Unless otherwise specified, baseline value is defined as the most recent non-missing measurement collected prior to the first dose. Change from baseline will be defined as post- baseline value minus baseline value. Unless stated otherwise, all statistical tests will be 2-sided with statistical significance level of 0.05
Note 1: since ADUHELM trials don’t have titration period, I think ITT/mITT defined as post titration but prior to treatment period is reasonable for Anavex. So p3 308/163 as baseline is valid ITT n. Note 2: no 1-side p
Considerations for multiple comparison adjustments A sequential (closed) testing procedure will be used to control the overall Type I error rate due to multiple comparisons for the primary endpoint. The order of treatment comparisons is as follows: aducanumab high-dose versus placebo and aducanumab low-dose versus placebo. All comparisons after the initial comparison with p > 0.05 will not be considered statistically significant. Secondary endpoints have been rank prioritized, in the order shown in Section 1.2. In order to control for a Type I error for the secondary endpoints, a sequential closed testing procedure will be used and will include both the order of the secondary endpoints and treatment comparisons. Specifically, for each of the secondary endpoints, a sequential (closed) testing procedure, as for the primary endpoint, will be used to control the overall Type I error rate due to multiple treatment comparisons. If statistical significance is not achieved for 1 or 2 treatment comparisons, all endpoint(s) of a lower rank will not be considered statistically significant for that 1or 2 treatment comparisons, respectively.There will be no multiple comparison adjustments for the sensitivity and supplementary analyses for the primary and secondary efficacy endpoints, the tertiary efficacy endpoints, the subgroup analyses or the additional analyses.
Note 3: no multiplicity adjustment required for multi-dose p3 trial if closed testing procedure is followed. Note 4: the procedure calls for high-dose test first, then lose dose, then all. Did Anavex SAP call a pooled first and high-dose next? Note 5: following list is ADUHELM test procedure. The responders analysis is way down the list. Did Anavex have a different order list? Can Anavex put responders analysis on top to replace the score delta?
CDR-SB Primary: Analysis of change from baseline at Week ITT 78 (MMRM) Sensitivity: Pattern mixture model (ANCOVA) ITT Sensitivity: Copy increment from reference method ITT (ANCOVA) Sensitivity: Imputation by natural disease progression ITT (ANCOVA) Sensitivity: Tipping point analysis (ANCOVA) ITT Supplementary: Censoring after intercurrent events ITT (MMRM)* Supplementary: Per-protocol analysis (MMRM) Per-protocol Supplementary: Responder analysis (Logistic ITT regression) Supplementary: Slope analysis (MMRM) ITT Supplementary: Divergence effect analysis (MMRM) ITT
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