Design
This study is an observer-blinded, multicenter randomized controlled trial with an economic evaluation alongside. The trial will be conducted by trained therapists of the participating centers. Within each type of setting, patients will be randomly allocated to either CME combined with e-health services (CARE4STROKE) in addition to usual care or to usual care alone. The study is registered in the Dutch trial register as NTR4300, registered 2 December 2013.
Setting
The study will take place in hospitals (stroke unit and outpatient clinic), rehabilitation centers and rehabilitation departments of nursing homes in the Netherlands.
A trained researcher, blinded to group allocation, will visit the participants in the center of admission for obtaining informed consent and conducting measurements during the study.
Reade Rehabilitation Center and VU University Medical Center are the initiators of this study. The study protocol is approved by the Medical Ethics Review Committee of the Slotervaart Hospital and Reade and is registered with the trial number: NL34618.048.12.
Participants
Sixty-six patients with a first-ever or recurrent stroke, who are admitted to one of the participating centers and their caregivers, will be recruited for this study. Stroke is defined by the World Health Organization as "a clinical syndrome typified by rapidly developing signs of focal or global disturbance of cerebral functions, lasting more than 24 h or leading to death, with no apparent causes other than of vascular origin" [32]. A caregiver is defined as someone close to the patient, who is willing and able to do exercises together with the patient, for example a partner, family member or friend. This caregiver is not a professional and is not paid for his/her efforts.
Inclusion criteria for both patient and caregiver are: (1) 18 years or older, (2) written informed consent, (3) able to understand the Dutch or English language (on a sufficient level to understand instructions on CME and e-health application), (4) motivated for CME, (5) a score of <11 on the domain ‘depression’ on the Hospital Anxiety and Depression Scale (HADS) [33, 34].
Additional inclusion criteria for the patient are: (1) willing and able to appoint a caregiver who wants to participate in the program (with a maximum of two caregivers), (2) living independently before the stroke, (3) planned to be discharged home, (4) being able to follow instructions (MMSE score > 18 points) [35], (5) Functional Ambulation Score (FAC) < 5 [36].
Additional inclusion criteria for the caregiver are: 1) being medically stable and 2) physically able to perform the exercises together with the patient.
Exclusion criterion for both patient and caregiver will be serious comorbidity, which interferes with mobility training. Patients will be excluded when they, for example, have another neurological disease like Multiple Sclerosis or Parkinson disease, fractures or congestive heart failure. Caregivers will be excluded when they are not able to walk 100 metres, stand and/or keep their balance.
To determine suitability in terms of safety, cognition and communication skills of both patient and partner, an intake exercise session with one of the trained physical therapists is scheduled prior to inclusion. This therapist checks the inclusion/exclusion criteria and judges if the exercises can be done adequately and safely. Reasons of exclusion will be recorded.
Baseline characteristics
Patient characteristics at baseline will be recorded from the medical status. These include demographics (age, gender), type of stroke, time post stroke, hemiplegic side, somato-sensory deficits (yes/no), homonymous hemianopia (yes/no), visuo-spatial neglect (yes/no), aphasia (yes/no) and comorbidity following the Cumulative Illness Rating Scale (CIRS) [37]. Characteristics of the caregiver that will be recorded are: demographics (age, gender), relation to patient, work and existing comorbidities following the CIRS.
Study procedures
Patients will be stratified by type of participating center (hospital stroke unit, rehabilitation center or nursing home) and subsequently randomized, by an independent researcher blinded for patient characteristics, to the control or the experimental group. An online randomization procedure with a minimization algorithm is used to prevent unequal group sizes [38]. Patients will start immediately after admission, continue for 8 weeks irrespective of time of discharge and will be followed-up until 12 weeks after randomization. Outcomes will be measured at baseline, 8 and 12 weeks (see Fig. 1: Study design). Outcomes are either self-reported by patients and caregivers (not blinded) or measured by an independent observer who is blinded for treatment allocation. A self-reported (cost) diary will be kept during the intervention period to monitor compliance and to collect relevant cost-data.
