Aerobic and strength training exercise programme for cognitive impairment in people with mild to moderate dementia: the DAPA RCT

Evidence review

We defined exercise as ‘a subcategory of leisure time physical activity in which planned, structured and repetitive bodily movements are performed to improve or maintain one or more components of physical fitness’. 33 Physical activity was taken to mean any activity (including exercise itself) that could mimic the physiological effects of exercise, for example gardening or housework. From our systematic review of trials and review of systematic reviews, we developed an evidence-based rationale for the intervention content.

The most recent Cochrane review of exercise programmes for people with dementia19 included 17 studies, nine of which assessed the effect of exercise on cognition. No clear conclusions could be drawn regarding the effect of exercise on cognition in people with dementia because of unexplained heterogeneity in the data. The review was unable to make recommendations as to the type and dose of exercise (i.e. intensity, frequency and duration).

Exercise type

To inform our decision around the types of exercise to deliver, we examined existing exercise models and evidence for mechanisms of action. There is evidence that aerobic exercise increases vascularisation of the brain and triggers the release of neurotrophic substances, which support cognitive functions. 34 Studies in healthy older adults report that increased aerobic fitness is associated with better preservation of grey matter volume and larger hippocampus volume. The hippocampus contributes to spatial memory and consolidation of short-term memory. 35 In dementia patients, the hippocampus is atrophied. Similarly, resistance training alters levels of circulating substances (insulin-like growth factor 1, homocysteine)36 in a manner that may positively affect cognitive function. Supporting evidence is summarised in Table 1. Hence, it was decided to include both aerobic and resistance training elements in the exercise programme.

Dose of exercise

There is a robust evidence base around the quantity of exercise needed to elicit health benefits in healthy older people, but these are not specific to cognitive outcomes. 32 Our systematic review (see Chapter 6) found that protocols for exercise interventions ranged from 60 to 210 minutes of exercise per week, with an average of 122 minutes per week. Although there is no direct evidence to inform dosing for improvement in cognitive performance, there is a link between cardiovascular status and dementia. We used the guidance, produced by the World Health Organization (WHO), for the quantity and quality of exercise required for cardiorespiratory and musculoskeletal good health for adults and older adults. 43 This WHO guidance recommends at least 150 minutes per week of moderate-intensity cardiorespiratory exercise. The same guidance recommends resistance exercises for the major muscle groups two or three times a week for musculoskeletal good health. Hence, we selected the target intensity as, at least, moderate to moderate to hard level for both exercise forms for an overall total of 150 minutes per week.

To gauge an individual’s fitness and exertion levels (mild, moderate, hard) we used the 6-minute walk test (6MWT). This assessment is relatively simple to implement, and an adapted version has been shown to be reliable in people with Alzheimer’s disease. 44 It requires less time to complete than the Incremental Shuttle Walk Test45 and, unlike the cycle ergometry test,46 requires no special equipment. We selected the Borg Scale of Perceived Exertion, adapted for use by people with dementia,47 as the primary method of assessing exercise intensity during sessions, coupled with soft indicators such as sweating, skin colour and breathing rate. Although heart rate could have been, and was occasionally planned to be, used as an indicator, these measures are complicated in situations in which, as we expected, there was a higher prevalence of beta-blockers and drugs/devices/conditions influencing heart rate.

We selected cycling as the core aerobic exercise38 because the cycling action is a simple, intuitive one and the risk of falls is minimised.

For resistance exercise, the gold standard method for identifying an initial resistance load is the one-repetition maximum using an isokinetic dynamometer. 48 However, exposing untrained individuals to resistance that is higher than 80% of the one-repetition maximum increases the likelihood of an adverse event (AE) and is not recommended for older people. 49 Given the probable frailty of the participants, we selected a validated method to prescribe the resistance by estimating the maximum number of lifts that could be made with good form for a given weight. 49 As dyspraxia is common among people with dementia,39 the exercises chosen were simple, functional movements aimed at enhancing participation and were selected to engage the major muscle groups, in accordance with the guidance from the WHO. 32

Duration of exercise intervention

Determination of the total duration of an intervention was challenging. Our systematic review (see Chapter 6) identified intervention duration ranges from 1.5 to 12 months, with an average duration of 5 months. Our funders requested that the duration of the intervention was 4 months in order to maximise the chance of it being found to be cost-effective, which is documented in Appendix 1.

To maximise the chance of the intervention being cost-effective, we used group supervision (with each participant working to their individual prescription) for 4 months, and included BCTs plus suggestions for continued activities to encourage continued physical activity.

Exercise intervention adherence

Behavioural modification is an important component of the intervention, to make adherence to the exercise intervention more likely. Simply providing information about the health benefits of exercise is not effective in increasing older adults’ participation in exercise. 41 The BCT taxonomy of Michie et al. 50 provides standardised definitions of 93 techniques used in behaviour change interventions and promotes clarity in the reporting of intervention content. During our intervention development there was no specific guidance for which BCTs to use for people with dementia. We adapted guidance for healthy older people32 and the NHS guidance for behaviour change,51 and examined BCT evidence for healthy older adults. A review identified self-efficacy as the most consistent predictor of initiation and maintenance of physical activity in adults aged > 50 years. 52 The BCTs of ‘goal-setting’ and ‘activity contracts’ are associated with increased physical activity levels and improved self-efficacy in adults. 53 The NHS guidance for behaviour change details how to implement these BCTs into an intervention. Group exercise, compared with individual home-based exercise, has been shown to improve exercise adherence in older people. 54 Substantial parts of the DAPA behavioural intervention depended on telephone contact, and there is precedence for this. A study of older women undertaking a 26-week group-based exercise programme found that those who were given a telephone-assisted coping plan, via a single telephone call, had better adherence to the programme than those who were given only written advice. 55 Staff encouraged a fun atmosphere in the classes, as enjoyment has been shown to improve exercise adherence in adults attending exercise groups. 56 Encouragement from spouses and carers has been recognised to strengthen self-efficacy and improve adherence. 57 Carers were welcome to come along to the sessions. They had no formal role during the class and did not participate as either coaches or individuals during the session. A break-out area was organised where carers could chat among themselves. When they wished to be, carers were involved in identifying activities that the participants were likely to find enjoyable and in encouraging compliance with home exercise.

Expert opinion

A key part of the intervention development process was the advice received from clinicians and other experts, including patient groups. The intervention development team gained opinions from specialist physiotherapy teams and visited exercise or physical activity group programmes that were being run for the target population. The team members also talked to people with MMD and their carers via local Alzheimer’s Society activities, as well as within the pre-pilot and pilot studies.

Guidelines

The intervention design was supported by information from a number of guidelines, principally the American College of Sports Medicine’s guidelines for exercise testing and prescription,32 NICE’s dementia guidelines58 and the WHO’s Global Recommendations on Physical Activity for Health. 43

The pilot studies

We ran two pilot studies. The first tested the feasibility of using the OPERA trial intervention59 (a randomised trial of an exercise intervention for older people in residential and nursing accommodation based on a music approach) in the DAPA trial target population. It was found that even the highest level of the OPERA exercise activities were not able to create an adequate exercise challenge, as the DAPA trial population were younger and fitter than the OPERA population. As a result, the intervention development team created an innovative and specially targeted exercise programme.

