Rachel Schindler

Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease LEADe

Background: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD. Methods: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13–25), were aged 50–90 years, and were taking donepezil 10 mg daily for ≥3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were >95 and <195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimers Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimers Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks. Results: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated. Conclusions: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. Classification of evidence: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50–90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimers Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimers Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.

Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer’s Association Research Roundtable Workgroup

Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid‐β burden in Alzheimers disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimers 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.

3-Year Study of Donepezil Therapy in Alzheimer’s Disease: Effects of Early and Continuous Therapy

Delays in the diagnosis of Alzheimer’s disease, and, therefore, delays in treatment, may have a detrimental effect on a patient’s long-term well-being. This studyassessed the effects of postponing donepezil treatment for 1 year by comparing patients treated continuously for 3 years with those who received placebo for 1 year followed by open-label donepezil for 2 years. Patients (n = 286) with possible or probable Alzheimer’s disease (according to DSM-IV, NINCDS-ADRDA, and Mini-Mental State Examination criteria; see text) were randomized to receive donepezil (5 mg/day for 4 weeks, 10 mg/day thereafter) or placebo (delayed-start group) for 1 year. Of the 192 completers, 157 began a 2-year, open-label phase of donepezil treatment. Outcome measures were the Gottfries-Bråne-Steen scale, the Mini-Mental State Examination, the Global Deterioration Scale, the Progressive Deterioration Scale, the Neuropsychiatric Inventory, and safety (adverse events). Mixed regression analysis was used to compare changes between the groups over 3 years on the efficacy measures. There was a trend for patients receiving continuous therapy to have less global deterioration (Gottfries-Bråne-Steen scale) than those who had delayed treatment (p = 0.056). Small but statistically significant differences between the groups were observed for the secondary measures of cognitive function (Mini-Mental State Examination; p = 0.004) and cognitive and functional abilities (Global Deterioration Scale; p = 0.0231) in favor of continuous donepezil therapy. Over 90% of the patients in both cohorts experienced one treatment-emergent adverse event; most were considered mild or moderate. In conclusion, patients in whom the start of treatment is delayed may demonstrate slightly reduced benefits as compared with those seen in patients starting donepezil therapy early in the course of Alzheimer’s disease. These data support the long-term efficacy and safety of donepezil.

Report of the task force on designing clinical trials in early (predementia) AD

Background: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. Method: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. Results: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. Conclusion: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

Donepezil in vascular dementia : Combined analysis of two large-scale clinical trials

Background and Objective: There are currently no drugs approved to treat vascular dementia (VaD).The objective of this study was to determine if treatment with donepezil, an acetylcholinesterase inhibitor, may provide benefit for VaD patients. Methods: Combined analysis of 2 identical randomized, double-blind, placebo-controlled, 24-week studies involving 1,219 patients enrolled at 109 investigational sites in the USA, Europe, Canada and Australia. Patients were randomized to receive donepezil 5 mg/day (n = 406) or 10 mg/day (after brief titration; n = 421) or placebo (n = 392). Patients were assessed on cognition [Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS[-]cog), Mini-Mental State Examination (MMSE)], global function [Clinician’s Interview- Based Impression of Change plus (CIBIC[-]plus), Clinical Dementia Rating – Sum of the Boxes (CDR[-]SB)] and function [Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS); instrumental activities of daily living (ADFACS[-]IADL)].Results:Both donepezil groups showed significant improvements in cognition compared with placebo (ADAS-cog, MMSE, p< 0.01). Significant global function benefits were seen on the CIBIC-plus in the 5 mg/day group (placebo vs. 5 mg/day, p < 0.001; vs. 10 mg/day, p = 0.006) and on the CDR-SB in the 10 mg/day group (placebo vs. 5 mg/day, p = 0.09; vs. 10 mg/day, p< 0.01). Significant functional benefits were also seen (ADFACS, placebo vs. 5 mg/day, p = 0.08; vs. 10 mg/day, p = 0.02; ADFACS-IADL, p < 0.05 for both donepezil groups). Donepezil was well tolerated, with low withdrawal rates due to adverse events. Conclusions: This combined analysis of the largest trial on VaD to date showed that donepezil-treated patients had significant benefits in cognition, global function and ability to perform IADL. Based on these findings and reported tolerability, donepezil should be considered as an important therapeutic element in the overall management of patients with VaD.

The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics

Growing evidence suggests that elevated cholesterol levels in mid‐life are associated with increased risk of developing Alzheimers disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitors Effect in Alzheimers Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily).

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease

With increasing numbers of people with Alzheimers and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimers Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimers Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimers disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long‐term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimers Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimers and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimers by 2025. This report presents these Workgroup recommendations.