CARE4STROKE intervention
The CARE4STROKE program consists of 8 weeks of exercise therapy executed with a caregiver, in addition to usual care. A total of 37 standardized exercises were developed that are aimed at improving mobility skills related to walking like, standing, turning and making transfers, or are supporting exercises to improve mobility, strength and (sitting) balance. Subsequently, exercises can be combined into a patient-tailored, weekly progressive and incremental training regimen. All exercises were developed in collaboration with rehabilitation specialists (movement scientists, physical therapists and physicians) and have been shown feasible in a pilot study.
The exercises are presented as instructional videos in an e-health application (‘app’) on a tablet computer. All exercises are explained by a voice over. Regular reminders to exercise can be set in the app. The patients and their caregivers are asked to perform the selected set of exercises minimally five times per whole week for 30 min. Patients and caregivers are in particular advised to do the exercises during the weekends, acknowledging that patients are often physically inactive during the weekend. When the intervention is correctly performed patients will thus have a surplus of 150 min of caregiver-mediated exercise training during a whole week.
During the intervention period patients and their caregivers will have a weekly session with one of the trained physical therapists. In these sessions, the set of exercises performed in the previous week is evaluated and adapted in a progressive manner. The participating couple is subsequently instructed as to which set of exercises should be performed during the next week. To make sure exercises are correctly performed, the therapist will give instructions about the new exercises and the patient-caregiver couple will be asked to do these exercises in the presence of the therapist during this session. The therapist will register all planned exercises and also if any adverse event happened during the last week. Furthermore, patient - caregiver couples are encouraged to contact the coordinating therapist through telephone, skype or email when appropriate.
The CARE4STROKE program starts when the patient is admitted to one of the participating centers. When the discharge date of the patient is earlier than the anticipated end date of the CME program, the CME program continues at home with the continuity of the use of the app, the weekly sessions with the therapist and the possibility to contact the therapist through tele-rehabilitation services when appropriate.
Usual care
The participants in the control group will receive usual care according to the Guidelines of Physical Therapy for patients with stroke of the Royal Dutch Physical Therapy Association KNFG [15].
Compliance
In order to conduct this trial uniformly in the different centers, all participating therapists will be thoroughly trained in a training course before they start delivering the program. Each therapist will be informed about 1) the aims, design and measurements of the CARE4STROKE study, 2) the in- and exclusion criteria, 3) the CARE4STROKE program: the standardized program and the possibilities to customize the CME, 4) their role in the intake exercise session and following exercise sessions, 5) how to fill in the diaries, 6) the use of the app. Regular retraining sessions will be organized for the participating therapists. A researcher (RN) will monitor if the intervention is implemented appropriately in the participating centers.
A self-reported diary will measure compliance of patient and caregiver with the CME program.
Outcome measures
Primary outcome measures are the mobility domain of the Stroke Impact Scale (SIS 3.0) and LOS.
Stroke Impact Scale (SIS) version 3.0, Mobility domain
The SIS is a self-reported, stroke specific measure that includes 59 items and assesses eight domains related to activities and participation. The mobility domain of the SIS includes questions about patients’ perceived competence to walk, keep balance, and move around in their own community. Each item is scored from ‘not difficult at all’ to ‘cannot do at all’ on a 5-point scale. The SIS has shown excellent clinimetric properties in English, as well as in the Dutch translation [39–43].
Length of Stay (LOS)
LOS will be defined as the number of days of inpatient stay in a rehabilitation facility and/or hospital setting, from the day of admittance until the day of discharge. Mean length of stay for each setting will be determined. Possible reasons for an extended inpatient stay, like medical complications or time needed for the realisation of facilities at home, will be recorded.
Secondary outcomes
* Patient
Stroke Impact Scale, other seven domains
The other self-reported domains of the SIS will be assessed as secondary outcome measures.