The acceptability and feasibility of the new intervention (including the behaviour change support strategies) was then tested in a second pilot study (n = 6 people with dementia).

Informal feedback interviews were conducted with the participants, carers and physiotherapists involved. No qualitative analysis was conducted on these data, but the data were used in real time to inform intervention development. Participants found the DAPA intervention to be acceptable, feasible and enjoyable. The exercise activities were able to create an adequate exercise challenge for the DAPA trial target group (using heart rate monitoring). This pilot study also highlighted that some participants needed more assistance and supervision than others and that the involvement of carers facilitated attendance and adherence in terms of timings, transport and emotional support, and so this also was accounted for in the programme design. Participants identified concerns that they held before starting the groups, which were used to inform our recruitment strategy information documents. Outcome measures and some aspects of the recruitment processes were also tested during the pilot phases.

Individual pre-exercise assessment

The pre-exercise assessment assessed the participant’s general health, current fitness and activity levels. The participant and/or carer was asked about cardiovascular, respiratory, neurological, musculoskeletal and psychiatric conditions, as well as diabetes mellitus and recent acute illnesses (for details please see Appendix 2). Current and previous physical activity levels, along with any physical, perceptual or sensory limitations, for example limited range of shoulder movement, were noted and considered in the individual tailoring of exercises. Carers were encouraged to attend when possible to provide additional information to the therapist, for example on medications, comorbidities and exercise preferences.

The main element of the pre-exercise assessment was to set the initial intensity of exercise for the sessions. A 6MWT was completed using two marker cones set up 15 m apart, and the participant was instructed to walk between and around the cones for 6 minutes, with standardised directions and phrases of encouragement. 44 The distance walked in 6 minutes was noted. The participant also wore a heart rate monitor, and the resting and average heart rates were recorded. This allowed calculation of the initial target aerobic intensity according to Luxton. 60 For resistance exercises, the maximum weight that could be lifted in good form over 20 repetitions was estimated.

Warm-up

A simple warm-up comprising movements of the neck, shoulders, trunk, hips and knees, together with marching on the spot was performed, lasting about 5 minutes.

Aerobic

The target intensity for aerobic training was 25 minutes in each session, with at least 15 minutes at moderate to hard intensity. Intensity was individually tailored to each participant’s baseline fitness, recognising that a low load may be a moderate challenge to some but a low challenge to others. The period of cycling was built over the sessions. For all sessions, the first 5 minutes of the aerobic exercise was spent cycling at low intensity. At the outset of the programme all participants were started at low intensity. The aerobic challenge was progressed by increasing the total duration spent cycling, up to 25 minutes, as well as the duration spent exercising at moderate and hard intensity over the ensuing sessions.

Resistance

Progression was individually tailored using recognised methods. 61 The resistance exercises always included sit-to-stand, using weighted belts and jackets, and biceps curls, using dumb-bells as resistance, and were set according to principles shown in Figure 3. Suppliers are detailed in Appendix 3.

FIGURE 3.

Calibrating load for resistance exercises. © 2015 Chartered Society of Physiotherapy. Published by Elsevier Inc. All rights reserved. Reproduced with permission.

Role of exercise assistant and physiotherapist

The physiotherapists were responsible for the examination and assessment of the participants, setting the prescription and reviewing and progressing the exercise prescription. The physiotherapists supervised the exercise assistants during the sessions. The role of the exercise assistants was to assist in welcoming carers and participants to the class, to monitor and encourage people during the class and to provide assistance when required. The physiotherapists undertook the telephone follow-up calls.

Good form = correct postural alignment maintained, contraction is controlled, full range of movement is used, normal breathing is maintained.

Ratamess et al. 61

The initial resistance load was determined on the basis that the lift should be at least moderately hard and on clinical observations, with the ability to lift 20 repetitions in ‘good’ form being the principal guide. Table 2 gives typical ranges of initial resistance for the sit-to-stand exercise. The weight lifted was increased, with participants performing 15 repetitions 3 weeks into classes and 10 repetitions at a higher weight again at 7 weeks. The weight was subsequently increased if the participant could perform two additional repetitions with good form, or decreased if the participant could not perform the required number of repetitions. A further 1–3 exercises (depending on time available) were selected from shoulder forward raise, shoulder lateral raise and shoulder press, again using dumb-bells as resistance. The resistance training element of the exercise class lasted approximately 25 minutes. The participants were congratulated and presented with a certificate at their last exercise class, to reinforce continuation with unsupervised exercise.

Goal-setting

During the supervised exercise intervention, a system of goal-setting was used that focused on the goals and activities that were important to the participants. The first goal-setting took place between weeks 3 and 5 of the supervised exercise sessions and focused on an action plan with specific physical activities, which were to be undertaken at agreed locations and times. The second goal-setting took place between weeks 13 and 16 and focused on a plan for the transition from the supervised to the unsupervised exercise period. This focused on how, and where, to perform the unsupervised exercise and included an exercise opportunities booklet detailing local facilities and opportunities.

Review behavioural goals (objective and subjective)

Between weeks 17 and 22, the 6MWT was used to review participants’ progress and to act as a prompt to revise goals and identify barriers or facilitators. An exercise calendar was given to participants and carers to encourage self-monitoring of behaviour, as a visual prompt to remind the participant to undertake physical activity and to assist the physiotherapist to monitor unsupervised exercise. The face-to-face meeting with the participant and (if possible) carer was to review the targets from the second target-setting discussion and amend them if necessary, together with praise and problem-solving assistance.

Behavioural contract

The action plan (goal-setting) was signed by the participant and physiotherapist to reinforce the commitment to carry it out.

Identification of barriers or facilitators and solutions

Telephone contact was made with participants who did not attend exercise sessions to identify and problem-solve any barriers to class attendance and encourage the habit of regular attendance. During the unsupervised part of the intervention, three telephone calls and one face-to-face meeting took place. The telephone calls were made approximately 2–3 weeks, 14–16 weeks and 22–23 weeks after the supervised exercise sessions had finished, and were intended to provide praise and encouragement and assist in solving any difficulties encountered in exercising independently.

Results of the quality control visits

There were 26 physiotherapists and 17 exercise assistants delivering the DAPA intervention across the DAPA trial sites. Of the physiotherapists, in the first QC assessment, 23 were rated as ‘satisfactory’, two were rated as ‘minor concerns’ and one had missing forms. Those who were rated as ‘minor concerns’ were followed up within 2 weeks of the initial assessment and both then reached a ‘satisfactory’ rating. Of the exercise assistants, 13 achieved a rating of ‘satisfactory’, three were rated as ‘minor concerns’ and one had missing forms. In the follow-up assessment, all three exercise assistants who had been rated as ‘minor concerns’, then reached the ‘satisfactory’ rating.

In the second QC assessment, all physiotherapists were rated as ‘satisfactory’, apart from three who had a missing assessment, and all exercise assistants were rated as ‘satisfactory’, apart from one who was rated as ‘minor concerns’ and one who had missing forms (unable to complete the QC visit). The exercise assistant who was rated as ‘minor concerns’ was rated as the same at their follow-up assessment.

The third and fourth QC assessments were performed only on physiotherapists, as they carried the predominant load and responsibility for the intervention. At the third QC assessment, all physiotherapists were rated as ‘satisfactory’ and one had missing forms.

