Statistical methods
non-ambulant, risdiplam, scoliosis
REGRESSION, DISEASE CHARACTERISTIC, SCOLIOSIS
Exploratory efficacy analyses were conducted based on the all-exposure-to-risdiplam treatment period (the treatment period after receiving the first dose of risdiplam). Randomized patients who did not receive risdiplam treatment were not included in the exploratory efficacy analyses; this condition applied to one patient who was originally randomized to the placebo group but left the study early, and thus did not receive risdiplam treatment. For each efficacy endpoint, individuals who fulfilled the corresponding missing motor function scale item rules were excluded at the corresponding time point, as predefined in the statistical analysis plan.Efficacy endpoints were summarized by randomized treatment (risdiplam or placebo switched to risdiplam) for the all-exposure-to-risdiplam treatment period. For patients initially on risdiplam treatment, results at month 12, month 18, and month 24 were summarized. For patients initially on placebo, the adjusted baseline (defined as the last measurement prior to the first dose of risdiplam) was used for the analyses and results at month 12 on risdiplam treatment (i.e., month 24 in the study) were summarized.All patients who received at least one dose of risdiplam (After month 12, all patients in SUNFISH received risdiplam while maintaining blinding to the initial treatment randomization. An external comparator group of untreated individuals with Type 2 and Type 3 SMA was, therefore, used to give context to SUNFISH Part 2 results at month 24 for those initially randomized to the risdiplam treatment arm. The external comparator population comprised 81 patients from the NatHis-SMA study (NCT02391831) [For the external comparator analysis, MFM total score was used for all analyses to compare motor function at month 24. To calculate MFM total score (hereinafter referred to as MFM-derived total score), the external control data were compared with SUNFISH Part 2 data based on the 20-item MFM (MFM20) total score [Since the SUNFISH Part 2 study population consisted of non-ambulant patients with types 2 and 3 SMA, ambulant patients were not included in the external control comparison analysis. To ensure robust analysis, patients from the external comparator data set were selected based upon similarities to the SUNFISH Part 2 risdiplam arm patients in terms of demographics, the MFM version, and disease characteristics. After applying the missing item rule on the MFM scale and trimming to exclude patients with missing information on selected prognostic factors (age, SMA type, Patients in the external comparator group were weighted using inverse probability of treatment weighting based upon the selected prognostic factors at baseline, creating a pseudo-population with similar covariate distributions in the treated and untreated groups. A propensity score for each patient was estimated using logistic regression incorporating potential predictors of treatment assignment (risdiplam versus no risdiplam) as independent variables. The potential predictors included in the model were age at baseline (years), SMA type (type 2 or non-ambulant type 3), baseline MFM total score, presence of scoliosis at baseline (yes or no), Change from baseline in MFM-derived total score was analyzed as an independent variable using a mixed model for repeated measures (MMRM). The independent variables in the MMRM included baseline MFM-derived total score, treatment, time of assessment (i.e., the categorical study visit weeks 17, 26, 35, 52, 78, and 104), treatment-by-time interaction, baseline-by-time interaction, age at baseline, SMA type, 