A randomised controlled trial of neuromuscular stimulation in non-operative venous disease improves clinical and symptomatic status.

Funder: Actergy HealthBACKGROUND: This randomised controlled trial investigates the dosing effect of neuromuscular electrical stimulation (NMES) in patients with chronic venous disease (CVD). METHODS: Seventy-six patients with CEAP C3-C5 were randomised to Group A (no NMES), B (30 minutes of NMES daily) or C (60 minutes of NMES daily). Primary outcome was percentage change in Femoral Vein Time Averaged Mean Velocity (TAMV) at 6 weeks. Clinical severity scores, disease-specific and generic quality of life (QoL) were assessed. RESULTS: Seventy-six patients were recruited - mean age 60.8 (SD14.4) and 47:29 male. Six patients lost to follow-up. Percentage change in TAMV (p<0.001) was significantly increased in Groups B and C. Aberdeen Varicose Veins Questionnaire Score (-6.9, p=0.029) and Venous Clinical Severity Score (-4, p-0.003) improved in Group C, and worsened in Group A (+1, p=0.025). CONCLUSIONS: Daily NMES usage increases flow parameters, with twice daily usage improving QoL and clinical severity at 6 weeks in CVD patients

Neuromuscular electrical stimulation as an adjunct to standard care in improving walking distances in intermittent claudication patients: the NESIC RCT

Background Peripheral arterial disease is common and associated with increased cardiovascular morbidity and mortality. While patients with peripheral arterial disease are known to benefit from supervised exercise therapy, it is not always available. Neuromuscular electrical stimulation devices may offer a similar benefit. A randomised controlled trial was required to ascertain whether such devices can benefit patients who receive supervised exercise therapy and those who do not. Objective(s) The primary objective was to assess the mean difference in absolute walking distance at 3 months in intermittent claudication patients receiving either a neuromuscular electrical stimulation device and local standard care (intervention), or local standard care alone (control). Design A pragmatic, multicentre, randomised controlled trial stratified by centre. Setting Secondary-care National Health Service hospitals in the United Kingdom. Participants Patients aged ≥18 years, with a diagnosis of intermittent claudication according to the Edinburgh Claudication Questionnaire and ankle–brachial pressure index (or stress test), without contraindications to neuromuscular electrical stimulation were deemed eligible to partake. Interventions Participants were randomised 1 : 1 to either local standard care or local standard care and neuromuscular electrical stimulation. Due to the nature of the intervention, it was unfeasible to blind the research nurse or participant to the study allocation. Main outcome measures The primary outcome measure was absolute walking distance measured by treadmill testing at 3 months. Secondary outcomes included change in initial claudication distance, quality of life, compliance with interventions and haemodynamic assessments. Results Two hundred patients underwent randomisation, with 160 patients having analysable primary outcome data for the intention-to-treat analysis intervention (n = 80); control (n = 80). As the data were right-censored, a Tobit regression model was used to analyse the primary outcome, utilising the square root of the absolute walking distance to accommodate the skewed data. However, as this made the data difficult to interpret, a Tobit regression model using raw absolute walking distance data was used as well. Neuromuscular electrical stimulation improved the difference in absolute walking distance at 3 months but this was not statistically significant (square root of absolute walking distance: 0.835 units, 95% confidence interval −0.67 to 2.34 units; p = 0.28/absolute walking distance raw data: 27.18 m, 95% confidence interval −26.92 to 81.28 m; p = 0.323). Supervised exercise therapy participants showed a markedly improved absolute walking distance compared with patients receiving best medical therapy only at 3 months (square root of absolute walking distance: 3.295 units 95% confidence interval 1.77 to 4.82; p < 0.001/absolute walking distance raw data: 121.71 m, 95% confidence interval 67.32 to 176.10; p ≤ 0.001). Neuromuscular electrical stimulation significantly improved absolute walking distance at 3 months for mild claudicants (square root of absolute walking distance: 2.877 units, 95% confidence interval 0.51 to 5.25; p = 0.019/absolute walking distance raw data: 120.55 m, 95% confidence interval 16.03 to 225.06; p = 0.03) compared to the control arm. This was an unplanned (post hoc) analysis. There were no clear differences in mechanistic measurements between the two treatment groups over the follow-up period. Serious adverse events were evenly reported between the two groups; all being classified as either not related or unlikely to be related to the study device. Limitations Absolute walking distance was used as the primary outcome measure; there was a large range of baseline distances in both groups with right-skewed distribution. We did not stratify by baseline absolute walking distance for the primary outcome analysis. Additionally, only 160 patients had analysable primary outcome data due to missing treadmill data. Conclusions Supervised exercise therapy is an effective treatment for intermittent claudication. Neuromuscular electrical stimulation appears to be beneficial as an adjunct to supervised exercise therapy and on its own in mild claudicants. Future work Further studies are needed to confirm the effectiveness of neuromuscular electrical stimulation in combination with supervised exercise therapy, and in mild to moderate claudicants in a larger sample size. Study registration This trial is registered as ISRCTN18242823. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership (project number 15/180/68). This will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 2. See the NIHR Journals Library website for further project information. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) (with others, e.g. NIHR Imperial CRF, Imperial College ECMC, NIHR Imperial PSTRC, NIHR London MIC, etc.)

