Randomised Controlled Trial of Domiciliary Transcutaneous Electrical Stimulation in Obstructive Sleep Apnoea
Phase: NA
Conditions: Obstructive Sleep Apnea
Sponsor: Guy's and St Thomas' NHS Foundation Trust

 
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Full title of trial 
 
 
 
Randomised controlled trial of domiciliary 
transcutaneous electrical stimulation in 
obstructive sleep apnoea: TESLA-home 
 
Short title 
 
TESLA home 
Version and date of Clinical Investigation 
Plan (CIP) 
Version 1.3, 22/11/2020; IRAS 217448 
 
Revision History 
N/A 
Sponsor: 
 
Sponsor CIP number 
Guy’s & St Thomas’ NHS Foundation Trust V1.8 
Funder (s) : 
British Lung Foundation 
Channel Scheme / Egyptian Educational Office 
Phase of trial 
Phase III 
Sites(s) 
Single site  
 
 
Chief investigator: 
 
Name: Joerg Steier 
Address: Lane Fox Unit / Sleep 
Disorders Centre, Guy’s and St 
Thomas’ NHS Foundation Trust, 
Westminster Bridge Road, London, 
SE1 7EH 
Telephone: 0207 188 3434 
Fax: 0207 188 6116 
Email: joerg.steier@gstt.nhs.uk 
 
Sponsor Representative: 
 
Jennifer Boston 
Guy's & St Thomas' Foundation NHS Trust 
R&D Department 
16th Floor, Tower Wing 
Great Maze pond 
London SE1 9RT 
Ext Tel: 02071887188 ext 54426 
Int tel:  54426 
Fax: 02071883472 
R&D@gstt.nhs.uk  
 
 
 

 
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Signatures 
 
The Chief Investigator and R&D (Sponsor office) have discussed this Clinical Investigation Plan (CIP). 
The investigators agree to perform the investigations and to abide by this CIP.  
 
The investigator agrees to conduct the trial in compliance with the approved CIP, EU GCP and UK 
Regulations for Devices, the UK Data Protection Act (1998), the Trust Information Governance Policy 
(or other local equivalent), the Research Governance Framework (2005’ 2nd Edition; as amended), the 
Sponsor’s SOPs, and other regulatory requirements as amended. 
 
Chief investigator 
Joerg Steier 
 
 
 
Signature 
Date 
Sponsor Representative 
R&D to Add  
 
 
GSTFT 
Signature 
Date 
 
 
 
 
 
 
This CIP template is intended for use with UK sites only. 
 
 
 
 
 
 
 

 
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Contents 
Title Page ................................................................................................................................................. 1 
Signatures ............................................................................................................................................... 2 
Table of Content ..................................................................................................................................... 3 
Abbreviations .......................................................................................................................................... 5 
1 
Trial Personnel ................................................................................................................................ 6 
2 
Synopsis of Clinical Investigation ................................................................................................................... 7 
3 
Identification and Description of the Investigational Device ................................................................ 9 
4 
Justification for the design of the clinical investigation ...................................................................... 15 
5 
Risks and benefits of the Investigational device and clinical Investigation ................................ 16 
6 
Objectives and hypotheses of the clinical investigation ...................................................................... 13 
6.1 
Objectives, primary and secondary. ................................................................................................................................. 15 
6.2 
Hypotheses, primary and secondary, to be accepted or rejected by statistical data from the clinical 
investigation. .............................................................................................................................................................................................. 15 
6.3 
Claims and intended performance of the investigational device that are to be verified…. ..................... 16 
6.4 
Risks and anticipated adverse device effects that are to be assessed. .............................................................. 16 
7 
Design of the clinical investigation ............................................................................................................... 18 
7.1 
General (to include the following) ................................................................................................................................. 18 
7.2 
Investigational device and comparators (to include the following) ........................................................... 18 
7.3 
Subject Selection ................................................................................................................................................................... 21 
7.3.1 
Inclusion criteria .......................................................................................................................................................... 21 
7.3.2 
Exclusion criteria .......................................................................................................................................................... 21 
7.3.3 
Criteria and procedures for subject withdrawal or discontinuation. .................................................... 22 
7.3.4 
Subject Enrolment (to include the following) .................................................................................................. 22 
7.4 
Procedures ................................................................................................................................................................................ 22 
7.4.1 
Informed Consent ........................................................................................................................................................ 22 
7.4.2 
Screening and Eligibility Assessment .................................................................................................................. 23 
7.4.3 
Baseline Assessments ................................................................................................................................................. 24 
7.4.4 
Randomisation .............................................................................................................................................................. 24 
7.4.5 
Subsequent assessments .......................................................................................................................................... 24 
7.5 
Definition of End of Trial .................................................................................................................................................... 25 
7.6 
Discontinuation/ Withdrawal of Participants from Study Treatment ......................................................... 26 
7.7 
Source Data .............................................................................................................................................................................. 26 
8 
Statistical Considerations ................................................................................................................................. 26 
9 
Data Management ................................................................................................................................................. 27 
9.1 
Data to be collected ................................................................................................................................................................. 27 
9.2 
Data handling and record keeping ................................................................................................................................... 27 
10 
Deviations from clinical investigation plan ................................................................................................ 27 
11 
Device accountability .......................................................................................................................................... 28 
12 
Statements of compliance ................................................................................................................................ 30 
12.1 
Declaration of Helsinki, International Standards and national regulations ................................................. 30 
12.2 
Approvals ..................................................................................................................................................................................... 30 

