Title: PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease (PEDAL Trial)
Funder: Department of Health and Social Care

Abstract: The PEDAL study aims to evaluate the effectiveness of a 9-month intradialytic exercise training intervention designed to improve quality of life (QOL) and functional limitations in patients with stage 5 CKD, against established treatment options available within UK NHS haemodialysis (HD)units. It is designed as a pragmatic, multicentre RCT (with an internal pilot study) with two treatment arms: intradialytic exercise training plus usual care maintenance HD (EXHD) versus usual care maintenance HD (UCHD). The internal pilot, run concurrently with the main trial, will explore patient participation metrics and intervention acceptability in a sample of 20% of patients. Within the RCT, a nested qualitative study will also investigate the experience and acceptability of the intervention for both participants and members of the renal care team. Health Economic analysis will be conducted to assess the cost effectiveness of the intervention. We propose to recruit participants to the PEDAL study from all adult eligible prevalent HD patients who have been receiving outpatient maintenance HD for at least 3 months. We propose to recruit participants to the PEDAL study from all eligible adult prevalent intra-dialytic exercise naïve HD patients receiving outpatient maintenance HD for at least 3 months. Patients will be recruited from hospital HD units. Recruitment for the trial will take place over a 21-month period in HD units from England, Wales and Scotland. Intradialytic exercise is the Health Technology being assessed. The type of exercise programme advocated is a combination of thrice weekly aerobic cycle exercise and twice weekly muscular endurance conditioning. The aerobic exercise involves steady, rhythmic movements of the large muscle groups of the body. In this instance it will be accomplished by pedalling at a preset cadence against a frictional resistance applied by a cycle ergometer specially adapted for dialysis chairs/couches. The aerobic exercise will be performed seated, in a semi-recumbent position, during the first two hours of haemodialysis. Twice per week and immediately after the aerobic cycling exercise, patients will also complete lower extremity muscular conditioning exercise, using ankle weights. These ankle weights are fitted with a Velcro strap attachment and of a type routinely used by NHS physiotherapists. All intradialytic exercise sessions will be supervised by a Physiotherapy Assistant. The aerobic exercise prescription will be individualised for all patients on the basis of a peak aerobic capacity assessment conducted during an incremental exercise test on a stationary cycle ergometer. Participants will have their QOL, functional limitations and selected clinical characterstics recorded via blinded outcome assessment prior to treatment randomisation and followed up after 6, 9 and 15 months. Following blinded outcome assessments conducted at entry to the study, a total of 380 patients will be randomised equally in 5 centres to either UCHD or EXHD, giving 190 per treatment arm. Based on evidence from phase II trials (23) we expect 17-25% of patients to discontinue the exercise programme due to transplant, death or personal choice over the 9 months of the programme. A similar discontinuation rate will occur in the UCHD group, leading to 133 patients per group completing the study. The primary outcome will be change in the Kidney Disease Quality of Life-36 (KDQOL-36) Physical Composite Score (PCS) and this will be evaluated at the primary endpoint after 6 months of the intervention. Based on the PCS variability seen in Painter et al (31) and comparing 6-month KDQOL PCS between groups by two sample t-test (two-sided 5% significance level), this sample size would give 83% power to detect a mean difference of 4 points in KDQOL PCS. The 4 point effect size is of clinical relevance: as there is an established relationship between each 1 point increase in PCS and reduced mortality and hospitalisation (9). Important secondary outcomes include the KDQOL-36 Mental Composite Score, KDQOL-36 Vitality subscale, estimates of functional limitations derived from both patient reported (Duke Activity Status Index) and performance assessments (10metre Timed Up and Go test, sit to stand test, peak aerobic capacity (also used to assess the fidelity of the intervention), habitual physical activity and arterial stiffness as a marker of cardiovascular health. We estimate that the entire study will take 48 months to complete (including writing of reports and initial dissemination). There will be a six month “run-in” period during which time the trial management and trial steering groups (including PPI participants) will be constituted, recruitment of staff, staff training and all regulatory and ethical committee approvals will be obtained. Formal confirmation of regional site management and operational roles will also occur at this time. This will be followed by a 21 month period of recruitment. We anticipate that we will recruit the largest proportion of our sample in the first 6 months mainly from the available pool of eligible maintenance HD patients who meet the inclusion criterion of receiving dialysis for at least 3 months. Thereafter we estimate a recruitment rate of 40 new patients per region per year. Qualitative investigations will occur at two time points: just prior to the end of the Internal Pilot Study phase and again after the majority (more than 75%) of patients have exited the exercise intervention. These will explore patients’ and renal care teams' expectations and experiences of exercise training, with the particular aims of understanding (i) the beliefs and attitudes of participants and of the renal care teams towards exercise training as a treatment and how this might affect QOL and (ii) the acceptability and experience of the intradialytic exercise training intervention as well as how being in the usual care arm affected behaviour. Finally, we will gather provisional evidence of the effect and value for money of this intervention. Using cost-utility analysis within an NHS costing perspective, within trial analysis will be performed and economic modelling will be used to model costs and effects over the longer term. Cost and QALY estimates will be combined to produce incremental cost-effectiveness ratios of intradialytic exercise to usual care with uncertainty assessed by probabilistic sensitivity analysis including the generation of cost-effectiveness acceptability curves.