At the fourth QC assessment, 10 physiotherapists were rated as ‘minor concerns’. In the follow-up assessment, it was not possible to reassess 4 out of these 10 physiotherapists and the remaining therapists were reclassified as a rating of ‘satisfactory.’

In all cases where forms were missing, the QC visit could not be completed within the scheduled time period, before the next QC visit was due.

Manuals are available at www.octru.ox.ac.uk/trials/trials-completed/dapa (accessed 17 April 2018).

Participant recruitment and setting

We recruited adults (aged ≥ 18 years) with a diagnosis of any type of dementia and their carers (when available). The dementia needed to be mild to moderate at the time of recruitment. Participants were recruited from 15 regions in the UK.

Approach and initial information

Participants were recruited from four sources:

1. NHS secondary care memory clinics and services: authorised NHS staff identified potential participants using electronic or case record searches to screen for eligibility. The lists were reviewed by a clinician involved in the clinical care of the participant and checked for patients who should be excluded. Potential participants and their carers were approached by their clinician or authorised NHS staff member either face to face at a clinic or by letter.

2. General practice registers of people with dementia: general practices searched their registers of patients to identify people with a diagnostic code for dementia. In most practices, this was done by a search of databases using Read Codes or Quality Outcomes Framework codes. General practitioners approved the final list of names and sent invitation letters to potential participants.

3. Research network participant-interested databases [e.g. the Dementia and Neurodegenerative Diseases Research Network (DeNDRoN); Join Dementia Research]: the UK Department of Health and Social Care has funded a number of networks and projects to enable people with dementia to register their interest in participating in research and to enable a rapid and simple approach. Participants were identified by a nursing or clinical staff of DeNDRoN from these databases. Participants deemed as meeting the inclusion criteria were contacted by DeNDRoN staff by telephone to explain the study and, if potentially eligible, sent an invitation letter.

4. Other dementia resources (e.g. Alzheimer’s cafes): we approached community-based dementia resources directly to determine if they were willing to approach potential participants. When service providers agreed and approached potential participants, a researcher from the team then visited the centres and provided further explanation about the study to potential participants and their carers. When participants or carers were interested, the researcher assessed their potential eligibility and contacted their health-care provider to confirm eligibility.

All procedures were consistent with relevant legislation to ensure data confidentiality. All invitations were accompanied by written information about what was involved in the study, supplemented by a verbal explanation when the opportunity arose. In all instances, the participants indicated their potential willingness to participate by sending a reply slip to either the local co-ordinating centres or the research office at the University of Warwick Clinical Trials Unit (WCTU) (depending on the local set-up). Once a participant confirmed their willingness to participate, they were contacted by a member of the recruitment team (a registered nurse or allied health professional with appropriate research training) to further assess eligibility and explain the trial. In all instances, participants received the written and verbal information and were given a minimum of 48 hours to decide whether or not they wished to join the trial. Potential participants were visited in their own homes to record consent in writing and to confirm eligibility [Standardised Mini Mental State Examination (sMMSE) score and functional abilities]. A baseline assessment was carried out and the participant was registered and randomised.

Eligibility criteria

Participants were required to:

1. have probable dementia according to the DSM-IV criteria1

2. have probable MMD (a score of > 10 on the sMMSE)65

3. be able to participate in a structured exercise programme determined by:

   1. being able to sit in a chair and walk 10 feet without human assistance

   2. having no unstable medical conditions, for example unstable angina, or acute or terminal illness

4. live in the community, alone or with a friend, relative or carer, or in sheltered accommodation.

Consent

People with MMD may lack the necessary mental capacity to provide fully informed consent. All potential participants were assessed for their capacity to consent by the registered research nurses or physiotherapists conducting the baseline visit. All nurses and physiotherapists were trained specifically in assessing and taking consent in trials recruiting people with dementia using the principles of the Mental Capacity Act 2005. 66 Training was provided by the NIHR Clinical Research Network or DeNDRoN and/or the lead research physiotherapist responsible for recruitment. When potential participants were assessed as having capacity, informed consent was obtained from the individual. If potential participants were assessed as lacking capacity, agreement to participate was still sought from these individuals. In this situation, additional advice would be sought from the primary carer or personal consultee on whether or not the person who lacked capacity should take part in the project and what their past and present wishes and feelings would have been about taking part. If participants were unable to give informed consent, and for whom no personal consultee was available, a nominated consultee (e.g. health-care professional) who was well-placed and prepared to act on behalf of the potential participant was sought. When a potential participant lacked capacity to provide informed consent, and a nominated consultee could not be found, that person was not recruited. Agreement for continued participation was checked at each follow-up visit. Consent was sought from carers, for the data on carers, after consent for participation had been secured from the person with dementia.

Risks and benefits

All participants had access to usual care, and thus no treatment was withheld from trial participants. There is some limited evidence of a very small increased risk of injury as a result of becoming more physically active. In our physical activity programme, however, health-care professionals tailored progressive exercises to individual need/ability and delivered the programme to small groups of participants in a supervised and safe context.

The usual-care arm

All participants had, or were receiving, usual care consistent with the recommendation of NICE’s clinical guidance,67 comprising diagnosis, information provision and limited social support. We recognised that the usual-care interventions vary across the country and, hence, we stratified the randomisation by region to ensure these effects were randomly distributed. There was no limit on co-interventions during the trial; medications and other treatments could be initiated, continued or discontinued at the discretion of the clinical team responsible for the care of the participants. We collected data on treatments provided to both arms of the trial at baseline and during the follow-up period, and described these in the study reports. Exercise is not currently part of recommended usual care for people with dementia, but each study participant (in both the control and intervention groups) was given one of two information sheets produced by the Department of Health and Social Care, appropriate to their age group. The information sheets recommend physical activity levels for adults (aged 19–64 years)68 and older adults (aged ≥ 65 years). 69

The Dementia and Physical Activity (intervention) arm

The intervention arm is fully described in Chapter 2.

Baseline data on the participants (persons with dementia)

Potential participants were visited at home by a registered research nurse or physiotherapist. Informed consent was obtained (see Consent), then eligibility was checked, including carrying out the sMMSE. Once the participant was confirmed as being eligible, descriptive data were collected, including age, gender, marital status, ethnicity, educational attainment and employment status.

The next stage was to collect the data for the primary and secondary outcomes, as given in Table 3. The type of dementia (vascular, Alzheimer’s or mixed) was ascertained after the baseline visit by reference to the participant’s medical notes.

The primary outcome was the global cognition score of the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog). 70 The funder’s brief was clear that the primary purpose of the trial and of the exercise programme should be to determine whether or not exercise can modify cognitive functioning. Cognitive deficits are central to dementia and widely understood as the most important treatment target. 77 The ADAS-Cog was collected directly from the participant, takes about 30–40 minutes to administer and has established sensitivity to change. It is widely considered the gold standard primary outcome in treatment trials for dementia, with relatively well-established treatment effect sizes. 78 We also collected the maze and number of cancellation optional items of the ADAS-Cog as additional items to be reported separately.

Initially, the primary outcome measure was to be the sMMSE, which, although widely used in clinical evaluation, is a very global, relatively insensitive measure of cognitive function. The ADAS-Cog is acknowledged to be more sensitive in detecting cognitive change in individuals with MMD than a variety of other measures, including the sMMSE. 79 The use of a valid but more sensitive primary outcome measure (the ADAS-Cog) made it possible to reduce the sample size of the study.

