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ENDPOINT SELECTION AND POWER ESTIMATES FOR TH PRIMARY COGNITIVE ENDPOINT IN A PHASE 2 TRIAL OF XPRO1595 IN ALZHEIMER’S DISEASE (AD) WITH INFLAMMATION (ADI)
Abstract
Aims
An alternative cognitive endpoint is needed to the ADAS-Cog, which is almost uniformly used in clinical trials in Mild Alzheimer’s Disease (AD). This is despite extensive empirical evidence of ceiling effects on most items rendering them 1) insensitive to change in the mild stage of the disease and 2) inaccurate estimators of change magnitude since it is unknown how much change must occur to move the measure off the ceiling.
Methods
An alternative endpoint, the Early Mild Alzheimer’s Cognitive Composite (EMACC) was empirically developed in a four cohort collaboration (Jaeger, 2018) and includes 6 validated neuropsychological test paradigms that together demonstrate the steepest slope decline in amyloid confirmed Early/Mild AD. All these paradigms have reliably been used in global clinical trials.
The statistical power of EMACC was calculated in the ADNI cohort and compared with that of ADAS-Cog and CDR while planning a phase 2 trial of XPro1595, an immune modulator being tested in early Mild Alzheimer’s patients with inflammation (ADi).
Results
Mild ADi patients declined more during 12 months than the non-inflammed (ADAS-Cog 13 ES=0.46 vs 0.33; EMACC ES=0.76 vs 0.37). The N required to detect a clinically meaningful drug effect (80%power, 2-sided, Alpha=0.05) at 12 months in patients with ADi (given upper and lower ES assumptions) ranged from 130 to 188 for ADAS-Cog, 126 to 224 for CDR-SB and 56 to 86 for EMACC.
Conclusions
Inflammation accelerates AD cognitive decline. EMACC’s superior sensitivity to disease progression permits half the sample size to test the hypothesis of immune modulator XPro1595’s benefit to cognition.