Neuromuscular electrical stimulation in the management of peripheral arterial disease and muscle recovery

Background and Aim Peripheral arterial disease (PAD) has a significant global health and economic burden. Intermittent claudication (IC) is an early manifestation of PAD, causing significant functional disability and poor quality of life (QoL). Management includes lifestyle and atherosclerotic risk factor modification. A supervised exercise programme (SEP) is the recommended first line strategy, showing significant improvements in pain free walking distance. This is underutilised and inaccessible to the majority in the UK. Neuromuscular electrical stimulation (NMES) is an evolving novel technology showing potential for use in vascular disease. The aim of this study was to assess the utility of NMES in the management of PAD, as an adjunct to SEPs and in muscle recovery following fatigue. Methods Background research included assessment of the outcomes associated with a local SEP, a national online audit of access to SEPs in UK and Ireland and a literature review on current evidence of the utility of NMES in IC. National ethics and regulatory approval was gained for NMES based research in PAD. Patients were recruited from the vascular outpatient clinic at Charing Cross Hospital. Two planned PAD studies were completed as follows: 1: NMES in the management of IC - a proof of concept study of the independent effect of 6 weeks intervention with NMES. 2: The adjuvant benefit of NMES to SEPs in the management of IC - a randomised controlled study to assess the adjunctive benefit of NMES to SEPs, comparing a control group receiving SEP only with another receiving SEP and footplate NMES, for 6 weeks. Outcomes included treadmill walking distances, disease specific and generic QoL scores, haemodynamic measures of the superficial femoral artery (Duplex ultrasound) and skin microcirculation (Laser Doppler Flowmetry). Ethics approval was gained for muscle recovery studies, recruiting healthy volunteers from Imperial College London and Kings College London. Two studies were undertaken: 1: Use of NMES in muscle recovery following high intensity exercise – a pilot randomised controlled study assessing the utility of NMES compared to passive rest in calf muscle recovery following high intensity exercise. 2: Use of NMES in the recovery of short and long term calf muscle fatigue – a randomised controlled trial assessing the utility of NMES compared to passive rest in muscle recovery following calf muscle fatigue over time. Outcomes assessed muscle performance by vertical jump test and numeric rating scale (NRS) for pain. Results NMES showed significant improvements in functional ability and both disease specific and generic QoL following 6 weeks intervention. There was a significant adjuvant benefit of NMES compared to SEP in improving the initial claudication distance in patients with IC following 6 weeks intervention as well as disease specific quality of life score. Blood flow and Time Averaged Mean Velocity increased significantly whilst the device was on. There were no significant improvements in calf muscle recovery following fatigue in healthy individuals. Conclusions Functional and QoL measures were improved by NMES intervention. These clinical trials provide a good foundation for further robust clarification of the utility of NMES in PAD. Exploration of the mechanisms by which this may occur, is also needed.Open Acces

Are Brain Natriuretic Peptide Levels Related to Flow through Autologous Aterio-Venous Fistulae for Chronic Haemodialysis?