 
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12.3 
Funding and Insurance .......................................................................................................................................................... 30 
13 
Monitoring ................................................................................................................................................................ 30 
13.1 
Confidentiality ........................................................................................................................................................................... 31 
13.2 
Record keeping and archiving ............................................................................................................................................ 31 
14 
Adverse events, adverse device effects and device deficiencies .................................................... 32 
14.1 
Definitions ................................................................................................................................................................................... 33 
14.2 
Safety Reporting requirements and timelines ....................................................................................................... 33 
14.3 
Assessments of adverse events ................................................................................................................................... 35 
14.3.1 
Severity ....................................................................................................................................................................... 35 
14.3.2 
Seriousness .............................................................................................................................................................. 35 
14.3.3 
Causality ..................................................................................................................................................................... 35 
14.3.4 
Expectedness .......................................................................................................................................................... 35 
14.4 
Procedures for recording and reporting Adverse Events and Device Deficiencies ........................ 36 
14.4.1 
Investigator responsibilities .............................................................................................................................. 36 
14.5 
Reporting of all Adverse Events and Device Deficiencies: Investigator and Sponsor 
responsibilities ......................................................................................................................................................................................... 36 
14.5.1 
Annual Safety Reports ........................................................................................................................................ 37 
14.5.2 
Progress reports ..................................................................................................................................................... 37 
14.6 
Foreseeable adverse events and anticipated adverse device effects .................................................... 37 
15 
Vulnerable population ......................................................................................................................................... 37 
16 
Suspension or premature termination of the clinical investigation ................................................ 37 
17 
Publication policy ................................................................................................................................................. 37 
18 
Bibliography ............................................................................................................................................................ 38 
19 
Appendix A: Schedule of Investigations ..................................................................................................... 39 
 
 
 

 
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LIST OF ABBREVIATIONS  
 
Commonly used abbreviations  
 
AE 
Adverse event 
ADE  
Adverse Device Effect  
AHI 
Apnoea-Hypopnoea-Index 
CI 
Chief Investigator 
CPAP 
 
Continuous Positive Airway Pressure 
CRF 
 
Case Report Form 
CRO  
Contract Research Organisation 
CT 
 
Clinical Trials 
CTA 
 
Clinical Trials Authorisation 
ESS 
Epworth Sleepiness Scale 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HRA 
Health Research Authority 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Independent Review Board 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
OSA 
Obstructive Sleep Apnoea 
ODI 
Oxygen Desaturation Index 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event  
SADE 
Serious Adverse Device Effect  
SIL 
Subject Information Leaflet (see PIL) 
SOP 
Standard Operating Procedure 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect  
  

 
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1 
Trial Personnel 
 
 
Chief Investigator (CI) 
[Consultant] 
Joerg Steier 
e-mail:  Joerg.steier@gstt.nhs.uk 
tel:  02071883434 
 
Principal Investigator (PI) 
[Consultant] 
Nicholas Hart 
e-mail:Nicholas.hart@gstt.nhs.uk 
tel:  02071883434 
 
Co-Investigator  
[Consultant] 
Michael I Polkey (Brompton) 
e-mail:  m.polkey@rbht.nhs.uk 
tel:  0207 352 8121 
 
Co-Investigator  
[Consultant] 
 
 
Co-Investigator 
[Consultant] 
 
 
Kai Lee (King’s) 
e-mail:  kai.lee@nbhs.uk 
tel: 02032999000 x2080 
 
John Moxham (KCL) 
e-mail:  john.moxham@kcl.ac.uk 
tel: 02032999000 x3165 
 
Sponsor’s representative 
Jennifer Boston 
e-mail: 
Jennifer.boston@gstt.nhs.uk  
tel:  02071887188 ext 54426 
fax: 02071883472 
 
Statistician 
Abdel Douiri (KCL) 
e-mail: abdel.douiri@kcl.ac.uk 
tel: 02078488224 
 
 
 
 
 
 
 
 
 
 
 

 
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2 
Synopsis of Clinical Investigation 
 
Title: 
Randomised controlled trial of domiciliary transcutaneous 
electrical stimulation in obstructive sleep apnoea: TESLA-
home V1.1 14/05/2018 
 
 
Short title: 
 
TESLA home 
 
IRAS ID: 
 
217448 
REC Reference: 
 
18/LO/0638 
Device: 
PREMIER PLUS easy rechargeable TENS (TENS+, Stockport, 
UK) 
Phase of trial: 
III 
 