Fugl Meyer (FM) motor score of lower extremity
The FM will be used to assess motor impairment. It is a reliable and valid motor performance test and evaluates the ability to make movements outside the synergistic movement pattern [44].
Motricity Index (MI), lower extremity
The MI is a valid and reliable measure of the strength of the lower extremity. Scores range from 0 (no activity) to 33 (maximum muscle force) for each dimension [45].
Six minute walking test
Gait performance and endurance will be assessed by the six minute walking test [46, 47]. The walking distance covered in six minutes will be recorded.
Ten meter walking test
Gait speed will be measured by the ten meter walking test. Comfortable walking speed will be assessed. The mean of three repeated walking speed measurements will be calculated [46, 47].
Timed up and go test (TUG)
The TUG is a test of basic functional mobility. The participant is asked to rise from an armchair, walk three metres as fast as possible, cross a line, turn, walk back and sit down again. The time to complete this test will be recorded [46, 47].
Berg Balance Scale (BBS)
Balance will be evaluated by the BBS. BBS is a widely used clinical test of a person's static and dynamic abilities. There are 14 items scored from 0–4 (maximum), with a total score of 56. The BBS is a valid and reliable measure [48, 49].
Rivermead Mobility Index (RMI)
The RMI is a test to evaluate functional mobility. It consists of 14 questions and one observation (of balance) covering aspects from turning in bed to running. The questions are scored dichotomously. The RMI is valid, reliable and responsive [50–52].
Barthel Index (BI)
The BI is an ordinal scale to measure performance in activities of daily living (ADL). It uses ten variables describing ADL and mobility. A higher score indicates higher independence in ADL. It has excellent clinimetric properties and can also be filled out by an experienced nurse or relative [53].
Nottingham Extended ADL scale (NEADL)
The NEADL is a self reported questionnaire on activities actually performed. It consists of 22 items in four domains (mobility, kitchen, domestic, leisure). Each item is rated by one of four responses (able, able with difficulty, able with help, unable). The NEADL has proved to be a reliable and valid outcome measure in patients with stroke [54].
Modified Rankin Scale (MRS)
The MRS is a measure for the degree of disability or dependence in the daily activities. The score runs from 0–6, ranging from perfect health without symptoms to death. The score will be dichotomised to good outcome (0–2) or poor outcome (3–6). It is a valid scale and frequently used in stroke outcome studies [55].
EuroQol (EQ-5D)
The EQ-5D measures health related quality of life. It consists of a self-assessment questionnaire about current health in five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/ depression) and a VAS score in which a person is asked to rate their own health status. It is a widely used generic questionnaire, which is validated for people with stroke. By combining the questionnaire and VAS score a health state is described, and each health state combined with population estimates can be transformed to a utility. A utility is an expression of the Quality Adjusted Life Years (QALY) and can be used in economic evaluations [56–59].
* Caregiver
Expanded Caregiver Strain Index (CSI+)
The CSI+ evaluates experienced strain of the caregiver. There are 18 items answered with ‘yes’ or ‘no’ and scored dichotomously. The CSI+ is an expansion of the Caregiver Strain Index and also rates positive aspects of caring. The CSI+ is proven valid and responsive [60–62].
Carer Quality of Life Scale (CarerQOL)
The CarerQOL is a valid instrument to evaluate care-related quality of life in informal caregivers. The instrument consists of a burden instrument (encompassing seven important burden dimensions) and a valuation component (a VAS scale for happiness). It consists of seven questions with each three-answer options (no, some, a lot) and a VAS scale (‘how happy are you at this moment?’) [63–65].
* Patient and caregiver
Hospital Anxiety and Depression Scale (HADS)
The HADS is a measure to evaluate mood: anxiety and depression. The HADS consists of 14 items (seven anxiety and seven depression), each with a 4-point rating scale (0–3) It is a brief, reliable, responsive, valid and widely used measure [33, 34].
