This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using Rey Auditory Verbal Learning Task total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n = 499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the Clinical Dementia Rating scale sum of boxes consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in Alzheimer's disease is enhanced by the use of biomarker inclusion criteria.
Studies of the biology of Alzheimer's disease (AD) have identified an array of targets for potential disease-modifying therapies (Mangialasche et al., 2010), but clinical trials in patients with dementia have been unsuccessful so far (Green et al., 2009, Sabbagh, 2009, Cummings, 2010, Quinn et al., 2010 and Samson, 2010). Biological substrates of AD can be identified before patients become demented (Morris et al., 2009), and some AD biomarkers reach peak levels of abnormality before diagnosis (Jack et al., 2010 and Lo et al., 2011). It is possible that failed dementia trials may have intervened too late in the disease process to be effective (St. George-Hyslop and Morris, 2008).
Clinical trials of investigational drugs targeting AD biology can enroll patients earlier in the disease, before criteria for dementia are fulfilled. Primary prevention trials enroll volunteers with no clinical or biological signs of AD at baseline but require thousands of participants and take many years to complete, as only a fraction of participants will develop AD (DeKosky, 2006). To date, few primary AD prevention trials have been conducted, and no agent has been shown to delay or prevent dementia onset. Secondary prevention trials can enroll participants at increased risk for dementia, affording decreased sample sizes and trial lengths. Secondary prevention trials have included individuals with mild cognitive impairment (MCI), a clinical syndrome defined by memory impairment or other cognitive problems, when compared with age- and education-matched norms, in the absence of functional decline (Petersen et al., 1999). Even some trials enrolling MCI participants have encountered low rates of disease progression (Feldman et al., 2007).
Biological markers of AD predict clinical progression and may be used to identify potential trial participants at greatest risk for dementia. Low levels of beta-amyloid (Aβ) or elevated levels of total tau (tTau) or tau phosphorylated at threonine 181 (pTau) in the cerebrospinal fluid (CSF; e.g., [Mattsson et al., 2009]), evidence of cerebral atrophy on magnetic resonance imaging (MRI; e.g., [Apostolova et al., 2006]), and brain glucose hypometabolism observed with fluorodeoxyglucose positron emission tomography (FDG-PET) (e.g., [Landau et al., 2010]) identify MCI patients at increased and more immediate risk for AD dementia. Even in asymptomatic individuals, the presence of biological evidence of AD significantly increases the risk for future cognitive impairment and AD dementia (Mosconi et al., 2009, Apostolova et al., 2010 and Dickerson et al., 2011).
Thus, it is likely that using AD biomarkers as enrollment criteria can reduce the number of participants needed and study duration for AD prevention trials. Using AD biomarkers as outcome measures in AD trials can similarly improve trial efficiency (Jack et al., 2004, Hua et al., 2009, Schuff et al., 2009, Chen et al., 2010, Kohannim et al., 2010, Leung et al., 2010 and Schott et al., 2010a). The U.S. Food and Drug Administration (FDA), however, has not accepted any biomarker as a surrogate suitable for use as a primary outcome measure in AD trials. Moreover, FDA guidance outlines the use of clinical measures to achieve marketing approval (Leber, 1996 and Katz, 2004). Therefore, registration trials, even those conducted in very mild disease, continue to use the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and other clinical scales as primary outcome measures.
The statistical power of predementia trials may be improved by population enrichment strategies using biomarkers. These trials might be able to use a single primary outcome measure (rather than dual primary outcomes, as is the case in dementia trials [Aisen et al., 2011]). Using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set, we sought to identify the best enrichment strategies for predementia trials in relation to outcome measures to optimize statistical power. We hypothesized that enriching cognitively normal (CN) and MCI trial populations through biomarker criteria would reduce required sample sizes.