Secondary outcomes were chosen to reflect the broad impact of dementia on function, behaviour and quality of life. When possible, we chose instruments that were dementia specific, well validated and not excessively burdensome. Secondary outcomes are also detailed in Table 3. In all instances we used the published guidance about who the primary respondent for the questionnaire should be. We used the Bristol Activities of Daily Living Scale (BADLS). 71 This carer-rated instrument of participant ability is dementia specific, sensitive to change and widely used in clinical trials. We also collected data using the Quality of Life in Alzheimer’s Disease (QoL-AD) scale. 73 This is a 13-item dementia-specific scale that can be completed by a carer or participant; both were collected for the DAPA trial but the participant response was considered the primary data source. We also collected the EuroQol-5 Dimensions, three-level version (EQ-5D-3L),72 a 5-dimension generic (i.e. not dementia-specific) measure of health-related quality of life (HRQoL). The EQ-5D-3L was reported by both the participant and carer, with the participant being the primary data source, and it allows a calculation of health utilities for application in economic evaluations.

We used the Neuropsychiatric Inventory (NPI),74 which includes important predictors of carer breakdown such as depression and agitation. We collected cost data using the Client Services Receipt Inventory (CSRI). 76 This detailed questionnaire is designed to be used with a carer and covers all social, health care, medication use and out-of-pocket expenses. Initially, mood was to be a secondary outcome, as measured by the Cornell Scale for Depression in Dementia. 80 This was removed prior to the collection of any data as mood is covered by the NPI and it would have added unnecessarily to participant burden during data collection.

Carer

We recorded carer age, gender, ethnicity, details about the relationship they had with the person with dementia and how much care they provided. Carers were asked to complete the Zarit Burden Interview (ZBI)75 and the EQ-5D-3L72 to assess their own HRQoL. These outcomes are all among those recommended by a consensus recommendation of outcome scales for non-drug interventional studies in dementia. 81

Sample size

A sample size of 360 participants would provide 80% power to detect a minimum clinical between-group difference of 2.45 points [baseline standard deviation (SD) of 7.8 points based on 66 participants] on the ADAS-Cog at 12 months with a 5% level of significance and 2 : 1 randomisation in favour of the intervention. This equated to a standardised effect size of 0.31. An overall difference of 2–2.5 change points on the ADAS-Cog is considered to be a worthwhile target. 83 To account for therapist effects, we inflated the sample size using a design effect of 1.04 (intracluster correlation = 0.01) assuming that there are five participants per group (recognising that it may not be possible to achieve and retain eight recruits to each group), which gave a sample size of 375. The sample size was further inflated to account for 20% loss to follow-up, of which 10% was estimated would be attributable to death. Thus, a final minimum sample size of 468 participants was required, with 312 participants to be randomly allocated to the intervention arm and 156 participants to the control arm.

Note that the sample size initially calculated was 728 participants based on the sMMSE score as the primary outcome. The use of ADAS-Cog score rather than sMMSE score as the primary outcome allowed the sample size to be reduced to 468. This change in sample size occurred before we started the trial and was approved as a formal protocol amendment.

Primary analyses

Data were summarised and reported in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines for RCTs,84 and we used intention-to-treat (ITT) analyses as the primary analysis.

For the primary analyses, multilevel models were used with a random effect for region to estimate the treatment effects and 95% confidence intervals (CIs). The clustering effects of therapist and group were assessed by measuring the intracluster correlation. Therapist and/or group effects were not included in the multilevel model if the clustering effects were found to be negligible. The models were adjusted for important covariates (age, gender, region, sMMSE score and baseline ADAS-Cog score). Owing to the nature of the population, certain items on the ADAS-Cog were missing and, hence, the missingness was classed as being not random. Thus, for the primary analyses, participants with missing ADAS-Cog outcome at each time point in the observed data had their item-level responses reviewed on an individual basis. If any items were missing as a result of the participant being either cognitively unable, too distressed or refusing to answer, then we estimated the treatment effects using multiple imputation (MI) methods. This approach was taken as we are aware that the missing item-level responses for the ADAS-Cog are non-ignorable. Therefore, doing a complete-case analysis (as done so in the first sensitivity analysis) could give highly biased results. However, baseline variables, such as baseline ADAS-Cog score and sMMSE score, are quite likely to be good predictors of missing items. We therefore applied MI methods, which is considered a plausible approach to address non-ignorable missing data, to impute missing item-level data, enabling us to compute and analyse the ADAS-Cog scores. 85

Sensitivity analyses

In addition to the primary analysis, three sensitivity analysis data sets were used to carry out sensitivity analyses. For the first sensitivity analysis, the treatment effect was estimated using the observed data with missing values present in the ADAS-Cog. This sensitivity analysis data set consisted of participants who provided complete primary outcome data. For the second sensitivity analysis, participants with missing ADAS-Cog outcome in the observed data had the worst score assigned at the item level, provided the item was missing as a result of the participant being either cognitively unable, too distressed or refusing to answer. For the third sensitivity analysis, an item response theory (IRT) approach was used. Between the estimation of the sample size and the finalisation of the statistical analysis plan, the literature had moved to suggest that the ADAS-Cog does not measure a single patient trait (cognitive impairment) but rather it measures cognitive impairment in multiple cognitive domains. 86 Therefore, IRT was used to assess treatment effects in each of the cognitive domains, namely language, memory and praxis86 (see Appendix 5).

Secondary analyses

For secondary analyses, we estimated treatment effects over the 12-month time period using longitudinal models adjusting for the same variables used in the primary analysis.

Subgroup analyses

Prespecified subgroup analyses looking at severity of cognitive impairment (sMMSE score of ≥ 20 for mild and < 20 for moderate), type of dementia (Alzheimer’s vs. other), physical performance (no problems walking vs. some problems/confined to bed, taken from the EQ-5D-3L) and gender (female vs. male) were conducted using formal tests of interaction. 87

Complier-average causal effect analysis

We measured compliance with the intervention by the number of sessions attended. This information was collected by the therapist providing the treatment. Complier-average causal effect (CACE) analysis was used to assess the effect of compliance with the intervention on the primary outcome. 88

Data set access

The final data set was accessible to all study members after data lock. The chief investigator assumed overall responsibility for the data report and had full access to the trial data set. There were no contractual agreements that limited access for investigators.

Serious adverse event and adverse event reporting

An AE was defined as any untoward medical occurrence in a participant that did not necessarily have a causal relationship with this treatment. These were most likely to be identified by the physiotherapist during the exercise sessions, from information at the sign-in, or after completion of the exercise sessions during support telephone calls or the face-to-face meeting.

As each participant had a pre-exercise assessment done, this provided information on comorbidities. The trial population included many participants aged > 70 years old and, therefore, they had many of the common chronic diseases of older age, for example osteoarthritis. It was expected that participants would experience some uncomfortable effects of participation in the intervention, for example muscle or joint soreness in response to exercise. Provided that these followed an expected pattern (e.g. as for delayed-onset muscle soreness), needed simple modifications to the exercise activity (e.g. changes to the bicycle seat height) or were non-serious exacerbations of existing medical conditions, they were not considered as AEs.

