Lucy Webster1, Derek Groskreutz2, Anna Grinbergs-Saull3, Rob Howard1, John T O'Brien4, Gail Mountain5, Sube Banerjee6, Bob Woods7, Robert Perneczky8, Louise Lafortune9, Charlotte Roberts10, Jenny McCleery11, James Pickett3, Frances Bunn12, David Challis13, Georgina Charlesworth14, Katie Featherstone15, Chris Fox16, Claire Goodman12, Roy Jones17, Sallie Lamb18, Esme Moniz-Cook19, Justine Schneider20, Sasha Shepperd21, Claire Surr22, Jo Thompson-Coon23, Clive Ballard24, Carol Brayne9, Orlaith Burke21, Alistair Burns25, Linda Clare23,26,27, Peter Garrard28, Patrick Kehoe29, Peter Passmore30, Clive Holmes31, Ian Maidment32, Fliss Murtagh33, Louise Robinson34, Gill Livingston1,35,36. 1. Division of Psychiatry, University College London, London, UK. 2. Division of Psychology and Language Sciences, University College London, London, UK. 3. Alzheimer's Society, London, UK. 4. Department of Psychiatry, University of Cambridge, Cambridge, UK. 5. School of Health and Related Research, University of Sheffield, Sheffield, UK. 6. Brighton and Sussex Medical School, University of Sussex, Brighton, UK. 7. Dementia Services Development Centre Wales, Bangor University, Bangor, UK. 8. Faculty of Medicine, School of Public Health, Imperial College London, London, UK. 9. Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK. 10. International Consortium for Health Outcomes Measurement, London, UK. 11. Oxford Health NHS Foundation Trust, Banbury, UK. 12. Centre for Research in Primary and Community Care, University of Hertfordshire, Hatfield, UK. 13. Personal Social Services Research Unit, University of Manchester, Manchester, UK. 14. Research Department of Clinical, Educational, and Health Psychology, University College London, London, UK. 15. School of Healthcare Sciences, Cardiff University, Cardiff, UK. 16. Norwich Medical School, University of East Anglia, Norwich, UK. 17. Research Institute for the Care of Older People, University of Bath, Bath, UK. 18. Oxford Clinical Trials Research Unit, University of Oxford, Oxford, UK. 19. Faculty of Health and Social Care, University of Hull, Hull, UK. 20. Institute of Mental Health, University of Nottingham, Nottingham, UK. 21. Nuffield Department of Population Health, University of Oxford, Oxford, UK. 22. School of Health & Community Studies, Leeds Beckett University, Leeds, UK. 23. Collaboration for Leadership in Applied Health Research and Care South West Peninsula, University of Exeter, Exeter, UK. 24. Wolfson Centre for Age-Related Diseases, King's College London, London, UK. 25. Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK. 26. School of Psychology, University of Exeter, Exeter, UK. 27. Centre for Research in Ageing and Cognitive Health, University of Exeter Medical School, Exeter, UK. 28. Neuroscience Research Centre, St George's, University of London, UK. 29. School of Clinical Sciences, University of Bristol, Bristol, UK. 30. Centre for Public Health, Queen's University Belfast, Belfast, UK. 31. School of Medicine, University of Southampton, Southampton, UK. 32. Aston Research Centre for Healthy Ageing, Aston University, Birmingham, UK. 33. Cicely Saunders Institute, King's College London, London, UK. 34. Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK. 35. Camden and Islington NHS Foundation Trust, London, UK. 36. North Thames Collaboration for Leadership in Applied Health Research and Care, London, UK.
Abstract
BACKGROUND: There is currently no disease-modifying treatment available to halt or delay the progression of the disease pathology in dementia. An agreed core set of the best-available and most appropriate outcomes for disease modification would facilitate the design of trials and ensure consistency across disease modification trials, as well as making results comparable and meta-analysable in future trials. OBJECTIVES: To agree a set of core outcomes for disease modification trials for mild to moderate dementia with the UK dementia research community and patient and public involvement (PPI). DATA SOURCES: We included disease modification trials with quantitative outcomes of efficacy from (1) references from related systematic reviews in workstream 1; (2) searches of the Cochrane Dementia and Cognitive Improvement Group study register, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Latin American and Caribbean Health Sciences Literature and PsycINFO on 11 December 2015, and clinical trial registries [International Standard Randomised Controlled Trial Number (ISRCTN) and clinicaltrials.gov] on 22 and 29 January 2016; and (3) hand-searches of reference lists of relevant systematic reviews from database searches. REVIEW METHODS: The project consisted of four workstreams. (1) We obtained related core outcome sets and work from co-applicants. (2) We systematically reviewed published and ongoing disease modification trials to identify the outcomes used in different domains. We extracted outcomes used in each trial, recording how many used each outcome and with how many participants. We divided outcomes into the domains measured and searched for validation data. (3) We consulted with PPI participants about recommended outcomes. (4) We presented all the synthesised information at a conference attended by the wider body of National Institute for Health Research (NIHR) dementia researchers to reach consensus on a core set of outcomes. RESULTS: We included 149 papers from the 22,918 papers screened, referring to 125 individual trials. Eighty-one outcomes were used across trials, including 72 scales [31 cognitive, 12 activities of daily living (ADLs), 10 global, 16 neuropsychiatric and three quality of life] and nine biological techniques. We consulted with 18 people for PPI. The conference decided that only cognition and biological markers are core measures of disease modification. Cognition should be measured by the Mini Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog), and brain changes through structural magnetic resonance imaging (MRI) in a subset of participants. All other domains are important but not core. We recommend using the Neuropsychiatric Inventory for neuropsychiatric symptoms: the Disability Assessment for Dementia for ADLs, the Dementia Quality of Life Measure for quality of life and the Clinical Dementia Rating scale to measure dementia globally. LIMITATIONS: Most of the trials included participants with Alzheimer's disease, so recommendations may not apply to other types of dementia. We did not conduct economic analyses. The PPI consultation was limited to members of the Alzheimer's Society Research Network. CONCLUSIONS: Cognitive outcomes and biological markers form the core outcome set for future disease modification trials, measured by the MMSE or ADAS-Cog, and structural MRI in a subset of participants. FUTURE WORK: We envisage that the core set may be superseded in the future, particularly for other types of dementia. There is a need to develop an algorithm to compare scores on the MMSE and ADAS-Cog. STUDY REGISTRATION: The project was registered with Core Outcome Measures in Effectiveness Trials [ www.comet-initiative.org/studies/details/819?result=true (accessed 7 April 2016)]. The systematic review protocol is registered as PROSPERO CRD42015027346. FUNDING: The National Institute for Health Research Health Technology Assessment programme.
