Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] 16S developing MCI due to AD in cognitively normal adults, ages 65 to 83 years, over a five-year time-frame. The initiative will incorporate age, APOE genotype (e2, e3, or e4), and TOMM40-523 genotype [Short (S), Long (L), or Very Long (VL)]. Evaluating a low dose of pioglitazone (relative to doses used in Diabetes) in delaying the onset of MCI due to AD can also add further information regarding subject profiles (Figure 1). As mentioned, this initiative is an event-based trial with duration of the study as the amount of time needed to achieve 410 events (e.g., detection of MCI) in the high-risk Caucasian group, which is estimated to take approximately four years. A reason for targeting Caucasians in this type of study relates to the prevalence of genetic risk factors for dementia. For instance, the onset of dementia in Japan is approximately 10 years after that of individuals who live in the United States, and the Japanese population has a lower prevalence of APOE4 as a potential contributor to this finding. Given such differences, a number of sites around the world will be participating in this study, such as United States, United Kingdom, Ireland, Italy, Switzerland, Germany, Russia, and Australia to help generalize results from this study to a real-world population. Enrollment and endpoints. Subjects will be genotyped and placed either into a high-risk or low-risk group according to the biomarkers of relevance. Approximately 2,311 high- risk subjects will be randomized to pioglitazone treatment and an equal number will be randomized to placebo. This randomization is to primarily evaluate the efficacy of the drug treatment while another group consisting of 600 low-risk subjects as determined by the algorithm is to receive placebo. This aspect will be used to qualify the biomarker algorithm as an appropriate risk factor. The low risk group will not be treated using pioglitazone due to the unknown medication efficacy. Traditional core clinical criteria for MCI endpoints in Phase III studies involve batteries that assess cognitive functioning with performance-based and observational measures. In this study, changes in cognition will be assessed by report from the subject, informant, or clinician (e.g., historical or observed evidence of decline over time), and from objective evidence of impairment in one or more cognitive domains, typically including memory (e.g., formal testing to establish level of cognitive function in multiple domains). For instance, conversion to MCI due to AD would show preservation of independence in functional abilities and criteria consisting of a clinical dementia rating (CDR) scale score of 0.5, AND one of the following: a) fails at least one of the two memory tests in the cognitive test battery; b) fails two or more of the 12 measures in the cognitive test battery representing separate cognitive d omains. There are also many things to rule out in a potential study subject prior to their enrollment, such as vascular, traumatic, and medical causes of cognitive decline. A decision that an individual has an outcome of MCI will be determined through evidence of a longitudinal decline in cognition and continued evidence of cognitive impairment or decline on a six-month follow-up (e.g., 2 consecutive study visits showing impairment). The tests that are used to assess the presence of MCI include five different cognitive domains: episodic memory (California Verbal Learning Test-2nd Edition (CVLT-III); visuospatial memory (Brief Visuospatial Memory Test-Revisited; BVMT-R); 3) executive function (Trail Making Test, Part B); 4) WAIS-III Digit Span Test (backwards span); and 5) language [Multilingual Naming Test (MINT); semantic fluency (animals), Lexical/Phonemic Fluency (FAS); attention (WAIS-III Digit Span Test- forward span; Trail Making Test (Part A), and visuospatial (Clock Drawing Test; Copy of BVMT figures]. An adjudication process will be used in all subjects to make the final determination of MCI. In short, all pertinent data will be shared with an adjudication committee comprising at least three expert clinicians who are blinded to the subject's risk and treatment assignments. The process will result in one of four possible clinical assessment and subsequent outcomes as measured in the trial design. This study utilizes a primary outcome of conversion rate to MCI in asymptomatic individuals. Secondary objectives are to the effects of a low dose of pioglitazone on 1) progression of cognitive decline. Safety objectives correspond to long-term safety and tolerability of pioglitazone versus placebo and incidence of treatment- emergent ARIA in cognitively normal elderly patients who received pioglitazone for six months (in a FIGURE 1. The Alzheimer's disease continuum and our proposed study

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