Objectives: 
Primary: To assess the efficacy of transcutaneous electrical 
stimulation of the pharyngeal dilator muscles in patients with 
obstructive sleep apnoea in the community compared to usual 
care, and follow up for 3 months. 
Secondary: To assess compliance of non-invasive electrical 
stimulation of the upper airway dilator muscles in obstructive sleep 
apnoea patients over time and evaluate the control of symptoms 
and improvement in quality of life. 
Type of trial: 
Prospective, interventional, randomized, controlled, two parallel 
arm trial  
Trial design and 
methods: 
Following randomisation into intervention group and usual care at 
baseline patients will be assessed followed up at 3-months. 
Outcome parameters will compare improvement in the apnoea-
hyopnoea index (AHI), sleepiness and quality of life at 3-months 
against baseline between the two groups. 
 
Trial duration per 
participant: 
Three months 
 
 
Estimated total trial 
duration: 
 
Three years 
Planned trial sites: 
Single site (Guy’s & St Thomas’ NHS Foundation Trust) with 
Royal Brompton & Harefield NHS Foundation Trust and King’s 
College Hospital NHS Foundation Trust as PIC sites. 
 
Total number of 
participants planned: 
 
n=68 
Main inclusion/exclusion 
criteria: 
Patients with obstructive sleep apnoea who have low CPAP 
adherence will be included. Exclusion criteria are very severe 
OSA, morbid obesity and enlarged neck circumference. 
 
Statistical methodology 
and analysis: 
Statistical analysis will compare the respective outcome 
parameters (primary outcome: AHI; secondary outcome: ESS, 
ODI, compliance in hours usage/night, comfort) between active 
stimulation and the control group. Full statistical description will be 

 
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provided and for each of the variables analysed, univariate 
descriptive statistics will present an overview of the data. 
Continuous variables will be presented as median and 
interquartile range (IQR), unless otherwise stated. For categorical 
variables, frequency counts and percentages will be presented as 
summary statistics for the subgroups of interest. To compare 
study groups, we will use the Wilcoxon and paired t-test for 
continuous paired variables, and the χ2 test for categorical 
variables. The primary outcome parameters (AHI) will be analysed 
using the Mann-Whitney test between treatment groups (active 
stimulation) and control group (CPAP). Similar analyses will be 
conducted for secondary outcomes. 
 

 
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3 Identification and Description of the Investigational Device 
 
Background 
Obstructive sleep apnoea is highly prevalent (1), with the obesity epidemic relentlessly increasing the 
problem (2, 3). The best treatment for uncomplicated and moderate-severe OSA remains CPAP therapy 
(4, 5). However, long-term adherence to treatment with CPAP is poor (6) and there are few alternatives. 
Electrical stimulation of the dilator muscles of the upper airway has been shown to reduce nocturnal 
apnoeas significantly using an invasive approach, hypoglossal nerve stimulation (7), as well as by non-
invasive transcutaneous stimulation (8, 9). Although non-invasive transcutaneous stimulation may not 
be as effective as CPAP therapy in many OSA patients it could be an important option to treat some of 
the large number of patients who fail CPAP (10) and might also be of use in those whose OSA is not 
judged sufficiently severe to warrant CPAP.  
 
We propose a study to use a transcutaneous electrical stimulation device in selected patients with OSA 
who do not tolerate CPAP therapy to treat them over a period of 3-months in the community and 
compare the results against usual care, ongoing CPAP therapy. The results of this study will help us to 
prepare a definitive multi-centre randomized controlled trial. 
 
The primary aim of this study is to assess efficacy and generate an accurate sample size estimation, test 
the subjective willingness of patients to use and objectively determined compliance with the treatment 
over a long period, as well as to specify the drop-out rate. The improvement in sleep apnoea severity 
will be primary outcome measures. The feasibility of the method, including compliance, comfort, 
adverse events, and sleepiness will be the secondary outcome measure. 
 
Electrical Stimulation 
The group of patients receiving continuous transcutaneous electrical stimulation will be trained on the 
device and settings will be recorded. The device will be hooked on a hydrogel patch which is placed in 
the submental area leaving the bony structure of the mandible free. Ideally, men should shave daily to 
guarantee a good contact of the hydrogel and low skin resistance to promote good transduction of the 
current and avoid skin discomfort. In order to allow for maximal adhesion and contact the hydrogel 
should be placed on dry skin. The device needs to be started by pressing the “on” button. Once the 
device is turned on the current intensity can be increased by pushing the ‘+’ button and lowered by 
pushing the ‘-‘ button. When a comfortable skin sensation is felt the patients should press the ‘-‘ button 
once more. At that time the device stimulates with a low current which is not felt but provides a 
neuromuscular tone to the muscles whilst asleep. The device is kept on all night and in the morning 
taken off with the hydrogel and disconnected. Once disconnected it should be turned off by pressing the 
“off” button. The device should then be placed on the provided charger so that it is fully charged again 
for the next night.  
 