A serious adverse event (SAE) was an AE that fulfilled one or more of the following criteria:

• resulted in death

• was immediately life-threatening

• required hospitalisation or prolongation of existing hospitalisation

• resulted in persistent or significant disability or incapacity

• required medical intervention to prevent one of the above.

The SAEs to be reported were defined as those that occurred within 2 hours of completing the exercise sessions or follow-on physical activities. SAEs were reported to the Trial Co-ordinating Centre within 24 hours of the physiotherapist becoming aware of them. The Trial Co-ordinating Centre was responsible for reporting AEs to the sponsor and ethics committee within required timelines.

The relationship of SAEs to trial treatment was assessed by the chief investigator and this was recorded on each SAE form. All SAEs were recorded in the trial database, when appropriate, reported to and reviewed by the Data Monitoring and Ethics Committee (DMEC) throughout the trial, and were followed up to resolution.

Trial Steering Committee

A Trial Steering Committee was responsible for monitoring and supervising the progress of the trial towards its interim and overall milestones.

Data Monitoring and Ethics Committee

The DMEC was independent of the trial and monitored the ethical, safety and data integrity aspects of the trial.

Formal approvals

The original ethics approval for this project was granted on 19 January 2012. A substantial amendment for the pre-pilot study was granted on 31 May 2012. Another amendment regarding randomisation was granted on 17 July 2012. The third amendment for a change to the primary outcome measure to ADAS-Cog was also granted on 17 July 2012. Amendments 4–6 were changes to the intervention materials based on the results of the pre-pilot study, and these were granted on 17 January 2013. Amendment 7, regarding sample size, was granted on 7 July 2014; and the final amendment, to add more elements to the qualitative study into the project, was granted on 19 January 2015.

Participant flow

The CONSORT flow diagram (Figure 4) describes the overall flow of participants through the study and Table 53, Appendix 6, describes the flow summarised by each region.

FIGURE 4.

The CONSORT flow diagram for the DAPA trial. a, Participants have more than one reason for ineligibility.

Screening

Recruitment occurred between 1 February 2013 and 24 June 2015 across 15 different regions. A total of 2929 potential participants were identified through the screening process, of whom 1082 were ineligible. The remaining 63% (1847/2929) of people were approached to participate in the trial through various organisations within each region (see Appendix 6, Table 54) using different approach methods (Table 4). Around 41% (750/1847) of these people were sourced through secondary care organisations and the main approach method was by letter (50%) and telephone (25%). Of the 1847 people approached, 73.3% (1353/1847) declined and 25.4% (461/1847) were eligible but were unwilling or unable to participate.

Recruitment

Of the 2929 participants screened, 17% (494/2929) of the participants were deemed eligible and consented to trial participation (Table 5). The majority of participants were able to provide informed consent (376/484, 76.1%), some required a personal consultee (117/494, 23.7%), and one required a nominated consultee (1/494, 0.2%). The personal consultee was the carer in most situations.

Although the original target sample size was set as 468 participants, by the time this target was reached a further 26 participants had been recruited and randomised because of the nature of recruiting participants to fill exercise groups. The final recruitment total was, therefore, 494 participants. There were no participants randomised in error. The proportion of participants in each arm across all regions is listed in Table 6 and across the randomisation strata is given in Table 55, Appendix 6.

Participant baseline characteristics

The dementia diagnosis of participants at the baseline assessment has been summarised in Table 7, with the most common diagnoses being dementia in Alzheimer’s disease with late onset at 35.6% (176/494), atypical or mixed type at 20.9% (103/494) and unspecified at 15.4% (76/494). The baseline demographic characteristics and outcome measures of the randomised participants are summarised by treatment group in Table 8. Overall, the demographic characteristics were well matched across treatment groups, with the majority of participants being white males with an average age of 77.4 years (SD 7.9 years), who were married and living with their wife/husband/partner.

Participant baseline medications

Medication use was similar in both treatment groups; the overall mean number of medications being taken was 5.7 (SD 3.5) and donepezil was the most used medication (50.6%) (see Table 8).

Participant baseline outcome measures

A summary of the baseline outcome measures is given in Table 8. We report only the primary data sources, as data were sufficiently complete that we did not have to rely on alternative sources (i.e. proxy). All outcome measures were similar across treatment groups at baseline. The overall mean imputed ADAS-Cog score (primary outcome) was 21.5 (SD 9.0) out of a possible score of 70, for which a higher score indicates greater cognitive impairment. The three subscales of the primary outcome, namely language, memory and praxis, had mean scores of 2.9 (SD 3.4), 16.9 (5.8) and 1.7 (SD 1.6), respectively.

Comparing the baseline self-reported and proxy-reported outcome measures

Self-reported and proxy-reported data were available for most of the participants at baseline (see Table 9). In total, self-reported data were provided by 98.4% (486/494) of the participants for the EQ-5D-3L, 98.0% (484/494) for the EQ-5D-3L visual analogue scale (VAS) and 85.8% (424/494) for the QoL-AD. The only reason that most participants with self-reported outcomes did not have proxy data was if their carer did not give consent to participate and provide data. The self-reported and proxy-outcome measures were compared for all participants who had both sets of data available at baseline (see Table 10). There is evidence of a significant difference between the self-reported and proxy-reported outcome measures when the participants reported a significantly higher quality of life. Therefore, participants rated their quality of life significantly more highly than their carers did.

Falls and fracture

In total, 31.8% (146/459) of the participants had a fall in the last 6 months at baseline. There was no evidence of a difference in the mean number of falls between the two treatment groups with an overall mean of 2.7 falls (SD 4.0 falls) in the last 6 months. About 3% (14/459) of all participants had broken bones as a result of falling in the last 6 months. There was no evidence of a difference in the mean number of broken bones between the two groups with an overall mean of 1.3 (SD 0.6) broken bones in the last 6 months (see Table 8).

Carer baseline characteristics

Of the 494 participants attending the baseline assessment, 96.2% (475/494) had a carer. Of those with a carer, 96.6% (459/475) of the carers consented to participate in the study. The carer baseline characteristics and outcome measures have been summarised, by treatment group, in Table 11. There is a higher number of female carers in the usual-care arm (81.2%) than in the exercise arm (71.5%). Apart from this, the carer demographic characteristics and outcome measures are well matched across treatment groups, with the majority of carers being white females with an average age of 69.5 years (SD 11.1 years) who are providing care on a daily basis. Most of the carers (99.1%) knew the participant before they had dementia and the reason for this was that they were either their spouse (77.6%) or their son/daughter (in-law) (18.9%). Around 91% of the carers had knowledge of the participant’s night-time behaviour.

Carer role and relationship

For most participants in both arms their spouse was the only caregiver: 66.2% (102/154) in the usual-care arm and 69.8% (213/305) in the exercise arm. Many of the remaining participants had either their spouse or son or daughter (in-law) as their main carer.

Carer baseline outcome measures

A summary of the carer baseline outcomes measures is given in Table 11. All outcome measures were similar across treatment groups at baseline. Carers had an overall mean EQ-5D-3L utility score of 0.8 (SD 0.22) and mean EQ-5D-3L VAS score of 77.5 (SD 17.9) with mild to moderate carer burden reflected by a mean Zarit Burden Interview (ZBI) score of 30.1 (SD 15.5).