Fatigue Severity Scale (FSS)
The FSS measures the impact of fatigue. It consists of nine items, and scores for each item range from 1 to 7. The total FSS score is the mean of the nine item scores. The FSS was validated and demonstrated to be a simple and reliable instrument to assess and quantify fatigue for clinical and research purposes [66].
General Self-efficacy Scale
The General Self-Efficacy Scale is a valid 10-item psychometric scale that is designed to assess optimistic self-beliefs to cope with a variety of difficult demands in life. It has a 4-point rating scale (‘not at all true’. ‘barely true’, ‘moderately true’ and ‘exactly true’). The scale has been originally developed in German and has been used in many studies with hundred thousands of participants. General self-efficacy is a universal construct that yields meaningful relations with other psychological constructs [67, 68].
(Cost) Diaries
Each patient-caregiver couple will be asked to keep a weekly cost diary during 12 weeks. Direct and indirect cost data will be collected. The diary will comprise questions for the patient on medical consumption (for example questions about consultation with doctors, therapists, re-admission, home care), missing hours at work, household, sports or hobbies and time invested by the caregiver in the caregiver-mediated training [69]. In addition, the patient will be asked to record the exercises done each day during the eight-week intervention period (in therapy, by themselves, with nurses or with a caregiver). Thereby we can evaluate the total time spent on (additional) exercises done by the couples in the intervention and control group. Problems and adverse events like for example falls, fractures, and concurrent illness will also be recorded.
Process analysis
At the end of the intervention, semi-structured interviews will be conducted with a subgroup of patients and caregivers to collect qualitative data regarding the experience of CME to evaluate facilitators and barriers for implementation.
Power analysis
We expect a significant reduction of five points (11 %) on the SIS mobility domain in favor of the experimental training group, with an estimated standard deviation for this population at a maximum of 14 points [70], requiring inclusion of minimally 30 patients per arm of the trial. Including 10 % dropouts, a minimum of 66 stroke patients, (i.e., 22 per type of center), is needed to achieve a sufficient statistical power of 80 % using a significance level alpha of p < 0.05.
Data analyses
Baseline characteristics will be presented and between group differences will be studied to determine whether groups are comparable at baseline. Normality of data distributions will be judged by visual plot. When data are not normally distributed, non-parametric Wilcoxon signed rank sum tests will be used. When the data are normally distributed student t-tests for independent samples will be used. The two-tailed α-level will be set at 0.05.
The main outcomes will be compared between the intervention and control group at the different time points using multilevel regression analysis. Depending on the number of settings of participating centers we will use random coefficient analysis (SPSS GLM). Time since stroke, group, location and baseline values will be added to the model. Intention-to-treat analysis will be done and missing data will be imputed using multiple imputation techniques. All hypotheses will be tested two sided, with a critical value of <0.05.
Economic evaluation
The economic evaluation will be performed from a societal perspective and a health care perspective with a time horizon of 12 weeks. For the measurement and valuation of the costs the Dutch costing guidelines will be used [71]. All relevant costs will be measured and valued, including cost of production loss where applicable. The analysis will be done according to the intention-to-treat principle. Missing cost and effect data will be imputed using multiple imputations according to the MICE (Multiple Imputation by Chained Equations) algorithm [72]. Bias-corrected and accelerated bootstrapping with 5000 replications will be used to calculate 95 % confidence intervals around the mean difference in total costs between the two groups. Incremental cost-effectiveness ratios (ICERs) will be calculated by dividing the difference in mean total costs by the difference in mean effects on the primary outcomes (SIS mobility and LOS) between the treatment groups. A cost-utility analysis will be performed estimating the incremental costs per QALYs gained. In the costs utility-analysis the outcome measure will be QALYs based on the Dutch tariff for the EuroQol [56]. Bootstrapping will be used to estimate the uncertainty surrounding the ICERs, which will be graphically presented on cost-effectiveness planes. Cost-effectiveness acceptability curves and net monetary benefits will also be calculated. To estimate indirect costs of production loss the human capital approach will be used. Sensitivity analyses will be performed on the most important and uncertain cost parameters.