Advice on sleep hygiene, posture in bed and general life style (the use of alcohol, sedatives) will be 
discussed, the potential impact of weight on OSA will be explained. Weekly phone calls and follow up 
visits at 6- and 12-weeks will be organized. At each visit comfort, compliance and adverse reactions will 
be recorded. At 12-weeks, the patients will be invited for a repeat assessment including 
polysomnography during a night of electrical stimulation. Usage time of the device will be discussed 

 
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with the patients and recorded. 
 
General Description 
The device works by passing mild electrical signals into the body via a disposable adhesive gel pad on 
the skin and stimulates muscles to contract, in particular those associated with opening the airways 
(genioglossus muscles). Application of regular electrical pulses to these muscles, which start after the 
user has fallen asleep, help to maintain more open airways. These muscles might otherwise be too 
relaxed and cause vibrations in the throat whilst breathing, manifesting as snoring or sleep apnoea. 
 
 
Warning: 
Before you start it is vital to read, understand, and strictly observe all 
warnings, cautions, contraindications, notes, and safety markings within this 
document and on the product 
 
 
Warning: 
Warning: 
• Ensure that the gel pads are correctly attached to the product and the 
correct area of the body. 
• Only use electrode pads provided. 
• Do not use with skin products, topically applied creams or ointments. 
• Avoid contact of the gel pads with any metallic objects, such as 
necklaces. 
• Electrode pads are for limited use, repeated use on the skin may 
increase the risk of irritation and infections. 
• Do not use on a wet body. 
• Keep device dry, do not bath or shower whilst wearing the device. 
• Do not use in the bathroom or in any other area of high humidity as 
this may cause uncomfortable levels of stimulation. 
• Apply device to intended area only. 
 
 
Warning: 
Do not attempt to wear the device whilst charging. 
 
Caution: 
This device is not waterproof 
 
Warning: 
Electrode pads are for limited use, repeated use on the skin may increase 
the risk of irritation and infections. 
 
Periodically clean device with a damp cloth or alcohol-based wipe. Do not immerse in cleaning fluid, 
allow to air-dry before charging or use. If required, clean disposable electrode pad with a damp cloth 
only. Avoid extensive cycles of cleaning and reuse on electrode pad, repeated use on the skin may 
increase the risk of irritation and infections. Replace protective film to prevent pad from drying out. 
 
Contraindications of Use 

 
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Warning: Do not use this device if any contraindication is applicable, if in 
doubt consult a medical professional. 
 
• Do not use on individuals with pacemakers, defibrillators, or any other implantable medical devices, 
including but not limited to hyperglossal nerve stimulators, or cerebral shunts. 
• Do not use near sources of enriched oxygen. 
• Do not use with metal implants (excluding fillings) in the head and neck region. 
• Do not use following recently diagnosed deep vein thrombosis (DVT). 
• Do not use if diagnosed with cancer, do not apply over or in proximity to cancerous lesions. 
• Do not use if suffering from migraine. 
• Do not use if pregnant or in labour. 
• Do not use if suffering from heart conditions, arrhythmias, recurrent seizures, epilepsy, alcoholism, 
leprosy. 
• Do not use following surgery where muscle contractions may disrupt the healing process. 
• Do not use on scarred areas following surgery for at least 10 months after operation. 
• Do not use when connected to high frequency surgical equipment. 
• Do not use in conjunction with any other medical devices, including but not limited to: TENS 
machine, electrical stimulation machine, electrocardiograph (ECG) meter, Magnetic Resonance 
Imaging (MRI), and electronic diagnosis scanners (e.g. CT scanner). 
• Seek medical advice prior to use for users suffering from severe mental illness, Alzheimer’s, 
dementia, or any other memory impairment. 
• Seek medical advice prior to use if suffering from: abnormal blood pressure, skin conditions 
including broken or damaged skin, loss of feeling in areas of the body, diabetes and acute 
disease/fevers. 
• Do not apply to swollen, infected, inflamed areas or broken skin. 
• In some cases, skin inflammation or irritation can develop in the contact area. Stop using the device 
immediately if you notice any reddening of the skin, if you feel any discomfort or feel unwell (seek 
medical advice).  
 
General Warnings and Cautions 
 
 Warning: Not to be used for children under 16. 
 Warning: Keep out of reach of children and pets. 
 
Warning: Do not apply to the head, face, eyes, mouth, oral cavity, limbs, 
sexual organs, torso, spine, over bones, or sides of the throat and neck (i.e. 
over thyroid or carotid sinus regions). 
 
Warning: Users with an implanted electronic device, such as a pacemaker, 
should not use this product without consulting their medical professional. 
 
Warning: Simultaneous connection of a patient to a h.f. surgical equipment 
may result in burns at the site of the stimulator electrodes and possible 

 
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damage to the stimulator. 
 
Warning: Operation in close proximity (e.g. 1m) to a short wave or 
microwave therapy equipment may produce instability in the stimulator 
output. 
 