Formation of arterio-venous-fistulae (AVF) may exacerbate cardiac failure in the ever increasing, elderly population on haemodialysis. Brain Natriuretic Peptide (BNP) may prove a useful marker of cardiac failure in this population. We aimed to determine effect of creation of an AVF and flow in AVF on BNP levels. Ten patients undergoing primary formation of an upper limb autologous AVF (pre-dialysis), were recruited. Serum BNP (pg/ml) and flow in AVF (cm3/s) were documented pre-operatively, and then 2, 6 and 12 weeks post-operatively. The relationship between flow and BNP levels was assessed. Ten patients (6 male), mean age of 66yrs were recruited. Five patients had a radio-cephalic and 5 had a brachio-cephalic AVF formed. There was no correlation between BNP levels and flow within the AVF (r=0.34, p=0.28) at any time point. There was a general trend towards increased flow in the AVF over time, with only the change between flow at 2-weeks and 3-months postoperatively reaching significance, p=0.043. There was a general trend for BNP to fall over time in the postoperative period, with no significant change between the postoperative sampling time points. BNP levels do not correlate with flow across an AVF

Neuromuscular electrical stimulation as an adjunct to standard care in improving walking distances in intermittent claudication patients: the NESIC RCT

Background Peripheral arterial disease is common and associated with increased cardiovascular morbidity and mortality. While patients with peripheral arterial disease are known to benefit from supervised exercise therapy, it is not always available. Neuromuscular electrical stimulation devices may offer a similar benefit. A randomised controlled trial was required to ascertain whether such devices can benefit patients who receive supervised exercise therapy and those who do not. Objective(s) The primary objective was to assess the mean difference in absolute walking distance at 3 months in intermittent claudication patients receiving either a neuromuscular electrical stimulation device and local standard care (intervention), or local standard care alone (control). Design A pragmatic, multicentre, randomised controlled trial stratified by centre. Setting Secondary-care National Health Service hospitals in the United Kingdom. Participants Patients aged ≥18 years, with a diagnosis of intermittent claudication according to the Edinburgh Claudication Questionnaire and ankle–brachial pressure index (or stress test), without contraindications to neuromuscular electrical stimulation were deemed eligible to partake. Interventions Participants were randomised 1 : 1 to either local standard care or local standard care and neuromuscular electrical stimulation. Due to the nature of the intervention, it was unfeasible to blind the research nurse or participant to the study allocation. Main outcome measures The primary outcome measure was absolute walking distance measured by treadmill testing at 3 months. Secondary outcomes included change in initial claudication distance, quality of life, compliance with interventions and haemodynamic assessments. Results Two hundred patients underwent randomisation, with 160 patients having analysable primary outcome data for the intention-to-treat analysis intervention (n = 80); control (n = 80). As the data were right-censored, a Tobit regression model was used to analyse the primary outcome, utilising the square root of the absolute walking distance to accommodate the skewed data. However, as this made the data difficult to interpret, a Tobit regression model using raw absolute walking distance data was used as well. Neuromuscular electrical stimulation improved the difference in absolute walking distance at 3 months but this was not statistically significant (square root of absolute walking distance: 0.835 units, 95% confidence interval −0.67 to 2.34 units; p = 0.28/absolute walking distance raw data: 27.18 m, 95% confidence interval −26.92 to 81.28 m; p = 0.323). Supervised exercise therapy participants showed a markedly improved absolute walking distance compared with patients receiving best medical therapy only at 3 months (square root of absolute walking distance: 3.295 units 95% confidence interval 1.77 to 4.82; p < 0.001/absolute walking distance raw data: 121.71 m, 95% confidence interval 67.32 to 176.10; p ≤ 0.001). Neuromuscular electrical stimulation significantly improved absolute walking distance at 3 months for mild claudicants (square root of absolute walking distance: 2.877 units, 95% confidence interval 0.51 to 5.25; p = 0.019/absolute walking distance raw data: 120.55 m, 95% confidence interval 16.03 to 225.06; p = 0.03) compared to the control arm. This was an unplanned (post hoc) analysis. There were no clear differences in mechanistic measurements between the two treatment groups over the follow-up period. Serious adverse events were evenly reported between the two groups; all being classified as either not related or unlikely to be related to the study device. Limitations Absolute walking distance was used as the primary outcome measure; there was a large range of baseline distances in both groups with right-skewed distribution. We did not stratify by baseline absolute walking distance for the primary outcome analysis. Additionally, only 160 patients had analysable primary outcome data due to missing treadmill data. Conclusions Supervised exercise therapy is an effective treatment for intermittent claudication. Neuromuscular electrical stimulation appears to be beneficial as an adjunct to supervised exercise therapy and on its own in mild claudicants. Future work Further studies are needed to confirm the effectiveness of neuromuscular electrical stimulation in combination with supervised exercise therapy, and in mild to moderate claudicants in a larger sample size. Study registration This trial is registered as ISRCTN18242823. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership (project number 15/180/68). This will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 2. See the NIHR Journals Library website for further project information. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) (with others, e.g. NIHR Imperial CRF, Imperial College ECMC, NIHR Imperial PSTRC, NIHR London MIC, etc.). Plain language summary Why did we conduct this research? Patients with intermittent claudication present with pain in the lower limbs on exercising, relieved by rest. This negatively impacts on exercise tolerance and quality of life. Initially, such patients should be offered best medical therapy, including exercise advice, and a supervised exercise therapy programme. Supervised exercise therapy involves leg and feet exercises supervised by health-care professionals and, despite evidence favouring supervised versus unsupervised exercise, are underutilised in the United Kingdom. Therefore, there remains a significant difference between recommended standard care (best medical therapy and supervised exercise therapy) and ‘real-world’ standard care (best medical therapy only). Neuromuscular electrical stimulation devices have emerged as safe, portable and readily accessible, with some evidence suggesting they can improve outcomes, including pain-free walking distance and quality of life. This study investigated whether a neuromuscular electrical stimulation device improved the walking distance of patients with intermittent claudication compared to local standard care available (which may include supervised exercise therapy). What did we do? Two hundred patients diagnosed with intermittent claudication at 11 hospitals in England took part. A computer program randomly assigned half the patients to local standard care only, while the other half were given a neuromuscular electrical stimulation device which delivers electrical stimulation to leg and feet muscles through foot-pads, plus local standard care. What did we find? There was no clear difference in maximal walking distances between those who received a device and those who didn’t. However, neuromuscular electrical stimulation improved walking distances in patients who attended a supervised exercise therapy programme (although not significant), and clearly improved walking distances in those patients with a good baseline upper walking limit. Supervised exercise therapy significantly improved walking distances. What could be done next? Future research studies should further evaluate the effectiveness of neuromuscular electrical stimulation in combination with supervised exercise therapy, and in patients who have a good baseline walking distance in a larger sample of patients with intermittent claudication. Scientific summary Background Peripheral arterial disease (PAD) is a common condition that is predominantly caused by atherosclerosis, resulting in a reduced blood flow to the affected limb. It presents a significant global health burden, affecting over 200 million people worldwide. These individuals are at higher risk of other cardiovascular events and PAD itself has its own associated sequelae – for example, ulcer development. Intermittent claudication (IC) is the commonest symptom of PAD, patients experiencing leg pain while walking which is relieved by rest. This has a significant impact on exercise tolerance and quality of life. According to National Institute for Health and Care Excellence guidelines, all patients suffering from IC should receive both first-line treatment of best medical therapy (BMT) (including exercise advice) and supervised exercise therapy (SET). SET is known to significantly improve absolute walking distance (AWD) in IC patients but despite these guidelines, recommended care for the first-line management of claudication is significantly below standard, largely due to lack of National Health Service capability. Without a demonstrable benefit of non-invasive strategies for the management of IC, there is an increased likelihood of invasive treatment options. Neuromuscular electrical stimulation (NMES) is an emerging technology and such devices are readily accessible and can be used in the patient’s own home. Although some evidence of the efficacy of NMES in the management of patients with IC exists, in improving both functional and quality-of-life measures, further high-quality research is required. The NESIC (A Multicenter Randomised Controlled Study: Does Neuromuscular Electrical Stimulation Improve the Absolute Walking Distance in Patients with Intermittent Claudication (NESIC) compared to best available treatment?) study provides an evidence base for the efficacy of the REVITIVE IXTM (Actegy Health Ltd, Bracknell, UK) device in the non-invasive management of claudicants and assesses the cost-effectiveness of the device compared to SET. Objectives (list of research questions) 1.Primary objective: To assess the clinical efficacy of a NMES device as an adjunct to the local standard care available at the study randomisation sites to improve AWD in patients with IC. 2.Secondary objectives: a.To understand the underlying mechanisms for change in clinical and subjective outcomes in the form of lower-limb gross (duplex ultrasound) and superficial haemodynamic assessment (laser doppler flowmetry) b.To determine compliance with NMES device and SET programme c.To compare quality of life between those receiving local standard care alone and those receiving both local standard care and NMES d.To assess the actual cost-effectiveness of the NMES device compared to SET. Methods Design A multicentre, pragmatic, randomised clinical trial to compare the mean difference in AWD in patients with IC who are given NMES in addition to local standard care and those receiving local standard care only. Setting Eleven secondary-care NHS hospitals across England; a combination of centres with and without established provision of SET. Participants Between March 2018 and 17 March 2020, 200 participants were randomised into the NESIC trial. Follow-up was completed on 31 March 2021. Written informed consent was obtained from all participants, who then underwent eligibility assessments. Participants, as defined by the inclusion and exclusion criteria, were randomised 1 : 1 to either local standard care alone (standard care), or NMES and local standard care (intervention). Inclusion criteria •positive Edinburgh Claudication Questionnaire •ankle–brachial pressure index 30 mmHg, 40 seconds post 1 minute treadmill at 10% gradient, 4 km/hour) •able to give informed consent to participate in the trial after reading the patient information documentation •age ≥18 years. Exclusion criteria •severe IC requiring invasive intervention as determined by the treating clinician •critical limb ischaemia as defined by the European Consensus Document •comorbid disease prohibiting walking on a treadmill or taking part in SET •able to walk for longer than 15 minutes on the study treadmill assessment •have attended SET classes in the previous 6 months •popliteal entrapment syndrome •commenced vascular-symptom-specific medication in previous 6 months – for example, naftidrofuryl oxalate, cilostazol •pregnancy •any implanted electronic, cardiac or defibrillator device •acute deep vein thrombosis •broken or bleeding skin, including leg ulceration •peripheral neuropathy •recent lower-limb injury or lower back pain •already using a NMES device. Randomisation Randomisation (1 : 1) was web-based and hosted by Oracle Health Sciences InForm™ (Oracle®; Health Sciences, Austin, TX, USA) electronic data capture on an Oracle platform. Randomisation used random block size and was stratified by centres. Interventions The NMES device (REVITIVE IX) can be used in the patient’s own home. It delivers a 30-minute pre-programmed session of electrical stimulation to the lower-limb muscles through foot pads while the patient is in a seated position. The user controls the intensity of the impulses, and therapeutic benefit is deemed to occur when impulses are sufficient to cause contraction of the calf muscles, increasing venous return to the heart. The IsoRocker feature allows the device to tilt back and forth as the muscles contract and relax. The device is to be used for at least one 30-minute session daily (up to a maximum of six sessions) for 3 months (treatment period). Diabetic patients are to use the device for a minimum of two 30-minute sessions daily for the duration of the treatment period to better reflect the evidence supporting the diabetic patient group and improvement of their symptoms. A SET programme is usually led by a physiotherapist or allied health-care provider supervising exercise, usually within the physiotherapy gymnasium with equipment including a treadmill, steps and walking cones. SET classes usually involve a circuit of lower-limb exercises, for a minimum of 30 minutes per week, and usually over a 3-month duration. Outcomes and follow-up The primary outcome was AWD at 3 months, measured by treadmill testing. Secondary outcomes included quality of life over 12 months as measured by generic health-related quality of life tools, European Quality of Life 5-Dimensions 5-Level (EQ-5D-5L®) (EuroQol Group, Rotterdam, The Netherlands), Short-Form Health Survey-36 (SF-36®) (RAND Health Care, Santa Monica, CA, USA) and the intermittent claudication questionnaire; compliance with NMES and SET as measured against self-report participant diaries and device data loggers; change in initial claudication distance measured by treadmill testing; and haemodynamic assessments measured by duplex ultrasound and laser doppler flowmetry. Participants in both groups were followed up for 12 months post randomisation. In-person visits were performed at screening/baseline (randomisation), 3 months, 6 months and 12 months. The treadmill assessment (Gardner-Skinner protocol) and laser doppler flowmetry of the foot were completed at each visit and the