A Multicentre Randomised Controlled Study

Introduction

There is a significant global health burden of peripheral arterial disease (PAD), commonly presenting as Intermittent Claudication (IC) or lower limb pain on exertion settling with rest. IC limits exercise tolerance andimpairs quality of life. Management includes cardiovascular risk factor control and supervised exercise therapy (SET),however SET is significantly underutilised and not available in all NHS Trusts, where only exercise advice is provided. Neuromuscular Electrical Stimulation (NMES) may improve the distance walked before symptomatic limitation and improvequality of life.

Aim

The aim is of the NESIC study is to assess the clinical efficacy and mechanism of NMES compared to best local therapy in the management of IC.

Design
UK-wide, pragmatic, multicentre, open randomised controlled trial.

Setting
Outpatients with IC from the following centres:

1. Imperial College Healthcare NHS Trust
2. University Hospitals Bristol NHS Trust
3. Hull and East Yorkshire Hospitals NHS Foundation Trust
4. University Hospital Southampton NHS Foundation Trust
5. Cambridge University Hospitals NHS Foundation Trust
6. The Newcastle Upon Tyne Hospitals NHS Foundation Trust
7. Taunton and Somerset NHS Foundation Trust
8. Nottingham University Hospitals NHS Trust

Duration
39 months (6 month set up, 15 month recruitment, 12 month follow up and 6 month close-out/analysis).

Population
Inclusions:

• Capacity to provide informed consent
• Aged 18 or above
• Positive Edinburgh Claudication Questionnaire 

• ABPI <0.9 OR positive stress test (fall in ankle pressure >30mmHg, 40 secs post 1 min treadmill at 10% gradient, 4 km/h) 


Exclusion Criteria:

• Severe IC requiring invasive intervention as determined by the treating clinician
• Critical Limb Ischaemia as defined by the European Consensus Document
• Co-morbid disease prohibiting walking on a treadmill
• Popliteal Entrapment Syndrome
• Commenced vascular symptom specific medication in previous 6 months e.g. Praxilene, cilostazol
• Pregnancy
• Any implanted electronic, cardiac or defibrillator device
• Existing Deep Vein Thrombosis
• Broken or bleeding skin including leg ulceration

Outcomes

Primary:

• Absolute walking distance (AWD) - treadmill test at 3 months

Secondary:

• Initial Claudication Distance (ICD)
• QoL – Intermittent Claudication Questionnaire (ICQ), EuroQoL 5D (EQ5D), Short Form 36 (SF-36)
• Haemodynamic assessment - Duplex ultrasonography, Laser Doppler Flowmeter
• Health economic assessment
• Compliance with interventions
• Device experience questionnaire
• Ankle Brachial Pressure Index (ABPI)

Interventions

This is a two-arm randomised controlled trial, where the control is locally available therapy, which may include either exercise advice (EA) or supervised exercise therapy (SET - a 30-minute supervised session per week for 3 months) depending on the centre. The intervention, in addition to the locally available therapy, is NMES (a commercially available class IIa CE marked medical device).

Sample size

A total of 192 participants, assuming a 10% drop out rate.

The following assumptions were made to calculate the sample size:

1. Mean AWD in the control group is 200m at 3 months
2. Common equal standard deviation is 120m
3. Expected effect size is 60m increase in the mean AWD
4. Two sided alpha of 0.05
5. 90% power
6. 10% drop-out rate

Sample size computed for a two-sample means test using the software Stata 13.

Without considering drop out, it is estimated that a sample size of 172 participants (86 per group) will have 90% power to detect a difference of 60m in the mean absolute walking distance at 3 months between the intervention and the control group. An internal pilot will be performed consisting of the first 25% of recruited patients.

Planned analyses

The primary analysis is the difference between the groups mean AWD using a two-sample t-test. Regression, adjusted for walking distance baseline values, stratification by centre and will investigate the relationship between AWD and one or more independent variables like BMI and intervention compliance. All analyses will be on an intention-to-treat basis and per protocol. 

Follow up

3 months (primary endpoint), 6 months and 12 months for repeated measures.

Summary

This study proposes to assess a Neuromuscular Electrical Stimulation (NMES) device to treat symptoms arising from reduced blood flow to the leg muscles caused by Peripheral Arterial Disease (PAD).

Intermittent Claudication (IC), or pain in the lower legs on exercise that settles with rest, affects approximately 5% of the UK population between 55 and 74 years. Patients may require bypass surgery or angioplasty (using a balloon to widen a narrowed artery) to restore blood flow, which is expensive and carries significant risks. Non-invasive management includes medication and exercise.

Nationally adopted guidelines (NICE) recommend all IC patients should undertake Supervised Exercise Therapy (SET), undergoing a circuit of exercises under the supervision of a healthcare professional. SET can improve the walking distances before the onset of symptoms and quality of life. However, due to lack of funding and resources, SET is only available to a minority of patients and therefore many patients are given exercise advice (EA) only.

NMES devices are an emerging technology for treating circulation problems in the legs. These readily available devices lack robust evidence of their benefit. A pilot study of 20 patients with IC using the Revitive IX device, over a 6-week period, significantly improved the distance walked before limitation due to pain and quality of life. This portable foot plate device can be used at the patient’s convenience and works by using electrical muscle stimulation contract and relax muscles, increasing the blood flow in the legs and feet.

The proposed study assesses the added benefit of NMES to locally available therapy (SET or EA only). Eligible patients will be randomly allocated to a control group (local therapy) or an intervention group (local therapy + NMES). Measures include a treadmill test, questionnaires and blood flow assessment to the legs at the beginning of the study and subsequently at 3, 6 and 12 months. Analysis of the differences in these measures between the groups may indicate a beneficial and cost-effective role for NMES in the first line management of IC patients.

Randomisation (performed through INFORM)

Randomise, consenting eligible patients through INFORM.

This project is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. 

The views expressed in this publication are those of the author(s) and not necessarily those of the MRC, NHS, NIHR or the Department of Health.

*The EME Programme is funded by the MRC and NIHR, with contributions from the CSO in Scotland and NISCHR in Wales and the HSC R&D Division, Public Health Agency in Northern Ireland.