Lay abstract: There is some evidence that people with chronic kidney disease who participate in short term exercise programmes can benefit their mobility, health and well-being, but the impact is short lived. Achieving a physically active lifestyle over the longer-term may offer a cost effective way for haemodialysis patients to maintain their walking and independence for longer, gain health and social benefits and possibly a means to slow disease progression and reduce its impact on themselves, their families and society. However, most haemodialysis (HD) patients, just like most people, fail to undertake any physical activity (PA) at all and those that do manage to initiate an exercise programme find it difficult to sustain this engagement longer-term. We also know that greater health benefits are achieved in individuals exercising more intensively and for longer durations. We believe that the thrice-weekly, 4 hour-long unit-based HD sessions provide a practical opportunity to deliver a safely structured and supervised exercise training (rehabilitation) programme for HD patients. We also think that more people may take up exercise if it is delivered this way as it will not impose any additional burden to patients in terms of time, effort and travel costs already incurred by their attendance at haemodialysis sessions. As a result, with the guidance of HD patients we have developed a rehabilitation programme to enable patients to exercise during their dialysis sessions. This exercise programme,called intradialytic exercise, comprises a combination of aerobic exercise (the type which increases stamina) and muscular endurance conditioning (the type which makes muscles stronger and more resistant to fatigue). The delivery of this type of aerobic exercise uses exercise equipment that has been specially modified for use whilst patients are seated on their dialysis chair or couch. Patients are thus able to pedal this modified stationary exercise bike whilst seated during their dialysis therapy. In addition to the stationary cycle exercise we propose to support patients in undertaking muscular endurance conditioning exercises of the legs. These exercises will be undertaken twice per week immediately after patients have completed their cycling exercise. Each patient will undertake some exercise based assessments, using a similar stationary exercise bike, in order that we can create an exercise plan that is matched to their current exercise abilities. Our aim is therefore to test whether this additional treatment option actually benefits HD patients in terms of their general well being and quality of life (QOL) and also if it benefits physical function and ability to participate in daily activities, like walking and rising from a chair. We also want to examine what effects participation in the intradialytic exercise programme may have on other aspects that may be important to the health of HD patients (for example blood pressure). In addition, we want to examine whether this type of additional treatment option is cost effective within the health service setting. To do this we aim to recruit three hundred and eighty adult patients from dialysis units throughout the UK to participate in this research. We propose to recruit exercise-naïve HD patients (that is not currently taking part in any exercise training during their dialysis sessions) as participants to the PEDAL study from all eligible adult prevalent intra-dialytic receiving outpatient maintenance HD for at least 3 months. We propose to recruit participants to the PEDAL study from all eligible adult prevalent patients receiving outpatient maintenance HD for at least 3 months. Patients will be recruited from hospital HD units. To be eligible to take part patients must not currently be participating in exercise training during their dialysis sessions. Recruitment for the trial will take place over a 21-month period in HD units from England, Wales and Scotland. Once patients have agreed to take part they will complete a series of assessments to measure their self-reported QOL and functional limitations. After this, patients will be allocated, by chance, to either a usual care haemodialysis plus intra-dialytic exercise group or the usual care haemodialysis group. This is called a randomised controlled trial and is considered the best way to obtain impartial evidence about the value of a treatment. The exercise group will receive the opportunity to exercise during their dialysis for a total duration of 9 months. We will then invite all patients to come back for reassessment of QOL and functional limitations after 6, 9 and 15 months. The 6 and 9 month assessments will allow us to examine the direct effects of the exercise programme on the outcome measures. The 15 month assessment will provide us with information about any longer lasting effects of the intradialytic exercise programme. All of these assessments will be conducted by someone who will be unaware as to which group patients were allocated to. This is called blinded outcome assessment and it is important so that patients’ test results are not influenced by the researchers. We will also arrange to meet with a smaller group of individual patients and separately with members of their renal care team in order to explore the attitudes and experiences of participants and healthcare staff in relation to the exercise intervention. This part of the research will allow us to better understand the views of patients and staff about the value of the exercise training programme but also of usual care. Finally, we will gather provisional evidence of the effect and value for money of this support package in order to inform future definitive trials of the effect and cost of this service, and how it runs when implemented as part of a an NHS service.

Research activity codes: 6.7 PHYSICAL;7.1 INDIVIDUAL CARE NEEDS
Health categories: RENAL AND UROGENITAL