FLAME: A computerized neuropsychological composite for trials in early dementia

Introduction: Sensitive neuropsychological tests are needed to improve power for clinical trials in early Alzheimer's disease (AD). Methods: To develop a neuropsychological composite (FLAME - Factors of Longitudinal Attention, Memory and Executive Function), we assessed, 10,714 participants over the age of 50 from PROTECT with validated computerized assessments for 2 years. A factorial analysis was completed to identify the key cognitive factors in all participants, and further analyses examined sensitivity to change in people with stage 2/3 early Alzheimer's disease (AD) according to the US Food and Drug Administration (FDA) framework. Results: The FLAME composite score (speed of attention, accuracy of attention, memory, and executive function) distinguished between normal cognition and stage 2/3 early AD at baseline, and was sensitive to cognitive and global/functional decline over 2 years, with the potential to improve power for clinical trials. Discussion: FLAME is sensitive to change, providing a straightforward approach to reduce sample size for RCTs in early AD. Conclusion: FLAME is a useful computerized neuropsychology composite with utility for clinical trials focusing on cognition.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.NIHR Maudsley Biomedical Research Centre for Mental Health Biomedical Research Centre for mental health at South London and Maudsley NHS Foundation Trust and King’s College London, Alzheimer’s Society, UK. Sponsor: The University of Exeter, UK Helen Brooker reports personal fees from Wesnes Cognition Ltd, owner of CogTrack, personal fees from University of Exeter, outside the submitted work. Professor Williams reports no conflict of interests. Professor Hampshire is owner and director of Future Cognition Ltd, which develops bespoke online cognitive tests for third parties. Dr. Corbett has nothing to disclose. Professor Aarsland reports grants and personal fees from Astra-Zeneca, grants and personal fees from H. Lundbeck, grants and personal fees from Novartis Pharmaceuticals, grants and personal fees from GE Health, grants and personal fees from Eisai, and grants and personal fees from Axovant, outside the submitted work. This paper represents independent research [part] funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Dr. Cummings has provided consultation to Acadia, Actinogen, AgeneBio, Alkahest, Alzheon, AnnovisBio, Avanir, Axsome, Biogen, BioXcel, Cassava, Cerecin, Cerevel, Cortexyme, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Karuna, Merck, Novo Nordisk, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Suven, Third Rock, and United Neuroscience pharmaceutical and assessment companies. Dr.Cummings has stock options in ADAMAS, AnnovisBio, MedAvante, BiOasis. Dr. Cummings owns the copyright of the Neuropsychiatric Inventory. Dr Cummings is supported by Keep Memory Alive (KMA); National Institute of Health (NIH) grant P20GM109025; National Institute of Stroke and neurological Disease grant U01NS093334; and National Institute of Aging grant R01AG053798. Jose Luis Molinuevo has served/serves as a consultant or at advisory boards for the following for-profit companies, or has given lectures in symposia sponsored by the following for-profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences, and NovoNordisk. Alireza Atri reported receiving honoraria for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for Allergan, the Alzheimer’s Association, Axovant, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, Lundbeck, Merck, Roche/Genentech, Sunovion, and Suven; receiving book royalties from Oxford University Press; and having institutional contracts or receiving investigational clinical trial–related funding from the American College of Radiology, AbbVie, Avid, Biogen, Lilly, Lundbeck, Merck, and vTV Therapeutics. Dr. Ismail reports grants and personal fees from Janssen, personal fees from Lundbeck, and personal fees from Otsuka, outside the submitted work. Dr. Creese has nothing to disclose. Professor Fladby reports no conflicts of interest. Dr Hansen is an employee of Novo Nordisk A/S and holds stock/shares in Novo Nordisk A/SÐ outside the submitted work. Keith Wesnes is CEO of Cogtrack. Professor Ballard reports grants and personal fees from Acadia pharmaceutical company, grants and personal fees from Lundbeck, personal fees from Roche, personal fees from Otsuka, personal fees from Biogen, personal fees from Eli Lilly, personal fees from Novo Nordisk, personal fees from AARP, grants and personal fees from Synexus, and personal fees from Exciva outside the submitted work.published version, accepted version (12 month embargo), submitted versio

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden