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1 King s Research Portal Document Version Peer reviewed version Link to publication record in King's Research Portal Citation for published version (APA): Al-Sherif, M., He, B., Schwarz, E. I., Cheng, M., Ratneswaran, C., Pengo, M. F., & Steier, J. S. Electrical Stimulation in Obstructive Sleep Apnoea: the TESLA-home trial Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rights Copyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the Research Portal Take down policy If you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. Download date: 16. Dec. 2018

2 Electrical Stimulation in Obstructive Sleep Apnoea: the TESLA-home trial Miral Al-Sherif 1,2,3, Baiting He 1,4, Esther Schwarz 1,5, Michael Cheng 1,6, Culadeeban Ratneswaran 1,2, Martino Pengo 1,7 and Joerg Steier 1,2 on behalf of the TESLA-investigators 1 Guy s & St Thomas NHS Foundation Trust, London, UK; 2 King s College London; 3 University of Mina, Egypt; 4 Guangzhou Medical College, China; 5 University of Zurich, CH; 6 University of Sydney, Australia; 7 University of Milan, Italy Obstructive sleep apnoea (OSA) is a highly prevalent sleep disorder, characterised by periods of apnoeas or hypopnoeas due to obstruction of the upper airway while asleep. Continuous positive airway pressure (CPAP) is the standard treatment, inflating the airway and avoiding upper airway obstruction. However, many patients experience difficulties with long-term adherence to CPAP and may not tolerate sleeping with a mask and, currently, there are few effective alternative treatment options. Electrical stimulation (ES) has long been used to stimulate skeletal muscles. By targeting specific dilator muscles of the upper airway electrical current can treat OSA by providing neuromuscular tone and maintaining upper airway lumen patency. Electrical stimulation can be applied invasively and, more recently, non-invasively. Hypoglossal nerve stimulation (HNS), one of the invasive techniques, leads to a significant reduction in the apnoea-hypopnoea-index and the oxygen desaturation index (ODI), but due to the nature of the procedure it has several associated adverse effects and risks, and it is relatively costly. Transcutaneous electrical stimulation in OSA (TESLA) uses a non-invasive stimulation technique that is safe and convenient, but there are sparse data on its usage. Electrical stimulation may not be as effective as CPAP therapy, but it could be a suitable 2 nd line treatment for patients who fail standard CPAP usage. This article summaries the state-of-the-art in electrical stimulation and introduces the first trial of domiciliary transcutaneous electrical stimulation (TESLA home), investigating efficacy and compliance in patients with OSA for a three-month period. Obstructive sleep apnoea (OSA) is the most common form of sleep-disordered breathing (1, 2), it is caused by intermittent and repeated upper airway (UA) collapse in a sleep-stagedependent manner which results in irregular breathing at night, loud snoring, and arousals from sleep, typically associated with excessive sleepiness while awake. The prevalence of OSA seems to increase with obesity rates, it affects up to 10% of the year-old men and 3% of the year-old women (1-3). OSA is associated with significant co-morbidities including hypertension, ischaemic heart disease, stroke, congestive heart failure, obesity and metabolic syndrome, and diabetes. It has been recognized as a significant cardiovascular risk (3). The Gold standard to assess OSA is polysomnography ( sleep study ), although symptom questionnaires and scores to assess OSA risk are used both in the clinical setting and in population-based cohorts (4). Treatment is focused on controlling the upper airway patency while asleep to improve any associated symptoms, as well as the control of potential long-term outcomes, including cardiovascular risks (3).

3 According to current guidelines, treatment with continuous positive airway pressure (CPAP) is indicated in patients with moderatesevere OSA (5), it is typically provided via a bedside machine connected with a tube to a tight-fitting face mask, stenting the upper airway open using pressurised air (6). CPAP is an effective therapy to improve symptoms in OSA and quality of life. Other treatment options include weight loss, postural advice, reduction of alcohol and sedative medication, as well as mandibular advancement devices (MAD) that might be considered in patients with milder OSA (7, 8). In patients with anatomical abnormalities, such as enlarged tonsils or adenoids, an ENT review and surgical options might be available (7). Although CPAP provides currently the best available treatment to control upper airway patency, adherence to this treatment is limited and dependent on symptoms and disease severity; approximately a quarter of patients develop problems with CPAP adherence within months (9), while half of the patients on CPAP have limited adherence at one-year follow up (10). It is therefore essential to develop 2 nd line therapies when patients fail on CPAP therapy to achieve symptom control and avoid adverse long-term outcomes (3). Importantly, patients support the development of novel therapeutic methodologies, such as electrical stimulation (11). Electrical Stimulation Airflow limitation with sleep onset results from the loss of neuromuscular tone of upper airway dilator muscles. In healthy subjects, neuromuscular tone is sufficiently maintained during sleep to sustain a patent upper airway. In patients with OSA, the loss of the neuromuscular tone associated with sleep results in an increased collapsibility of the UA, causing snoring and high resistance, and, when airflow ceases, upper airway obstruction resulting in OSA. Targeted electrical stimulation of the upper airway dilator muscles, specifically the genioglossus muscle, provides an ongoing neuromuscular tone that maintains upper airway patency when asleep (12, 13); this is possible using an invasive approach, hypoglossal nerve stimulation (HNS) (13), as well as by non-invasive transcutaneous stimulation (TESLA) (12, 14). Hypoglossal nerve stimulation (HNS) HNS is an invasive stimulation method using an implanted stimulator device, targeting the genioglossus muscle via the hypoglossal nerve unilaterally. It leads to a significant reduction in the apnoea-hypopnoea-index (AHI) and the oxygen desaturation index (ODI) in patients with OSA (15). However, HNS remains an invasive and costly procedure with associated risks. Following the publication of the STAR-trial (13) this method has been approved in the US, and the National Institute for Health and Care Excellence (NICE) have published a public consultation on this method in 2017 (16). Transcutaneous electrical stimulation in OSA (TESLA) TESLA is currently an experimental method to treat patients with OSA who have failed on CPAP therapy. It uses a non-invasive stimulation method with transcutaneous patches applied to the skin in the submental area; it is safe and convenient (14), and a well-tolerated method by patients which is titrated to levels of comfort

4 while awake (11). TESLA stimulates the upper Our patient-and-public involvement published airway the data of 162 patients with OSA established on genioglossus, to maintain a patent upper airway CPAP who were asked about their preference for while asleep (12) (Figure 1). The specifications different treatments, including existing (CPAP, of electrical current for both HNS and TESLA mandibular advancement devices) and emerging are the focus of ongoing research trials (13, 14). treatments (HNS, TESLA). It confirmed that dilator muscles, particularly more than 9-out-of-10 patients were interested in trying emerging technologies (11). However, despite the above evidence additional data on longer term efficacy, compliance, safety and feasibility of TESLA in the domiciliary setting are required to advance this methodology. TESLA-home Trial (NCT ) The TESLA-home trial is the 1st randomised controlled trial of domiciliary transcutaneous electrical stimulation in OSA, testing the Figure 1: contraction of the genioglossus muscle resulting in an increase in pharyngeal space. feasibility of transcutaneous electrical stimulation compared to ongoing usual care (Figure 2). A physiological feasibility study using TESLA was published by our group in 2011 (12). Patients with OSA were monitored during nocturnal apnoeas and hypopnoeas and TESLA was applied for 10-minute periods (12). It reduced the AHI and the ODI by about 2/3, improved oxygenation and reduced snoring. Moreover, a randomised, sham-controlled double-blinded crossover trial was performed identifying groups of responders and non- Figure 2: Frontal view of the placement of the responders to this method (14). Responders to stimulation patches on the neck. TESLA are characterised by less severe disease Patients with OSA (AHI <35/h) will be (AHI <35/h), lower body-mass-index (BMI <32) randomised into a prospective, interventional, and a slimmer neck circumference; although the controlled, two parallel arms trial for a three- numbers were small, all women included in this months period, using either TESLA or remaining trial were responders. on their previous treatment (CPAP). This NIHR portfolio study started in July 2018 at Guy s &

5 St Thomas NHS Foundation Trust, London, with additional recruitment sites from King s College Hospital NHS Foundation Trust and the Royal Brompton & Harefield NHS Foundation Trust; the trial is supported by a grant of the British Lung Foundation (BLF). The primary outcome will be to assess the efficacy of transcutaneous electrical stimulation in patients with obstructive sleep apnoea in the community compared to usual care (CPAP), and follow up for 3 months. Secondary outcomes are to assess feasibility and compliance with the method, assess symptom control and improvement in quality of life. The sample size calculation based on the data from the previous crossover trial indicated that a total number of 68 participants are required, 34 randomised into each arm (14). The main in- and exclusion criteria are patients with obstructive sleep apnoea (AHI <35/h) who have failed CPAP (adherence < 4hours/night). Patients with severe obesity are excluded as an increased load and a large neck circumference have been shown to adversely impact on the effective delivery of TESLA. Participants are assessed at baseline, 6-weeks, and three months, including polysomnography assessments at the beginning and the end of the trial. Weekly follow up phone calls record adherence and symptoms scores. Additional measurements are directed at muscle contraction and the visualisation of diameters of the upper airway. Conclusion In summary, electrical stimulation is an emerging treatment for patients with OSA when 1 st line therapy has failed. NICE has published a public consultation on HNS which could soon become available in selected centres in the UK under audit conditions. TESLA-home is the 1 st non-commercial trial using transcutaneous electrical stimulation in the domiciliary setting which has recently started recruitment. Due to the safe nature of TESLA and its low costs, the results of this trial may help to support the case to establish this novel method in routine clinical practice. Professor Joerg Steier, FRCP, MD, PhD Guy s & St Thomas NHS Foundation Trust King s College London Westminster Bridge Road London SE1 7EH mailto:joerg.steier@gstt.nhs.uk Acknowledgements: The TESLA-investigator group includes Professor John Moxham, Professor Michael I Polkey, Professor Yuanming Luo, Professor Adrian Williams, Dr Gerard Rafferty, Dr Deeban Ratneswaran, Dr Esther I Schwarz, Dr Michael Cheng, Dr Miral Al-Sherif, Dr Baiting He, Dr Brian Kent, Ms Gill Arbane, Ms Jennifer Owusu-Afriyie, Mr Paul Eze-John, Mr Athanasius Ishak, Dr Gerrard Rafferty, Dr Kai Lee, Dr Nimish Shah, Professor Yuanming Luo, Professor Nicholas Hart, Dr Martino Pengo and Professor Joerg Steier. We gratefully acknowledge the support of the clinical team at the Lane Fox Unit and the Sleep Disorders Centre at Guy s and St Thomas NHS Foundation Trust, London. The TESLA-home trial is supported by a grant of the British Lung Foundation (BLF).

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