Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer’s disease clinical trials

Abstract

IntroductionMost Alzheimer’s disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region.MethodsWe used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan.ResultsNorth America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E ε4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR-SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan.ConclusionsThese findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials.

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“…Recent studies of global trials show that North American and Western European data are very similar with regard to baseline characteristics, placebo group behavior, outcome measures, and adverse event reporting. Substantial variations on these parameters were observed for other global regions …”

“…Substantial variations on these parameters were observed for other global regions. 46,47 The lesson to be derived from these studies is that sponsors should seek ways of minimizing variability in global trials to insure greater data homogeneity. Table 1 Guidelines to establish the likely validity of a subgroup as a guide to additional trials; a "yes" answer is most consistent with a nonspurious subgroup (from 51,52)…”

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