Effectiveness of Donepezil in Reducing Clinical Worsening in Patients with Mild-to-Moderate Alzheimer’s Disease

Background: Therapeutic endpoints based on reduced clinical worsening represent clinically relevant and realistic goals for patients suffering from progressive neurodegenerative disorders such as Alzheimer’s disease (AD). Methods: Data from 906 patients (388 receiving placebo; 518 receiving donepezil) with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score 10–27] were pooled from 3 randomized, double-blind placebo-controlled studies. Clinical worsening was defined as decline in (1) cognition (MMSE), (2) cognition and global ratings (Clinician’s Interview-Based Impression of Change plus Caregiver Input/Gottfries-Bråne-Steen scale) or (3) cognition, global ratings and function (various functional measures). Results: At week 24, lower percentages of donepezil-treated patients than placebo patients met the criteria for clinical worsening, regardless of the definition. The odds of declining were significantly reduced for donepezil-treated versus placebo patients (p < 0.0001; all definitions). Among patients meeting criteria for clinical worsening, mean declines in MMSE scores were greater for placebo than donepezil-treated patients. Conclusion: In this population, donepezil treatment was associated with reduced odds of clinical worsening of AD symptoms. Moreover, patients worsening on donepezil were likely to experience less cognitive decline than expected if left untreated. This suggests that AD patients showing clinical worsening on donepezil may still derive benefits compared with placebo/untreated patients.

Assessing cognition and function in Alzheimer's disease clinical trials: Do we have the right tools?

Several lines of evidence from Alzheimers disease (AD) research continue to support the notion that the biological changes associated with AD are occurring possibly several decades before an individual will experience the cognitive and functional changes associated with the disease. The National Institute on Aging—Alzheimers Association revised criteria for AD provided a framework for this new thinking. As a result of this growing understanding, several research efforts have launched or will be launching large secondary prevention trials in AD. These and other efforts have clearly demonstrated a need for better measures of cognitive and functional change in people with the earliest changes associated with AD. Recent draft guidance from the US Food and Drug Administration further elevated the importance of cognitive and functional assessments in early stage clinical trials by proposing that even in the pre‐symptomatic stages of the disease, approval will be contingent on demonstrating clinical meaningfulness. The Alzheimers Associations Research Roundtable addressed these issues at its fall meeting October 28–29, 2013, in Washington, D.C. The focus of the discussion included the need for improved cognitive and functional outcome measures for clinical of participants with preclinical AD and those diagnosed with Mild Cognitive Impairment due to AD.

Assessing Therapeutic Efficacy in a Progressive Disease A Study of Donepezil in Alzheimer's Disease

AbstractObjective: To determine the value of continued donepezil treatment in patients with Alzheimer’s disease for whom clinical benefit was initially judged to be uncertain. Methods: The study consisted of three phases: (i) a 12- to 24-week, pre-randomisation, open-label donepezil-treatment phase; (ii) a 12-week, randomised, double-blind, placebo-controlled phase; and (iii) a 12-week, single-blind (i.e. patient-blind) donepezil-treatment phase. Patients with mild to moderate Alzheimer’s disease received open-label treatment with donepezil (5 mg/day for 4 weeks, then 10 mg/day for the remainder of the phase) for 12–24 weeks. Patients who exhibited a decline or no change from baseline on the Mini-Mental State Examination (MMSE) and whose physician was not sufficiently certain of clinical benefit to warrant continued treatment were randomised into the double-blind phase in which patients received 12 weeks of treatment with donepezil (10 mg/day) or placebo. At the end of the double-blind phase, donepezil-treated patients continued to receive donepezil, while placebo-treated patients were rechallenged with donepezil, in a 12-week single-blind phase. Patients were assessed at the start of the double-blind phase and at weeks 6 and 12 of this phase, and at the end of the single-blind phase. Results: Six hundred and nineteen patients completed the open-label phase; 69% showed clear clinical benefit and 31% showed uncertain benefit. 202 patients were randomised to continued donepezil treatment (n = 99) or placebo (n = 103). Differences in favour of continued donepezil versus placebo were observed in cognition and behaviour. In addition, there was a non-significant trend favouring donepezil in activities of daily living (ADL) [week 12 observed case mean treatment differences: MMSE, 1.13 (p = 0.02); Alzheimer’s Disease Assessment Scale - cognitive subscale, 0.57 (p = 0.5); the Neuropsychiatric Inventory, −3.16 (p = 0.02); Disability Assessment for Dementia scale, 3.67 (p = 0.1)]. Conclusion: Most patients showed clear clinical benefit during initial donepezil treatment. Among patients for whom clinical benefit was uncertain, improvement in cognition and behaviour were observed for those who continued donepezil treatment compared with the group switched to placebo. Initial decline or stabilisation does not necessarily indicate a lack of efficacy in Alzheimer’s disease, and the decision to discontinue treatment should be based on an evaluation of all domains (cognition, behaviour and ADL) and performed at several timepoints.