Comparison of retained participants to those lost to follow-up

Tables 56 and 57, Appendix 6, present the baseline characteristics of participants not completing (died, withdrew and lost to follow-up) and completing follow-up at 6 months and 12 months, respectively. At both time points, people who completed follow-up were, on average, younger than those who died but were similar in age to those who withdrew or were lost to follow-up. There is evidence of a significant association between marital status and whether or not a participant completed follow-up, with those who are separated or divorced being less likely to complete follow-up. Moreover, participants completing follow-up had significantly better HRQoL at 6 months (measured by the EQ-5D-3L) and at 12 months (measured by the EQ-5D-3L and QoL-AD) than those not completing follow-up. At 12 months, participants completing follow-up had significantly better cognition, as measured by the sMMSE score, than the non-completers. In addition, both the ADAS-Cog (imputed) and the ADAS-Cog (raw) scores suggest that, on average, participants who died had poorer cognition than those who completed follow-up at both time points.

Research protocol violations

A summary of the protocol violations has been presented by treatment arm in Table 14. There were no participants who were found to be ineligible once randomised.

Clinical protocol violations

Of the 329 participants who were allocated to the exercise arm, 12.5% (41/329) withdrew from the intervention alone, having completed only ≤ 75% of their scheduled sessions. In the exercise arm, 35% (115/329) of the participants were non-compliers, that is, they attended ≤ 75% of their scheduled sessions. In total, 9.1% (45/494) of the participants did not complete follow-up at any of the time points.

Numbers analysed

All 494 randomised participants completed their baseline assessments (usual-care arm, n = 165; exercise arm, n = 329). A reduced number of 445 participants provided 6-month follow-up data (usual-care arm, n = 145; exercise arm, n = 300) and a total of 418 participants provided 12-month follow-up data (usual-care arm, n = 137; exercise arm, n = 281).

Table 15 summarises the completeness of the ADAS-Cog, both overall and at the item level, at each time point. The ADAS-Cog had missing items for 5.7% (28/494) of the participants at baseline, 6.7% (30/445) at 6 months and 12.9% (54/418) at 12 months. The two items that were mostly missing were the word recognition and remember test items.

Primary outcome: Alzheimer’s Disease Assessment Scale – Cognitive Subscale (imputed at the item level)

On average, cognition declined over time (Tables 16 and 17 and Figures 5 and 6). There was evidence of a statistically significant difference at 12 months, which suggests that participants in the usual-care arm have a lower ADAS-Cog score (better cognition) of 1.4 (95% CI –2.62 to –0.17) than participants in the exercise arm (Table 17 and Figure 6).

FIGURE 5.

Plot of the unadjusted ADAS-Cog score (imputed) over time by treatment arm.

FIGURE 6.

Plot of adjusted treatment estimates (mean difference and 95% CI) for the ADAS-Cog score at 6 and 12 months.

Secondary outcomes

Secondary outcomes collected at 6 months and 12 months have been presented in Tables 18 and 19, respectively.

Alzheimer’s Disease Assessment Scale – Cognitive Subscale (imputed) subscale scores

The ADAS-Cog subscale scores of language, memory and praxis at 6 months and 12 months have been presented in Tables 18 and 19, respectively. No statistical differences were found in the subscale scores between the two treatment groups at any of the time points.

Health-related quality of life (EuroQol-5 Dimensions, three-level version and Quality of Life in Alzheimer’s Disease)

There was no evidence of a difference between the two treatment groups for the HRQoL measures, that is, the EQ-5D-3L (utility) score, EQ-5D-3L VAS score and QoL-AD score at 6 months and 12 months (see Tables 18 and 19).

Behavioural symptoms (Neuropsychiatric Inventory)

There was no evidence of a difference between the two treatment groups at 6 months’ follow-up and at 12 months’ follow-up (see Tables 18 and 19).

Function (Bristol Activities of Daily Living Scale)

There was no evidence of a difference between the two treatment groups at 6 months’ follow-up and at 12 months’ follow-up (see Tables 18 and 19).

Carer outcomes

A summary of the carer-reported outcomes collected at 6 months and 12 months has been presented in Table 20.

Carer health-related quality of life (EuroQol-5 Dimensions, three-level version)

There was no evidence of a difference between the two treatment groups for the carer’s HRQoL measures, namely the EQ-5D-3L (utility) score and EQ-5D-3L VAS score, at 6 months and 12 months (see Table 20).

Carer burden (Zarit Burden Interview)

Carer burden was assessed using the ZBI, which was completed by the carer. No evidence of a difference in the carer’s mean ZBI score was observed between the two treatment groups at 6 months’ and 12 months’ follow-up (see Table 20).

Carer benefit from the study

Carer benefit was measured using a five-level Likert scale, that is, substantial benefit to substantial harm. At 6 months, most carers (around 73%) in the exercise group felt that they had gained moderate or substantial benefit, whereas the majority of carers in the usual-care arm (58.1%) felt that they had gained no benefit (see Table 20). Similarly, at 12 months, most carers (around 71%) in the exercise group felt that they had gained moderate or substantial benefit, whereas the majority of carers in the usual-care arm felt that they had gained no benefit (46.1%) or gained moderate benefit (43.1%).

Participant dementia change

Participant dementia change was reported by their carer at 6 and 12 months’ follow-up and was measured using a five-level Likert scale, that is, much improved to much worsened. There was no evidence of a difference between the two treatment groups at both time points. At 6 months, around 23% of carers reported no change in the participant and 52% felt that the participant had slightly worsened. At 12 months, 18% of carers reported no change in the participant, 55% felt that the participant had slightly worsened and 17% felt that the participant had much worsened.

Participant falls and fractures

Table 21 summarises the falls and fractures of the person being cared for, as reported by the carer, at 6 and 12 months. There was no evidence of a significant difference in the reported number of falls and the number of broken bones at 6 and 12 months’ follow-up sustained by the participant. Moreover, there was no evidence of a significant difference in the number of falls over the entire follow-up period.

Sensitivity analyses

Three sensitivity analyses were conducted to see how the treatment effect estimate differs to the primary analysis if the ADAS-Cog (primary outcome) was computed or analysed differently. The first sensitivity analysis estimated the treatment effect using the ADAS-Cog score that was computed using the observed data, that is, only the data provided by those participants who were well enough to complete. Table 22 presents the results of this sensitivity analysis. There was evidence of a statistically significant difference at 12 months, with an estimated between-group difference of –1.7 (95% CI –2.97 to –0.39) in favour of the usual-care arm. These results are similar to the primary analysis results, with the between-group difference here being slightly larger at 12 months (Figure 7).

FIGURE 7.

Plot of adjusted ADAS-Cog score (imputed) estimates at 12 months for the primary analysis and sensitivity analyses.

The second sensitivity analysis estimated the treatment effect using the ADAS-Cog score that was computed using the observed data, for which the worst score was assigned at the item level if the participant was too distressed or cognitively unable to answer the item. Table 23 presents the results of this sensitivity analysis. There was no evidence of a difference between the two groups at 6 months (estimated between-group difference 0.4, 95% CI –0.83 to 1.66) and 12 months (estimated between-group difference –0.9, 95% CI –2.60 to 0.73) at 12 months. Here, the estimated between-group difference at 12 months was smaller than that estimated by the primary analysis (see Figure 7).