Warning: Application of electrodes near the heart could increase the risk of 
cardiac fibrillation. 
 
Warning: Do not use whilst driving, operating machinery, or during any 
activity where involuntary muscle contractions may put the user or others at 
risk. 
 Warning: Do not use if packaging is open or appears damaged. 
 Warning: Check the device is functioning correctly. 
 Warning: Do not switch on until correctly attached. 
 Warning: The device is intended to be used for a maximum of 9 hours.  
4 Justification for the design of the clinical investigation 
 
Obstructive sleep apnoea (OSA) is the most common form of sleep-disordered breathing (1-3). The 
prevalence has significantly increased over the last two decades due to the obesity epidemic and OSA 
affects now roughly 10% of the middle aged male population (2), leaving some populations with 
difficulties to find enough sleep services within their area (3). Untreated OSA leads to adverse long term 
health outcomes, including cardiovascular risks (11) including stroke, and excessive daytime sleepiness. 
The best available treatment for moderate-severe OSA remains CPAP therapy (4), which is currently 
recommended by NICE (5). The need to sleep with a mask impacts on long-term compliance with 
treatment and contributes to the low long-term uptake of CPAP (6) leaving few alternatives (12). 
Mandibular advancement devices, although used in the treatment of mild OSA, are not sufficient for the 
long-term therapy of moderate-severe OSA, which is reflected in current guidance (13).  
 
The need to develop additional alternatives to CPAP therapy has recently led to a renaissance of 
electrical stimulation (10). The stimulation of upper airway dilator muscles, invasively via hypoglossal 
nerve stimulation (7, 14, 15) and non-invasively via transcutaneous electrical stimulation (8, 9) has 
attracted considerable interest (16). Hypoglossal nerve stimulation does not seem to be as efficient as 
CPAP therapy, but in a recent analysis of published data positive studies report an improvement in the 
apnoea-hypopnoea-index (AHI) or the oxygen-desaturation-index (ODI), both markers of the severity of 
OSA, of between 50-75% (7, 10). In untreated patients with OSA (in whom CPAP was not tolerated), 
this effect size would be sufficient to downstage severe OSA, as defined by an AHI or ODI above 30 
events per hour, to a milder category (mild OSA <15 events per hour), which could still cause symptoms 
like sleepiness but would be likely to be associated with no or minimal cardiovascular long-term risks 
(11). 
 
Following our initial pilot study using non-invasive electrical stimulation for short periods at night (8) 
we have studied the feasibility of this method for whole night use in a randomized sham-controlled 

 
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cross-over trial with a prototype device at the bedside in the sleep laboratory (NCT01661712), the 
TESLA trial (9). This trial revealed that there was a modest improvement in sleep apnoea in the studied 
cohort with some patients being identified as responders and some as non-responders. 17/36 patients had 
a clinically relevant improvement, as defined by a more than 25% improvement in the oxygen 
desaturation index (4%ODI) and/or a 4%ODI of less than 5/hour on treatment (9).  
 
In order to establish whether transcutaneous electrical stimulation can be used to treat sleep apnoea in 
the responding cohort in the domiciliary setting a medical device has been developed for use in a 
domiciliary study. We propose to recruit suitable patients with obstructive sleep apnoea and provide the 
treatment at home over a three-month period; patients would need to use transcutaneous electrical 
stimulation every night when asleep. The focus of this study is on efficacy, as assessed by the sleep 
apnoea severity and symptomatic improvement, patient compliance, as measured by usage (total hours / 
per night), and on subjective comfort and acceptance. The results of this study would be used to inform 
us about sample size generation and recruitment for a later multi-centre trial (Phase III) of this method. 
 
 
 
5 Risks and benefits of the Investigational device and clinical 
Investigation 
 
General Benefit 
The proposed study will provide us with information about the efficacy of domiciliary treatment with 
electrical stimulation, the number of eligible patients and data to perform a sample size analysis for a 
definitive and prospective multi-centre randomized controlled trial (Phase III). The study design will test 
the willingness of patients for randomisation, it will reveal whether clinicians refer patients to participate 
in this study, and the follow up of patients on continuous transcutaneous electrical stimulation (CTES) 
over a period of three months will test retention in the study. We will get an understanding whether the 
proposed outcome parameters, the AHI and 4%ODI, the ESS, as well as compliance and comfort are 
suitable measures and whether the collection of data, questionnaires and time to collect the data are 
within reasonable acceptance for the patients and the study team, as well as genioglossus thickening, as 
determined by ultrasound.  
 
