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F3‐01‐01: THE DIAGNOSTIC FRAMEWORK FOR ALZHEIMER'S DISEASE
Author(s) -
Scheltens Philip
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.4596
Subject(s) - disease , biomarker , medicine , intensive care medicine , data science , computer science , pathology , biology , biochemistry
large samples and broad measures of change to accommodate the marked heterogeneity of AD’s demographics, genetics, symptoms, pathophysiologies, comorbidities and rates of progression. Even if such trials fail to meet their outcomes, post-hoc responder analyses may identify subsets of participants for whom the treatment was very effective. But at that point, the size, length, expense and risk of another conventionally designed study focused on a more select group of AD patients may be too daunting. Less conventional but equally rigorous RCT designs offer highly efficient ways to test treatment effects in targeted subgroups or even individuals. Multi-crossover, placebo-controlled, double-blind RCTs, including those with sample sizes as small as a single participant (“N-of-1”), are robust designs wherein participants serve as their own controls in repeated blocks of randomly sequenced crossover treatments. Heterogeneities are inherently controlled and the sensitivity, specificity and clinical relevance of outcomes can be enhanced further by including personalized outcome measures for each person. Multi-crossover RCTs enable unbiased estimation of efficacy for individual participants, and joint analysis of multiple N-of-1 trials enables estimation of efficacy for populations with much smaller sample sizes than those needed in conventional parallel group studies. It is important to identify carryover effects and natural history time trends to achieve unbiased estimation and testing of the treatment effect. We assert that in AD, multi-crossover RCTs offer many advantages over standard parallel group trials for drugs or other treatments with suitable mechanisms of action, pharmacokinetics and pharmacodynamics; despite the fact that they are almost never conducted. They may be especially useful for therapies directed at symptomatic improvement of cognitive and neuropsychiatric symptoms, but also can be used in early phase studies of disease modifying treatments with biomarker outcome measures.