The third sensitivity analysis used IRT to analyse the ADAS-Cog computed using the observed data. Moreover, the analysis looked at three particular traits measured by the ADAS-Cog: language, memory and praxis. The baseline model converged within 0.001 tolerance after 305 Metropolis–Hastings Robbins–Monro iterations. The model fit was adequate, with a root-mean-square error of approximation of 0.047 (95% CI 0.043 to 0.051). Furthermore, individual items fit the model well, with all chi-squared statistics being insignificant. The memory and language traits had a correlation of 0.78, the memory and praxis traits 0.76 and the language and praxis traits 0.72. A summary of the abilities at each time point is presented in Table 58, Appendix 6. Tables 60–62, Appendix 6, present univariate analyses of the between-group differences for each of the traits at baseline and at 6 months and 12 months, respectively. The respondent ability scores at each time point for each latent trait have also been presented as a box plot in Figure 22, Appendix 6. No significant between-group differences were observed in the univariate analyses. The adjusted analyses results for the language, memory and praxis scores at 12 months are presented in Tables 61–63, Appendix 6, respectively. There was no evidence of a significant difference between the two groups for any of the three traits at 12 months.

Complier-average causal effect

A CACE analysis was conducted to estimate the treatment effect at each time point, having adjusted for non-compliance. Participants in the exercise arm who attended > 75% of their scheduled sessions were defined as compliers of treatment. The baseline outcome measures for the usual-care arm and for compliers and non-compliers in the treatment arm have been summarised in Table 24.

Statistically significant differences in the baseline characteristics were found when comparing compliers and non-compliers. The compliers were mostly male, lived with their wife or partner and had better quality of life, as measured by the EQ-5D-3L. The ITT and CACE analysis estimates have been presented in Table 25. Similar to the ITT results, the CACE results found no difference in treatment effect at 6 months but found a statistically significant treatment effect of –2.0 (95% CI –3.87 to –0.22) at 12 months in the primary outcome (imputed ADAS-Cog), having adjusted for non-compliance. The CACE analysis estimates of treatment effect at 6 months and 12 months were larger than the ITT estimates.

Subgroup analyses

Subgroup analyses were conducted on gender, sMMSE score, EQ-5D-3L mobility score and type of dementia using the 12-month ADAS-Cog (imputed) score as the outcome measure. No statistically significant subgroup effects were found (Table 26).

Process measurements

The time to pre-assessment and first session remained within the protocol-defined boundaries (Table 29).

The delivery of the exercise intervention has been summarised in Table 30. The average number of sessions attended by each participant was 21 (SD 8.7).

Table 31 details the compliance rates of participants in the intervention group. In total, 65% of the participants in the intervention group demonstrated > 75% compliance with the exercises and 79.9% achieved > 50% compliance.

Participant’s individual fitness was measured with the 6MWT. The reasons for non-completion and the pre- and post-intervention data for the 6MWT are presented in Table 32.

The demographics, dose received and physical activity of the participants in the intervention arm have been summarised in Table 33 by compliance status. By taking part in the intervention, participants were able to lift more weight for the sit-to-stand exercise, indicating an improvement in strength (see Table 33 and Figure 8). On average, across all sessions, participants fully achieved their target number of repetitions and sets for the sit-to-stand exercise as shown in Figure 9. Regarding the aerobic component (cycling) of the intervention, participants were able to achieve a large proportion of their set target at each session both at moderate and hard intensity, as shown in Figure 10. We modelled the association between the dose achieved and cognition for both the aerobic and resistance components of the intervention; however, no evidence of an association was found.

FIGURE 8.

Plot of the median (interquartile range) weight lifted (kg) over time by compliance status for the sit-to-stand exercise. (a) Complier and (b) non-complier. The total number of participants attending each session is presented above each interquartile range bar. IQR, interquartile range.

FIGURE 9.

Mean % target repetitions and sets achieved by the intervention group for the sit-to-stand exercise.

FIGURE 10.

Mean % target achieved by the intervention group at moderate and hard intensity.

The intervention was intended to increase participants’ fitness levels through increasing exercise intensity over the intervention period. From all of the outcomes generated by the 6MWT, the distance travelled has been proven as a reliable estimate of fitness. 60 There is evidence of a statistically significant increase in the distance walked post assessment compared with pre-assessment (paired t-test, p < 0.001), suggesting that the intervention was successful in increasing participants’ fitness levels.

Sampling and recruitment

Sampling of participants and their carers was consecutive and participants were drawn from five intervention delivery sites. Sites were selected to reflect a range of settings and reflexive observations were carried out at each site. Once observations of the sites were completed, we invited participants and carers to take part in an interview. Participants had already consented to be approached to take part in the qualitative study as part of the consent process for the RCT. Ten participants and 10 carers were approached in person, asked if they would like to learn more about taking part in an interview and given a participant information leaflet. At the next observation, they were approached again and asked if, having read the information, they would like to agree to an interview. Once an interview date was agreed, participants were asked to sign an interview consent form. Participants were advised that they could terminate the interview at any time and that it would not affect their participation in the intervention.

As we began to reach data saturation, we checked that the sample broadly reflected the population of the intervention arm of the trial in relation to gender, ethnicity and social class. All of the physiotherapists delivering the intervention at the included sites were approached for interview and offered a participant information leaflet and an informed consent form.

Observations

A qualified and experienced qualitative researcher (Samantha Lyle) observed classes at three time points across the duration of the 4-month-long supervised aspect of the intervention. At the start of the observations, the researcher was introduced to participants by the physiotherapist who was delivering the class. Observations consisted of watching participants and carers and the interactions of the physiotherapists with them as they arrived to the classes, and watching and taking handwritten notes of the delivery and end of the classes. The researcher took notes while visible to those present. She also took time to engage briefly with participants in order to hear about their particular experience on that day. Observations notes were typed up and formed part of the data set. No one made any objections to being observed.

Interviews

A semistructured interview guide was developed by the research team to gather data from the participants, carers and physiotherapists to answer the research questions (see Appendix 8). This was tested and refined during the second pilot study. The interviews were carried out by a researcher who was trained and experienced in qualitative research methodologies (Samantha Lyle).

Participants and carers were offered the opportunity to be interviewed separately or together. When both expressed indifference, the researcher suggested that the interviews be conducted separately starting with the participant, thereby allowing participants to engage in the research as autonomous research subjects89,90 and allowing carers the opportunity to speak freely.

Physiotherapists were offered the choice of being interviewed at their workplace or at home via telephone. The interviews were audio-recorded and transcribed verbatim.

Data analysis

Our data comprised:

• notes taken during observations of exercise classes

• interviews with trial participants

• interviews with carers of trial participants

• interviews with physiotherapists delivering the classes.

The data were analysed as a single data set. Identifying information was anonymised to ensure interviewees’ confidentiality was maintained. Interview transcripts and field notes were uploaded into NVivo version 10 (QSR International, Warrington, UK), a computer program for qualitative data, to assist with data management and analysis.