Specific Risks and Benefits 
The patient will be given a printed information sheet informing them of potential benefits and risks of 
the trial on the day of their outpatient clinics appointment. They will be explained the treatment options 
for sleep apnoea. It will then be explained what intervention is planned in the trial. The potential 
participant will be contacted >24h later to be given time to reconsider, ask friends, family members and 
GP`s about this trial and come to a decision. If the potential participant agrees to be included in the trial 
they will be invited to come back and informed written consent will be taken following sufficient time to 
ask further questions. Participants will be screened and treated for obstructive sleep apnoea. The 
transcutaneous electrical stimulation device will be introduced to patients as a new treatment that they 
may be able to choose at a later stage. Electrical stimulation with transcutaneous patches, similar to 
those used in transcutaneous electrical nerve stimulation (TENS) machines, is widely and safely used 
without significant side effects reported. Hypothetically, high electrical current can lead to discomfort 
on the skin and muscle spasm but the titration of the current according to patient perception will help to 

 
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minimise these effects. 
 
We recently published results from a randomised controlled trial using a similar medical device to the 
one we propose to use in this trial and found that patients tolerated the electrical stimulation well (Pengo 
M et al, THORAX 2016). Patients did not report any local skin reaction, nor any unpleasant or painful 
sensation on the skin. There were no adverse effects when using the device. 
 
However, we acknowledge that the new device that we are proposing to use in this trial differs from the 
TENS machine that we used in the above trial. The current device will be used every night for three 
months, as opposed to a one-off treatment. Therefore, we have the following procedures in place to 
avoid problems:  
 
The group of patients receiving continuous transcutaneous electrical stimulation will be trained on the 
device and settings will be recorded. The device will be hooked on a hydrogel patch which is placed in 
the neck area leaving the bony structure of the mandible free. The device can only be charged when off 
the body. Ideally, men should shave daily to guarantee a good contact of the hydrogel and a low skin 
resistance to promote good transduction of the current and avoid skin discomfort. In order to allow for 
maximal adhesion and contact the hydrogel should be placed on dry skin. The device needs to be started 
by pressing the ‘on’ button. Once the device is turned on the current intensity can be increased by 
pushing the ‘+’ button and lowered by pushing the ‘-‘ button. When a comfortable skin sensation is felt 
the patients should press the ‘-‘ button once more. At that time the device stimulates with a low current 
which is not felt but will maintain a neuromuscular tone to the muscles whilst asleep. The device is kept 
on all night and in the morning is taken off together with the hydrogel and disconnected. Once 
disconnected it should be turned off by pressing the ‘off’ button. The device should then be placed on 
the provided charger so that it is fully charged again for the next night. 
 
Advice on sleep hygiene, posture in bed and general life style (the use of alcohol, sedatives) will be 
discussed, the potential impact of weight on OSA will be explained. Weekly phone calls and follow up 
visits at 6- and 12-weeks will be organized. At each visit comfort, compliance and adverse reactions will 
be recorded. At 12-weeks, the patients will be invited for a repeat assessment including 
polysomnography during a night of electrical stimulation in the sleep laboratory. Usage time of the 
device will be discussed with the patients and recorded. 
 
We will discuss the following instructions (see below) in detail with the patient, in order to ensure they 
understand how to use the device, and what action to take in case of a safety issue. 
6 Objectives and hypotheses of the clinical investigation 
 
General Objectives and Hypotheses 
The objective is to assess efficacy and compliance of transcutaneous electrical stimulation of the upper 
airway dilator muscles in obstructive sleep apnoea patients over time and evaluate acceptability and 
comfort. The proposed study will provide us with information about the efficacy of domiciliary 
treatment, the number of eligible patients and data to perform a sample size analysis for a definitive and 
prospective multi-centre randomized controlled trial (Phase III). The study design will test the 
willingness of patients for randomisation, it will reveal whether clinicians refer patients to participate in 
this study, and the follow up of patients on continuous transcutaneous electrical stimulation (CTES) over 

 
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a period of three months will test retention in the study. We will get an understanding whether the 
proposed outcome parameters, the AHI and 4%ODI, the ESS, as well as compliance and comfort are 
suitable measures and whether the collection of data, questionnaires and time to collect the data are 
within reasonable acceptance for the patients and the study team, as well as genioglossus thickening, as 
determined by ultrasound. 
 
6.1 Objectives, primary and secondary. 
 
The primary outcome parameter will be the reduction in severity of OSA at 12-weeks compared to 
baseline, as defined by the AHI. A response to treatment will be a more than 50% reduction in the AHI 
from baseline and a total AHI< 20/h, in line with previous trials (7, 9). 
 
Secondary outcome parameters will address the ESS, the 4%ODI, compliance with treatment, as 
measured by the usage of transcutaneous electrical stimulation at night (total hours / per night). 
Subjective comfort and acceptance will be assessed using a visual analogue scale (0 – 10 points), the 
disease-specific symptoms, as assessed by sleep-related Quality of Life (FOSQ, EQ-5D), as well as 
snoring (total duration, intensity, spouse reporting). Ultrasound will be used to assess genioglossus 
thickness and preserved contractibility. 
 
