Alzheimer's disease progression by geographical region in a clinical trial setting.
David B. Henley,Sherie A. Dowsett,Yun-Fei Chen,Hong Liu-Seifert,Joshua D. Grill,Rachelle S. Doody,Paul S. Aisen,Rema Raman,David S. Miller,Ann Marie Hake,Ann Marie Hake,Jeffrey L. Cummings +11 more
TLDR
Assessment of disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology suggests that in multi- national clinical trials, AD progression or its measurement may differ across geographical regions.Abstract:
To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer’s disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology. Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI). Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline. These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm. ClinicalTrials.gov NCT00594568
– IDENTITY. Registered 11 January 2008. ClinicalTrials.gov NCT00762411
– IDENTITY2. Registered 26 September 2008 ClinicalTrials.gov NCT00905372
– EXPEDITION. Registered 18 May 2009 ClinicalTrials.gov NCT00904683
– EXPEDITION2. Registered 18 May 2009read more
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Re-Engineering Alzheimer Clinical Trials: Global Alzheimer's Platform Network.
J. Cummings,Paul S. Aisen,R Barton,J Bork,Rachelle S. Doody,J Dwyer,J C Egan,Howard Feldman,D Lappin,L Truyen,Stephen Salloway,Reisa A. Sperling,G Vradenburg +12 more
TL;DR: GAP-NET proposes to establish a standardized network of continuously funded trial sites that are highly qualified to perform trials that will conduct trials for academic and biopharma industry partners using standardized instrument versions and administration.
Journal ArticleDOI
Incident cognitive impairment: longitudinal changes in molecular, structural and cognitive biomarkers
Catherine M. Roe,Beau M. Ances,Denise Head,Ganesh M. Babulal,Sarah H. Stout,Elizabeth A. Grant,Jason Hassenstab,Chengjie Xiong,David M. Holtzman,Tammie L.S. Benzinger,Suzanne E. Schindler,Anne M. Fagan,John C. Morris +12 more
TL;DR: Conversion from cognitively normal to CDR > 0 is characterized by not only the magnitude of molecular biomarkers but also rate of change in cognitive and structural biomarkers, and theoretical models of biomarker changes seen during transition to cognitive impairment are supported.
BookDOI
Alzheimer's Disease Drug Development
TL;DR: This is a definitive overview of how the ecosystem works in transferring an AD drug from its discovery in the laboratory through clinical trial testing to regulatory review and eventual marketing.
Journal ArticleDOI
Insights into globalization: comparison of patient characteristics and disease progression among geographic regions in a multinational Alzheimer's disease clinical program.
Jeffrey L. Cummings,Alireza Atri,Alireza Atri,Clive Ballard,Neli Boneva,Lutz Frölich,José Luis Molinuevo,Lars Lau Raket,Pierre N. Tariot +8 more
TL;DR: Regional heterogeneity—in terms of study conduct, patient characteristics, and outcomes—exists, and should be accounted for, when planning and conducting multinational AD clinical trials.
Journal ArticleDOI
Historical Controls in Randomized Clinical Trials: Opportunities and Challenges
Kathryn T. Hall,Kathryn T. Hall,Lene Vase,Deirdre K Tobias,Deirdre K Tobias,Hesam Dashti,Hesam Dashti,Jan Vollert,Jan Vollert,Ted J. Kaptchuk,Ted J. Kaptchuk,Nancy R. Cook,Nancy R. Cook +12 more
TL;DR: Challenges in utilizing historical controls related to heterogeneity in trial design, outcome ascertainment, patient characteristics, and unmeasured pharmacogenomic effects are examined.
References
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“Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician
Marshal F. Folstein,Marshal F. Folstein,Susan E B Folstein,Susan E B Folstein,Paul R. McHugh,Paul R. McHugh +5 more
TL;DR: A simplified, scored form of the cognitive mental status examination, the “Mini-Mental State” (MMS) which includes eleven questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely.
A practical method for grading the cognitive state of patients for the clinician
TL;DR: The Mini-Mental State (MMS) as mentioned in this paper is a simplified version of the standard WAIS with eleven questions and requires only 5-10 min to administer, and is therefore practical to use serially and routinely.
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The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia
Jeffrey L. Cummings,Michael S. Mega,Kevin F. Gray,S. Rosenberg-Thompson,Daniela Carusi,Jeffrey Gornbein +5 more
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Journal ArticleDOI
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease
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TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Journal ArticleDOI
Alzheimer's Disease International.
Nori Graham,Henry Brodaty +1 more
TL;DR: The output of the 1994 Xth Alzheimer's Disease International meeting in Edinburgh in 1994 reflects the international experience of the disorder in self‐help groups in Eastern Europe, difficulties of epidemiological studies in India and the complex interplay between staff attitude and residents' sexuality in nursing homes in the USA.