Safety profile of Alzheimer's disease populations in Alzheimer's Disease Neuroimaging Initiative and other 18-month studies
ABSTRACT Demonstration of a disease-modifying effect of a therapeutic agent on Alzheimer's disease (AD) requires a trial lasting for at least 18 months. An understanding of expected rates of adverse events (AEs), overall discontinuations, and discontinuations due to AEs, serious AEs, and deaths would be useful in planning such trials.
We examined safety information for patients taking placebo from five published 18-month AD trials and for patients from the Alzheimer's Disease Neuroimaging Initiative study.
AEs reported consistently across multiple studies were dyspnea (occurring in 5.3%-5.8% of patients), headache (4.0%-5.5%), constipation (4.3%-4.7%), nausea (2.0%-5.8%), joint swelling (3.6%-3.7%), vomiting (3.6%-3.7%), and anxiety (3.2%-3.6%). Larger multinational studies, as compared with smaller studies with fewer sites and geographies, demonstrated greater overall discontinuations (24.6%-33.0% vs 8.2%-21.0%) and greater discontinuations due to AEs (9.5%-11.6% vs 2.7%-3.2%). Rates of death (1.8%-2.4%) and SAEs (19.9%-21.2%) were consistent across 18 month published studies and in ADNI; fall was the most common SAE (2.6%-4.0%) where SAEs were reported.
In general, comparable types of AEs, frequency of deaths, and serious AEs were seen for patients taking placebo in five randomized, controlled 18-month AD trials and in Alzheimer's Disease Neuroimaging Initiative, whereas rates of discontinuations were more variable. Evaluation across studies was complicated by inconsistent methods of reporting safety information. Evaluation of large databases of placebo patients from therapeutic AD trials is needed to further enhance the understanding of expected safety outcomes in clinical trials of AD patients.
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ABSTRACT: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. Published by Elsevier Inc.Alzheimer's & dementia: the journal of the Alzheimer's Association 10/2011; 8(1 Suppl):S1-68. DOI:10.1016/j.jalz.2011.09.172 · 12.41 Impact Factor
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ABSTRACT: Selective modulation of different Aβ products of an intramembrane protease γ-secretase, could be the most promising strategy for development of effective therapies for Alzheimer's disease. We describe how different drug-candidates can modulate γ-secretase activity in cells, by studying how DAPT affects changes in γ-secretase activity caused by gradual increase in Aβ metabolism. Aβ 1-40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves. The biphasic mechanism is a result of modulation of γ-secretase activity by multiple substrate and inhibitor molecules that can bind to the enzyme simultaneously. The activation is due to an increase in γ-secretase's kinetic affinity for its substrate, which can make the enzyme increasingly more saturated with otherwise sub-saturating substrate. The noncompetitive inhibition that prevails at the saturating substrate can decrease the maximal activity. The synergistic activation-inhibition effects can drastically reduce γ-secretase's capacity to process its physiological substrates. This reduction makes the biphasic inhibitors exceptionally prone to the toxic side-effects and potentially pathogenic. Without the modulation, γ-secretase activity on it physiological substrate in cells is only 14% of its maximal activity, and far below the saturation. Presented mechanism can explain why moderate inhibition of γ-secretase cannot lead to effective therapies, the pharmacodynamics of Aβ-rebound phenomenon, and recent failures of the major drug-candidates such as semagacestat. Novel improved drug-candidates can be prepared from competitive inhibitors that can bind to different sites on γ-secretase simultaneously. Our quantitative analysis of the catalytic capacity can facilitate the future studies of the therapeutic potential of γ-secretase and the pathogenic changes in Aβ metabolism.PLoS ONE 01/2013; 8(1):e50759. DOI:10.1371/journal.pone.0050759 · 3.23 Impact Factor
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ABSTRACT: Background Interpreting Alzheimer's disease (AD) clinical trial (CT) outcomes is complicated by treatment dropouts and adverse events (AEs). In elderly participants, AE rates, dropouts, and deaths are important considerations as they may undermine the validity of clinical trials. Published discontinuation and safety data are limited. Methods Safety data from 1054 placebo-treated participants in IDENTITY and IDENTITY-2, 76-week, Phase 3 AD studies conducted in 31 countries, were pooled, annualized, and summarized overall, by country and age group. Results Median age was 74.2 (interquartile range 67.9–79.5) years; 57.4% were female; and median observation time was 63.2 (interquartile range 41.6–77.4) weeks when study drug dosing was halted. Overall annualized rates for discontinuations, discontinuations due to AEs, serious adverse events (SAEs), and deaths were 21.6% (range 19.6%–24.0%), 8.2% (range 8.1%–8.3%), 12.0%, and 1.7%, respectively. AE and discontinuation rates varied by country and age groups. Fall, pneumonia, and atrial fibrillation AEs were more frequent in the oldest age group. Conclusions These annualized placebo safety data provide insight into the course of enrolled patients with mild-to-moderate AD, and are useful in planning longer term trials and in monitoring safety.Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2014; 11(1). DOI:10.1016/j.jalz.2013.11.008 · 12.41 Impact Factor