6.2 Hypotheses, primary and secondary, to be accepted or rejected by statistical data 
from the clinical investigation. 
Statistical analysis will compare the respective outcome parameters (primary outcome: AHI; secondary 
outcome: ESS, 4%ODI, compliance in hours usage/night, comfort) between active stimulation and the 
control group. Full statistical description will be provided and for each of the variables analysed, 
univariate descriptive statistics will present an overview of the data. Continuous variables will be 
presented as median and interquartile range (IQR), unless otherwise stated. For categorical variables, 
frequency counts and percentages will be presented as summary statistics for the subgroups of interest. 
To compare study groups, we will use the Wilcoxon and paired t-test for continuous paired variables, 
and the χ2 test for categorical variables. The primary outcome parameters (AHI) will be analysed using 
the Mann-Whitney test between treatment groups (active stimulation) and control group (CPAP). 
Similar analyses will be conducted for secondary outcomes. The trial follows up each patient for at least 
12 weeks and some patients will be inevitably lost to follow-up. Sample size estimation assumed 20% of 
patients would not provide end of study information that could be evaluated. If this rate is observed, data 
for many patients will be only partially observed. For patients who withdraw or drop out before the end 
of the study, the “no change assumption” will be used to impute the missing subsequent values. This 
may introduce a bias if the main reason for drop-out was deterioration. To examine this possibility, 
sensitivity analysis will be performed to assess the primary efficacy outcome using different imputation 
methods including “best-case scenario”, and “worst- case scenario” possible scores for the missing data 
as well as Markov Chain Monte Carlo Multiple Imputation. A second per protocol analysis, including 
only those subjects with complete follow-up data will also be performed. All analyses will be performed 
using StataTM version 12. Differences will be considered significant at p<0.05. 

 
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6.3 Claims and intended performance of the investigational device that are to be 
verified 
 
The Zeus device is a portable, battery powered apparatus for treatment of snoring or sleep apnoea, 
comprising: 
• A pair of electrodes, and  
• A power supply that generates an electrical signal between the electrodes to stimulate the 
patients’s tongue muscle (genioglossus) when the electrodes are attached to the patients. 
• The device will be used in patients with obstructive sleep apnoea and compared to usual care, 
continuous positive airway pressure (CPAP) therapy. 
 
6.4 Risks and anticipated adverse device effects that are to be assessed. 
 
The patient will be given a printed information sheet informing them of potential benefits and risks of 
the trial on the day of their outpatient clinics appointment. They will be explained the treatment options 
for sleep apnoea. It will then be explained what intervention is planned in the trial. The potential 
participant will be contacted >24h later to be given time to reconsider, ask friends, family members and 
GP`s about this trial and come to a decision. If the potential participant agrees to be included in the trial 
they will be invited to come back and informed written consent will be taken following sufficient time to 
ask further questions. Participants will be screened and treated for obstructive sleep apnoea. The 
transcutaneous electrical stimulation device will be introduced to patients as a new treatment that they 
may be able to choose at a later stage. Electrical stimulation with transcutaneous patches, similar to 
those used in transcutaneous electrical nerve stimulation (TENS) machines, is widely and safely used 
without significant side effects reported. Hypothetically, high electrical current can lead to discomfort 
on the skin and muscle spasm but the titration of the current according to patient perception will help to 
minimise these effects. 
 
We recently published results from a randomised controlled trial using a similar medical device to the 
one we propose to use in this trial and found that patients tolerated the electrical stimulation well (Pengo 
M et al, THORAX 2016). Patients did not report any local skin reaction, nor any unpleasant or painful 
sensation on the skin. There were no adverse effects when using the device. However, we acknowledge 
that the new device that we are proposing to use in this trial differs from the TENS machine that we used 
in the above trial. The current device will be used every night for three months, as opposed to a one-off 
treatment. Therefore, we have the following procedures in place to avoid problems: 
 
The group of patients receiving continuous transcutaneous electrical stimulation will be trained on the 
device and settings will be recorded. The device will be hooked on a hydrogel patch which is placed in 
the neck area leaving the bony structure of the mandible free. The device can only be charged when off 
the body. Ideally, men should shave daily to guarantee a good contact of the hydrogel and a low skin 
resistance to promote good transduction of the current and avoid skin discomfort. In order to allow for 
maximal adhesion and contact the hydrogel should be placed on dry skin. The device needs to be started 
by pressing the ‘+’ and the ‘-‘ button together for 3s. Once the device is turned on the current intensity 
can be increased by pushing the ‘+’ button (8 levels) and lowered by pushing the ‘-‘ button. When a 
comfortable skin sensation is felt the patients should press the ‘-‘ button once more. At that time the 
device stimulates with a low current which is not felt but will maintain a neuromuscular tone to the 
muscles whilst asleep. The device is kept on all night and in the morning is taken off together with the 

 
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hydrogel and disconnected. Once disconnected it should be turned off by pressing the ‘+’ and the ‘-‘ 
button for 3s. The device should then be placed on the provided charger so that it is fully charged again 
for the next night. Advice on sleep hygiene, posture in bed and general life style (the use of alcohol, 
sedatives) will be discussed, the potential impact of weight on OSA will be explained. Weekly phone 
calls and follow up visits at 6- and 12-weeks will be organized. At each visit comfort, compliance and 
adverse reactions will be recorded. At 12-weeks, the patients will be invited for a repeat assessment 
including polysomnography during a night of electrical stimulation in the sleep laboratory. Usage time 
of the device will be discussed with the patients and recorded. 
 
