Outcomes and statistical analysis
dementia
SECONDARY, SENSITIVITY
The primary analysis was absolute change (δ) from baseline on ADAS-cog or ADCS-ADL over 24 weeks (positive δADAS-cog indicating worsening dementia while negative δADCS-ADL indicates worsening function), with treatment effect being demonstrated by a significant between-group difference (Δ, masitinib versus placebo) on at least one of the multiple primary endpoints, with a significance level of 0.025. A negative ΔADAS-cog value or positive ΔADCS-ADL value favors masitinib. Results were calculated using a model of analysis of covariance (ANCOVA) adjusted on the aforementioned stratification variables and expressed as least-squares mean (LSM) change from baseline with corresponding 97.5% two-sided confidence intervals (CI) and statistical test P-value. Primary efficacy analysis was done according to a full analysis dataset (FAS) in which patients received at least one dose of the trial regimen and whose scores had not been potentially influenced by any source of strong bias during the 24-week assessment period (according to predefined rules and validated by the IDMC prior to unblinding; see Sensitivity analyses and secondary endpoints were tested at the 0.05 significance level. Consistency of the primary analysis was tested using predefined sensitivity analyses including multiple imputation and the conservative jump-to-reference method. This latter approach assumes that patients who discontinue treatment for lack of efficacy or safety will no longer benefit from it in the future, and thus will tend to have outcomes similar to those in the control group [Based on phase 2 (AB04024) study data, we estimated that change in ADCS-ADL at week 24 would be −0.6 (±9.0) for placebo, +2.5 (±9.0) for masitinib 4.5 mg/kg/day, and +3.2 (±9.0) for masitinib 6.0 mg/kg/day, while change in ADAS-cog at week 24 would be +2.0 (±7.0) for placebo, −0.4 (±7.0) for masitinib 4.5 mg/kg/day, and −1.0 (±7.0) for masitinib 6.0 mg/kg/day. Detection of this difference, with a two-sided 0.05 significance level and a power of 80%, would require a minimum sample size of 300 patients for the masitinib 4.5 mg/kg/day parallel group (150 per treatment-arm), and a total of 225 patients for the titrated masitinib 6.0 mg/kg/day parallel group (150 masitinib versus 75 placebo).