Analysis was thematic and broadly followed the principles of grounded theory. 98 A thematic analysis involves identifying, describing, analysing, interpreting and reporting repeated themes and categories in the data that relate to the research questions and represents some level of patterned response or meaning across a data set. 99 We compared data relating to an individual participant from the participant themselves, their carer and their physiotherapist. The data were initially organised into broad descriptive codes such as ‘experiences of the intervention’. The data within these broad codes were reread and subcodes were identified such as ‘positive experiences of participants’, negative experiences of participants’ and ‘ambivalent experiences of participants’. During the coding process, we compared data between participants, between carers and between physiotherapists to sharpen our understanding and refine our subcodes. Transcripts were analysed by the researcher who carried out the interviews (Samantha Lyle). A second researcher (Frances Griffiths) independently analysed approximately 20% of the transcripts. 99 The two researchers met to discuss and reflect on the coding and analysis as it proceeded. Discussion of the analytic process and findings were shared within the wider research team, including the chief investigator (Sarah E Lamb), for their reflections, which further informed subcode refinement. Disagreements regarding the identification, description, analysis or interpretation of data were resolved through discussion and further analysis.

Data collected and the characteristics of sites and interviewees

In total, five sites were observed four times, for approximately 1.5 hours each, between November 2013 and March 2015. Settings for the delivery of the intervention included pleasant leisure centres with cafes and soft seating for carers to use, large warehouse-style gyms situated on industrial estates with very loud heating systems and rather run-down local authority amenities with no facilities for carers to use. They were located in a range of urban, suburban and rural settings.

Eight participants took part in an interview and two declined to do so. Six carers agreed to take part in an interview and two declined. Six participants chose to be interviewed on their own and two chose to have their carer present (one was a spouse who had her interview on her own and the other was a friend). Five carers chose to be interviewed on their own and one to be interviewed with the participant. All participant interviews took place in their homes and three carer interviews took place in quiet rooms while classes were being delivered. Interviews lasted between 30 minutes and 2 hours.

All five physiotherapists delivering the intervention at the included sites agreed to an interview (one via the telephone).

The participants interviewed were slightly younger than the overall study sample. They were all white British, with five men and three women. Their cognitive function indicated only mild dementia for all but one participant who had moderate dementia. Their mean cognitive function score is slightly better than that of the main study sample. The sample of carers interviewed (n = 6) comprised two men and four women, all were white British and their current level of burden ranged from 8 (low burden) to 64 (high burden). Table 34 describes the interviewees.

Participant and carer experiences of taking part in the intervention

In this section, we first describe positive experiences that the participants and carers had of the intervention and then the more burdensome aspects of their experiences.

The therapeutic alliance between participant and physiotherapist

Therapeutic alliance is a term used to describe the fit between therapists and patients; a good or positive alliance potentially contributes to patient well-being and successful rehabilitation,101 although this is contested. 102 A good therapeutic alliance must be continually reproduced between the patient and the therapist. 103 Trying to maintain a good therapeutic alliance with participants who have dementia is challenging.

One physiotherapist seems to have overestimated what participant 5 could achieve, while perhaps underestimating his understanding of what was possible:

She loaded the whole waistcoat up with lead, the fronts, the middle, the lot, everything and she sat me on this chair and then she said right stand up so I went to get up and she said no, no put your feet there, now get up and I said you can’t do that . . . I knew what I was doing and how to do it and I said I can’t move. She said you’re not going until you do it once so I got up and I put my knee out, I thought this is it, I’m going to be punished like this.

Patient 5 (male, sMMSE score of 19)

Participant 5 reported his experience to the trial team and was offered a different class in which he enjoyed the exercise and the company of the other members of the class:

In contrast, participant 8 talked about how too much surveillance contributed to an incident that he found stigmatising. This participant was observed to have a lot of energy and was described to the researcher as having a big personality and that he could sometimes be disruptive. He was positive about the physiotherapist and exercise assistant but he felt that their surveillance of him undermined his sense of autonomy:

They are frightened to death that you’re going to do something and injure yourself . . . if I pick up a dumb-bell and start doing oh my . . . [they say], ‘just a minute, just a minute’ . . . and I think well I’ve just had a bit of a [telling off] for doing something on my own and there’s these other people they’re doing the same. I don’t feel as though I’ve got anything at the moment. My son calls them ‘window lickers’ and ‘smell of wee tours’ when they all get on the bus . . . it’s only a little thing, it uh . . . when I say uh, ‘oh I’ll be back in a minute’, ‘no, no hang on a minute, where are you going?’ I said ‘I’m going to the toilet’ and then I’ve got [exercise assistant] standing outside the lavatory door!

Patient 8 (male, sMMSE score of 24)

The wife of participant 8 joined the interview saying that those leading the class had behaved reasonably in the situation and that the participant lacked insight (the gym was in a warehouse with the toilets near the exit and no one at the exit to see people leave). However, participant 8 had sufficient insight to express that he felt was being treated like people who his son call ‘gagas’ and ‘window lickers’.

Participants getting to the classes

Of those participants interviewed, three were unaccompanied to the classes at least some of the time. Participants 5 and 8 arrived by taxi (provided by the trial) and participant 7 drove himself, with his wife not accompanying him at least some of the time. Of the carers who had to accompany participants to the class, none of them spoke of the difficulty in doing so. Carer 1 was still in work but he lived locally to his mother and was able to work his around his job, and his brother was also on hand should he be unable to take her to the odd class. He attributed the ease of getting her to classes to her willingness to attend:

When I pulled into her drive I could see her figure behind the door waiting, so she was just ready for me.

Carer 1 (son, ZBI score of 16)

Do participants and carers think that the classes ‘worked’?

Some participants spontaneously offered their view on whether or not they thought the classes ‘worked’ and others were asked directly. With the exception of one participant and one carer, no one reported that they thought the classes had made an impact on their dementia. But, with the exception of one carer, everyone interviewed thought that there had been a positive impact on participants physically and that the class had generally done them some good.

Physiotherapists’ experiences of delivering the intervention

We now consider the experience of the physiotherapists, how they delivered the intervention while negotiating the participant’s dementia symptoms and how they negotiated the label of dementia and its associated stigma.

Study population

A total of 494 participants were randomised into the trial: 329 to the exercise programme (experimental arm) and to usual care (control arm). Complete baseline information was available for 488 participants (exercise arm, n = 326; control arm, n = 162). Consequently, the baseline study population for the bulk of the health economic analyses is 488 participants. Between 91% and 99% of all health resource-use data were complete at baseline for the exercise group; for the usual-care group, this ranged between 91% and 98% (Table 36). Similarly, these values ranged between 84% and 91% and 78% to 86% at 6 months; and between 77% and 85% and 78% and 82% at 12 months, for exercise and usual care, respectively. A complete QALY profile was available for 435 (88%) participants based on the patient-reported EQ-5D-3L (84% for the carer-reported EQ-5D-3L).

Cost of intervention

Estimates of the total costs of delivering the exercise programme are provided in Tables 37 and 38 for each group within each study site. The cost components are aggregated into four headings, namely (1) staff costs, inclusive of training activities, planning, direct delivery, administrative activities, meetings with professionals, telephone calls and supervision activities associated with group delivery, (2) travel costs, based on distances travelled by practitioners by mode of transport, (3) venue hire costs and (4) equipment and other costs for each site, including cost of belts, stopwatches, timers, cones, lap counters, compact discs, stationery (e.g. pens, erasers) and trial manuals, associated with group delivery. Total intervention costs are also presented within each group within each site. These varied between £4443.90 (Worcester, cohort 53) and £11,342 (Wolverhampton, cohort 50).