Abstract
Background
There are no disease-modifying treatments for dementia. There is also no consensus on disease modifying outcomes. We aimed to produce the first evidence-based consensus on core outcome measures for trials of disease modification in mild-to-moderate dementia.
Methods and findings
We defined disease-modification interventions as those aiming to change the underlying pathology. We systematically searched electronic databases and previous systematic reviews for published and ongoing trials of disease-modifying treatments in mild-to-moderate dementia. We included 149/22,918 of the references found; with 81 outcome measures from 125 trials. Trials involved participants with Alzheimer’s disease (AD) alone (n = 111), or AD and mild cognitive impairment (n = 8) and three vascular dementia. We divided outcomes by the domain measured (cognition, activities of daily living, biological markers, neuropsychiatric symptoms, quality of life, global). We calculated the number of trials and of participants using each outcome. We detailed psychometric properties of each outcome. We sought the views of people living with dementia and family carers in three cities through Alzheimer’s society focus groups. Attendees at a consensus conference (experts in dementia research, disease-modification and harmonisation measures) decided on the core set of outcomes using these results. Recommended core outcomes were cognition as the fundamental deficit in dementia and to indicate disease modification, serial structural MRIs. Cognition should be measured by Mini Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale. MRIs would be optional for patients. We also made recommendations for measuring important, but non-core domains which may not change despite disease modification.
Limitations
Most trials were about AD. Specific instruments may be superseded. We searched one database for psychometric properties.
Interpretation
This is the first review to identify the 81 outcome measures the research community uses for disease-modifying trials in mild-to-moderate dementia. Our recommendations will facilitate designing, comparing and meta-analysing disease modification trials in mild-to-moderate dementia, increasing their value.
Trial registration
PROSPERO no. CRD42015027346.
To produce the first evidence-based consensus on core outcome measures for trials of disease modification in mild-to-moderate dementia.
ContributorsAlzheimer’s Society - James Pickett
Applied psychosocial dementia research/ Occupational therapy - Gail Mountain (co-applicant)
Cochrane Dementia and Cognitive Improvement Group- Jenny McCleery (co-applicant)
Dementia care - Frances Bunn, Claire Goodman
Dementia pharmacist - Ian Maidment
Health service research - Sasha Shepperd
Health Outcome Measurement - Sallie Lamb, Charlotte Roberts (co-applicant),
Neurology - Peter Garrard
Old age medicine - Patrick Kehoe, Roy Jones, Peter Passmore, John Young
Old age psychiatry - Clive Ballard, Sube Banerjee, Alistair Burns, Chris Fox, Clive Holmes, Rob Howard (co-applicant), Gill Livingston (Principal Investigator), John O’Brien, Robert Perneczky
Palliative medicine - Fliss Murtagh
Primary care dementia research - Louise Robinson
Psychology and dementia - Linda Clare, Georgina Charlesworth, Murna Downs, Esme Moniz-Cook, Bob Woods
Public Health and ageing - Carol Brayne , Louise Lafortune (co-applicant)
Scale measurement – Orlaith Burke
Social care and social policy - David Challis, Katie Featherstone, Justine Schneider, Claire Surr
Systematic Reviews - Jo Thompson-Coon
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
Disease Category: Neurology
Disease Name: Dementia
Age Range: 18 - 100
Sex: Either
Nature of Intervention: Disease modification treatments
- Charities
- Clinical experts
- Consumers (caregivers)
- Consumers (patients)
- Methodologists
- COS for clinical trials or clinical research
- Consensus conference
- Focus group(s)
- Systematic review
There are four stages of the project.
1. Use of current knowledge:
We will use any relevant data from outcomes sets from overlapping systematic reviews by co-applicants of the group, including reference lists, how outcome measures were selected, and evidence on particular outcome domains.
2. Systematic review:
We will conduct a brief systematic review, for trials with quantitative outcomes regarding disease modification in dementia, using search terms decided upon by the projects steering group. We will search the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, ALOIS (www.medicine.ox.ac.uk/alois), a study based register of dementia trials, and additional databases, including Medline, PsycInfo, Embase, Lilacs, Cinahl, and the Cochrane Central Register of Controlled Trials (CENTRAL).
Inclusion criteria will include:
1. Interventional treatment study aimed at modifying the underlying disease of dementia
2. Clinical dementia diagnosis
3. At least some of the participants have mild or moderate dementia
4. Quantitative outcome measure related to disease modification
5. Validated measure of outcome
6. Study set in clinical practice i.e. primary care, inpatient, outpatient, day hospital, community
7. Types of study: We will include randomised and non-randomised controlled trials where the intervention is directed at the person with dementia.
8. The control or comparator arm could comprise: treatment as usual, no intervention, sham therapy, other therapy or placebo
9. Types of intervention: We will include all interventions
10. Any age group
11. Either gender
12. Paper written in English (as considering outcome measures available in English)
We will exclude studies set in a care home, as very few people resident in care homes will have mild to moderate dementia, and studies where all patients have severe dementia. We will also exclude outcomes that are qualitative, economic, only about carers or those where there are no validation data in people with mild to moderate dementia published or known to the group.
We will extract data from included trials on methodological characteristics, the intervention used, and details of the relevant outcome measurement tool or method used. Data will be extracted to assess the frequency of use of each outcome, with separate literature searches conducted to assess validity, and to find each relevant assessment scale if possible. Data will be extracted in regards to validity, including: the severity of dementia in which measure is validated, which patient group or setting and whether it is validated in particular groups e.g. different ethnicities, languages, and to set out length of measure and any data regarding acceptability and floor and ceiling measures and who is interviewed for it.
We will divide all validated outcomes into different domains, which we anticipate will include cognition, activities of daily living, biological outcomes, neuropsychiatric symptoms etc., but will be guided by the outcomes found in the review.
3. Patients and Public Involvement (PPI consultation):
We will conduct three to four focus groups, in partnership with the Alzheimer’s Society involving patients with dementia, and family carers, to assess which of the included outcomes are most important and appropriate to both patients and carers.
4. Consensus conference:
Towards the end of the project all the members of the group will be invited to a consensus conference, where a core set of outcomes to be recommended for use in NIHR applications for trials of disease modification in mild to moderate dementia will be agreed upon, through discussion of the evidence from the review. The conference will be divided into the domains of outcomes found in the review, with a “champion” with expertise in the area leading on the presentation of information for each domain.