duplex ultrasound was performed by a vascular scientist at baseline and 3 months only. Self-report health resource-use participant diaries were completed throughout the 12-month duration of the study. Additionally, the self-report exercise diaries were completed by all participants for 3 months or for the duration of the SET programme, and the device compliance diaries were completed by participants randomised to NMES for the duration of the treatment period. A device experience questionnaire was completed at 3 months for participants in the NMES arm of the trial. The quality-of-life questionnaires were administered at baseline and each follow-up either in person, via the telephone or via post. Participant follow-up is summarised in Appendix 1. Due to the COVID-19 crisis, a substantial amendment was submitted to Ethics in April 2020 to allow all follow-up visits to take place remotely (i.e. over the telephone completely or in combination with postal questionnaires) in the event that the participant was unable to attend in clinic or the site was unable to accommodate the on-site visit. Missed (physical) assessments as a result of a remote visit were rescheduled at a later date as a separate on-site visit, where possible. If an on-site visit was rescheduled at a later date, all quality-of-life questionnaires that were completed remotely were repeated at the on-site visit. Results (research findings) Two hundred participants underwent randomisation and 160 were included in the intention-to-treat primary analysis [intervention (n = 80); control (n = 80)]. NMES improved AWD in patients with IC following the 3-month treatment period but this was not statistically significant [square root of AWD: 0.835 units, 95% confidence interval (CI) −0.67 to 2.34; p = 0.276/AWD raw data: 27.18 m, 95% CI −26.92 to 81.28; p = 0.323]. Participants who had access to a SET programme showed a clear improvement in AWD compared with patients who received BMT only at 3 months (square root of AWD: 3.295 units, 95% CI 1.77 to 4.82; p < 0.001/AWD raw data: 121.1 m, 95% CI 67.32 to 176.10; p < 0.001). Improvements in the AWD at 3 months were seen when NMES was used in combination with SET, but this was not significant (square root of AWD: 1.724 units, 95% CI −0.56 to 4.01; p = 0.137/AWD raw data: 64.26 units, 95% CI −20.03 to 148.54; p = 0.13). NMES significantly improved AWD at 3 months for patients who could walk for more than 340 m at baseline (square root of AWD: 2.877 units, 95% CI 0.51 to 5.25; p = 0.019/AWD raw data: 120.55 m, 95% CI 16.03 to 225.06; p = 0.03) compared to the control arm. Mechanistic findings of the laser doppler flowmetry found no clear differences in blood flux between the two treatment groups over the 12-month follow-up period, nor any significant differences in volume flow or time average mean velocity (duplex ultrasound) groups at 3 months. Serious adverse events (n = 29) were reported in 24 participants, with all events being classified as either not related or unlikely to be related to the study device. The number of SAEs in the treatment arm was 13 and 16 in the control arm. Most of the events required hospitalisation; there were four deaths. Conclusions The results of the NESIC trial indicate that SET is the most effective treatment option for patients with IC. Although not significant, NMES improves walking distances when used in combination with a SET programme, and significantly improves AWD in mild claudicants. Implications for health care Findings from this trial suggest that all IC patients should have access to a SET programme and changes to such programmes may need to be made to encourage and/or retain participants. NMES may be an effective adjunct to SET and in patients with a good baseline walking distance. Recommendations for research (numbered in priority order) 1.Randomised controlled trial of NMES as an adjunct to SET in IC patients stratified by baseline AWD, as the NESIC study showed promise of non-invasive effectiveness in mild and/or moderate claudicants at improving walking distances, but larger numbers are required to validate this finding. 2.Research to examine the poor patient motivation and adherence to SET, as SET is clearly an effective treatment option for claudicants as seen in this study and many other studies but uptake/compliance remains an issue. 3.Research to evaluate the long-term effectiveness of SET programmes on maximal walking distance (MWD) and secondary outcomes such as quality of life and long-term engagement in physical activity. The NESIC study showed the effectiveness of SET at 12 months at improving AWD but longer-term follow-up is required to evaluate whether this is sustained years later. Previous studies have shown mixed results on the impact of SET on other outcomes, such as quality of life, and therefore further research is required. Study registration This trial is registered as ISRCTN18242823. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership (project number 15/180/68). This will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 2. See the NIHR Journals Library website for further project information. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) (with others, e.g. NIHR Imperial CRF, Imperial College ECMC, NIHR Imperial PSTRC, NIHR London MIC, etc.)