMDs (Weeks 1–12), which was estimated using a restricted maximum likelihood–based mixed model for repeated measures (MMRM) approach. The analysis was performed on MMDs by month using an MMRM, with month defined as 4-week intervals (Weeks 1–4, Weeks 5–8, Weeks 9–12), with baseline MMDs as a continuous covariate, and treatment, stratum (< 20 MHDs, ≥ 20 MHDs at baseline), month, and region as fixed factors. In addition, the model included treatment-by-month interaction, baseline MMDs-by-month interaction, and stratum-by-month interaction. Within-patient errors were modeled using an unstructured variance.For the key secondary endpoints based on responder rates, treatment effects compared to placebo were analyzed using a logistic regression model that included MMDs at baseline as a continuous covariate, and treatment and stratification factor (< 20 MHDs, ≥ 20 MHDs at baseline) as factors. Migraine rate on the day after dosing (Day 1), was analyzed using a Cochran–Mantel–Haenszel test controlling for stratification factor (< 20 MHDs, ≥ 20 MHDs at baseline). Change from baseline in the number of MMDs with use of AHM (Weeks 1–12) and change from baseline in the number of MHDs (Weeks 1–12) were analyzed similarly to the primary endpoint.The formal statistical testing of the primary endpoint and the 6 key secondary endpoints was done hierarchically, in a sequence of a maximum number of 7 steps. For each step, the treatment effect was tested on a 5% significance level, using a two-sided test, and testing only continued to the next step if all prior effects in the hierarchy were found to have p-values below the specified significance level (Supplemental Figure 