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Articles by Eric R. Siemers
Total Records ( 6 ) for Eric R. Siemers
  Reisa A. Sperling , Clifford R. Jack , Sandra E. Black , Matthew P. Frosch , Steven M. Greenberg , Bradley T. Hyman , Philip Scheltens , Maria C. Carrillo , William Thies , Martin M. Bednar , Ronald S. Black , H. Robert Brashear , Michael Grundman , Eric R. Siemers , Howard H. Feldman and Rachel J. Schindler
  Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-β burden in Alzheimer‘s disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer‘s Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent ”vasogenic edema“ and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2∗ thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. The etiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. The workgroup proposes recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research.
  Nicolas M. Furiak , Kristin Kahle- Wrobleski , Christopher Callahan , Timothy M. Klein , Robert W. Klein and Eric R. Siemers
  Background Advances in screening and treatment are needed to mitigate increasing prevalence of dementia due to Alzheimer‘s disease (DAT). Current proposals to revise Alzheimer‘s disease (AD) diagnostic criteria incorporate diagnostic biomarkers. Such revisions would allow identification of persons with AD pathology before the onset of dementia. The population-level impact of screening for preclinical AD and treating with a disease-modifying agent is important when evaluating new biomarkers and medications. Methods A published computer simulation model assigned AD-related event times, such that delays in disease progression due to therapy effectiveness can be estimated for a preclinical AD cohort. Attributes such as screening sensitivity/specificity, treatment efficacy, age at first screening, and rescreening intervals were varied. Outcomes included incident mild cognitive impairment (MCI-AD), incident DAT, and number of patients recommended for treatment. Results One-time screening at age 65 years, 50% efficacy, and literature-based proxy persistence rates yielded 12.4% incidence of MCI-AD and 0.9% decrease in DAT incidence from base case of no screening/treatment. Modest reductions in incident MCI-AD and DAT were observed with more sensitive testing. Reducing specificity yielded greater reductions in MCI-AD and DAT cases, albeit by treating more patients. Probabilistic sensitivity analysis predicted that for a cohort of patients aged 65 years, the number that needed to be treated to avoid one AD case was 11.6 (range: 5.7–104). Conclusion The reduction in MCI-AD and DAT depends on initial screening age, screening frequency, and specificity. When considering population-level impact of screening–treatment, the effect of these parameters on incidence would need to be weighed against the number of individuals screened and treated.
  Martin Farlow , Steven E. Arnold , Christopher H. van Dyck , Paul S. Aisen , B. Joy Snider , Anton P. Porsteinsson , Stuart Friedrich , Robert A. Dean , Celedon Gonzales , Gopalan Sethuraman , Ronald B. DeMattos , Richard Mohs , Steven M. Paul and Eric R. Siemers
  Objectives To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer‘s disease. Cognitive measures were also obtained. Methods In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer‘s disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer‘s Disease Assessment Scale–cognitive portion was administered. Results Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ1–40 and Aβ1–42 in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aβ1–40 and Aβ1–42 in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ1–40 in CSF (P < .01), but increased unbound Aβ1–42 in CSF in a dose-dependent manner. The Alzheimer‘s Disease Assessment Scale–cognitive portion was unchanged after the 12-week antibody administration. Conclusions Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ1–42 suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ1–42 from amyloid plaques.
  David B. Henley , Karen L. Sundell , Gopalan Sethuraman and Eric R. Siemers
  Background 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. Methods 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. Results 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. Conclusions 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.
  Barry D. Greenberg , Maria C. Carrillo , J. Michael Ryan , Michael Gold , Kim Gallagher , Michael Grundman , Robert M. Berman , Timothy Ashwood and Eric R. Siemers
  Over the past 30 years, many drugs have been studied as possible treatments for Alzheimer‘s disease, but only four have demonstrated sufficient efficacy to be approved as treatments, of which three are in the same class. This lack of success has raised questions both in the pharmaceutical industry and academia about the future of Alzheimer‘s disease therapy. The high cost and low success rate of drug development across many disease areas can be attributed, in large part, to late-stage clinical failures (Schachter and Ramoni, Nat Rev Drug Discov 2007;6:107–8). Thus, identifying in phase II, or preferably phase I, drugs that are likely to fail would have a dramatic impact on the costs associated with developing new drugs. With this in mind, the Alzheimer‘s Association convened a Research Roundtable on June 23 and 24, 2011, in Washington, DC, bringing together scientists from academia, industry, and government regulatory agencies to discuss strategies for improving the probability of phase II trial results predicting success when considering the go/no-go decision-making process leading to the initiation of phase III.
  Maria C. Carrillo , H. Robert Brashear , Veronika Logovinsky , J. Michael Ryan , Howard H. Feldman , Eric R. Siemers , Susan Abushakra , Dean M. Hartley , Ronald C. Petersen , Ara S. Khachaturian and Reisa A. Sperling
  Current research including the basic biology of Alzheimer's disease (AD) provides a foundation to explore whether our current state of knowledge is sufficient to initiate prevention studies and allow us to believe prevention of AD is possible. Current research and recently revised criteria for the diagnosis of AD by the National Institutes on Aging and the Alzheimer's Association suggest a continuum of disease from preclinical asymptomatic to symptomatic Alzheimer's dementia. In light of these revised criteria, the possibility of secondary prevention and even primary prevention is under discussion. The Alzheimer's Association Research Roundtable convened a meeting to discuss the rationale and feasibility of conducting secondary prevention trials in AD.
 
 
 
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