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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The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement
Michael W. Weiner,Dallas P. Veitch,Paul S. Aisen,Laurel A. Beckett,Nigel J. Cairns,Robert C. Green,Danielle J Harvey,Clifford R. Jack,William J. Jagust,John C. Morris,Ronald C. Petersen,Jennifer Salazar,Andrew J. Saykin,Leslie M. Shaw,Arthur W. Toga,John Q. Trojanowski +15 more
TL;DR: The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease clinical trials.
Journal ArticleDOI
Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes.
TL;DR: Drug development decision making can be improved based on lessons learned from past trials, improved interpretation of animal models, better pharmacologic characterization in phase I and phase II trials, appropriate sample size, diagnosis of AD with biomarker support, optimization of global recruitment, and avoiding inappropriate subgroup analyses can improve drug development success rates.
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The "rights" of precision drug development for Alzheimer's disease.
TL;DR: Attention to disciplined drug development will increase the likelihood of success, decrease the risks associated with AD drug development, enhance the ability to attract investment, and make it more likely that new therapies will become available to those with or vulnerable to the emergence of AD.
Journal ArticleDOI
Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future
TL;DR: Alzheimer’s disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed.
Journal ArticleDOI
Sex and gender differences in the treatment of Alzheimer’s disease: A systematic review of randomized controlled trials
Marco Canevelli,Federica Quarata,Francesca Remiddi,Flaminia Lucchini,Eleonora Lacorte,Nicola Vanacore,Giuseppe Bruno,Matteo Cesari +7 more
TL;DR: A considerable amount of data, with an adequate representativeness in terms of sex/gender distribution, seem to be already available for dedicated analyses on this topic and a greater effort should be made to collect and report data on those factors interacting with sex and gender that may significantly influence clinical manifestations, outcomes, and trajectories over time of AD patients.
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