BACKGROUND: There is currently no disease-modifying treatment available to halt or delay the progression of the disease pathology in dementia. An agreed core set of the best-available and most appropriate outcomes for disease modification would facilitate the design of trials and ensure consistency across disease modification trials, as well as making results comparable and meta-analysable in future trials. OBJECTIVES: To agree a set of core outcomes for disease modification trials for mild to moderate dementia with the UK dementia research community and patient and public involvement (PPI). DATA SOURCES: We included disease modification trials with quantitative outcomes of efficacy from (1) references from related systematic reviews in workstream 1; (2) searches of the Cochrane Dementia and Cognitive Improvement Group study register, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Latin American and Caribbean Health Sciences Literature and PsycINFO on 11 December 2015, and clinical trial registries [International Standard Randomised Controlled Trial Number (ISRCTN) and clinicaltrials.gov] on 22 and 29 January 2016; and (3) hand-searches of reference lists of relevant systematic reviews from database searches. REVIEW METHODS: The project consisted of four workstreams. (1) We obtained related core outcome sets and work from co-applicants. (2) We systematically reviewed published and ongoing disease modification trials to identify the outcomes used in different domains. We extracted outcomes used in each trial, recording how many used each outcome and with how many participants. We divided outcomes into the domains measured and searched for validation data. (3) We consulted with PPI participants about recommended outcomes. (4) We presented all the synthesised information at a conference attended by the wider body of National Institute for Health Research (NIHR) dementia researchers to reach consensus on a core set of outcomes. RESULTS: We included 149 papers from the 22,918 papers screened, referring to 125 individual trials. Eighty-one outcomes were used across trials, including 72 scales [31 cognitive, 12 activities of daily living (ADLs), 10 global, 16 neuropsychiatric and three quality of life] and nine biological techniques. We consulted with 18 people for PPI. The conference decided that only cognition and biological markers are core measures of disease modification. Cognition should be measured by the Mini Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog), and brain changes through structural magnetic resonance imaging (MRI) in a subset of participants. All other domains are important but not core. We recommend using the Neuropsychiatric Inventory for neuropsychiatric symptoms: the Disability Assessment for Dementia for ADLs, the Dementia Quality of Life Measure for quality of life and the Clinical Dementia Rating scale to measure dementia globally. LIMITATIONS: Most of the trials included participants with Alzheimer's disease, so recommendations may not apply to other types of dementia. We did not conduct economic analyses. The PPI consultation was limited to members of the Alzheimer's Society Research Network. CONCLUSIONS: Cognitive outcomes and biological markers form the core outcome set for future disease modification trials, measured by the MMSE or ADAS-Cog, and structural MRI in a subset of participants. FUTURE WORK: We envisage that the core set may be superseded in the future, particularly for other types of dementia. There is a need to develop an algorithm to compare scores on the MMSE and ADAS-Cog. STUDY REGISTRATION: The project was registered with Core Outcome Measures in Effectiveness Trials [ www.comet-initiative.org/studies/details/819?result=true (accessed 7 April 2016)]. The systematic review protocol is registered as PROSPERO CRD42015027346. FUNDING: The National Institute for Health Research Health Technology Assessment programme.
Authors: Lucy Webster; Derek Groskreutz; Anna Grinbergs-Saull; Rob Howard; John T O'Brien; Gail Mountain; Sube Banerjee; Bob Woods; Robert Perneczky; Louise Lafortune; Charlotte Roberts; Jenny McCleery; James Pickett; Frances Bunn; David Challis; Georgina Charlesworth; Katie Featherstone; Chris Fox; Claire Goodman; Roy Jones; Sarah Lamb; Esme Moniz-Cook; Justine Schneider; Sasha Shepperd; Claire Surr; Jo Thompson-Coon; Clive Ballard; Carol Brayne; Alistair Burns; Linda Clare; Peter Garrard; Patrick Kehoe; Peter Passmore; Clive Holmes; Ian Maidment; Louise Robinson; Gill Livingston Journal: PLoS One Date: 2017-06-29 Impact factor: 3.240
Authors: Sarah E Goldberg; Veronika van der Wardt; Andy Brand; Clare Burgon; Rupinder Bajwa; Zoe Hoare; Pip L Logan; Rowan H Harwood Journal: BMC Geriatr Date: 2019-12-16 Impact factor: 3.921
Authors: Stefan Teipel; Alexandra König; Jesse Hoey; Jeff Kaye; Frank Krüger; Julie M Robillard; Thomas Kirste; Claudio Babiloni Journal: Alzheimers Dement Date: 2018-06-21 Impact factor: 21.566