We will discuss the following instructions (see below) in detail with the patient, in order to ensure they 
understand how to use the device, and what action to take in case of a safety issue.  
 
Instructions: 
Before patients start it is vital to read, understand, and strictly observe all warnings, cautions, 
contraindications, notes, and safety markings within this document and on the product. 
 
Warning: 
• Ensure that the gel pads are correctly attached to the product and the correct area of the body. 
• Only use electrode pads provided. 
• Do not use with skin products, topically applied creams or ointments. 
• Avoid contact of the gel pads with any metallic objects, such as necklaces. 
• Electrode pads are for limited use, repeated use on the skin may increase the risk of irritation and 
infections. 
• Do not use on a wet body. 
• Keep device dry, do not bath or shower whilst wearing the device. 
• Do not use in the bathroom or in any other area of high humidity as this may cause uncomfortable 
levels of stimulation. 
• Apply device to intended area only. 
• Do not attempt to wear the device whilst charging. 
 
The device must not be used with a cardiac pacemaker or a metal implant in situ, dental prostheses are 
excluded. Periodically cleaning of the device with a damp cloth or alcohol-based wipe might be 
required, but it should not be immersed in cleaning fluid, time should be allowed to air-dry before 
charging or use. If required, participants should clean the disposable electrode pad with a damp cloth 
only, but avoid extensive cycles of cleaning and reuse of electrode pads; repeated use on the skin may 
increase the risk of skin irritation and infections. Participants will be shown how to replace the 
protective film to prevent pad from drying out. 
 
For any queries, there is the chance to contact a 24/7 staffed telephone line to seek advice (Lane Fox 
Unit 02071883434/-83435). 

 
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7 Design of the clinical investigation  
7.1 
General  
This is a prospective trial in a randomized controlled two-arm parallel group design testing 
transcutaneous electrical stimulation in obstructive sleep apnoea for use at home for a 3-months’ period 
and compare outcomes against usual care (CPAP).  Patients will be admitted to the Lane Fox Unit / 
Sleep Disorders Centre at Guy’s & St Thomas’ NHS Foundation Trust for their baseline assessment. 
Following a diagnostic sleep study they will be randomized into transcutaneous electrical stimulation at 
home and usual care treatment. All patients will be followed up at 6 weeks in outpatient clinic and at 3-
months’ for a repeat sleep study. 
 
7.2 Investigational device and comparators  
 
Description of Active Treatment  
The group of patients receiving continuous transcutaneous electrical stimulation will be trained on the 
device and settings will be recorded. The device will be hooked on a hydrogel patch which is placed in 
the submental area leaving the bony structure of the mandible free. Ideally, men should shave daily to 
guarantee a good contact of the hydrogel and low skin resistance to promote good transduction of the 
current and avoid skin discomfort. In order to allow for maximal adhesion and contact the hydrogel 
should be placed on dry skin. The device needs to be started by pressing the ‘on’ button together. Once 
the device is turned on the current intensity can be increased by pushing the ‘+’ button and lowered by 
pushing the ‘-‘ button. When a comfortable skin sensation is felt the patients should press the ‘-‘ button 
once more. At that time the device stimulates with a low current which is not felt but provides a 
neuromuscular tone to the muscles whilst asleep. The device is kept on all night and in the morning 
taken off with the hydrogel and disconnected. Once disconnected it should be turned off by pressing the 
‘off’ button. The device should then be placed on the provided charger so that it is fully charged again 
for the next night.  
Advice on sleep hygiene, posture in bed and general life style (the use of alcohol, sedatives) will be 
discussed, the potential impact of weight on OSA will be explained. Weekly phone calls and follow up 
visits at 6- and 12-weeks will be organized. At each visit comfort, compliance and adverse reactions will 
be recorded. At 12-weeks, the patients will be invited for a repeat assessment including 
polysomnography during a night of electrical stimulation. Usage time of the device will be discussed 
with the patients and recorded. 
 
Description of Usual Care  
Patients who will be randomized to the usual care group will be given their own CPAP device, this is the 
standard treatment according to guidelines. In addition, the mask will be reviewed and explained again, 
advice on sleep hygiene, posture in bed and general life style, as well as the potential impact of weight 
loss on OSA will be explained. The device will be fitted and explained in the same way as in he clinical 
service. Weekly phone calls and follow up visits at 6- and 12-weeks will be organized. At the last visit, 
the patients will be studied during a repeat inpatient polysomnography and the initial assessment will be 
repeated.  
 
In order to improve recruitment and retention of patients to the usual care group all participants will be 
offered a free and voluntary trial of the non-invasive electrical stimulation following successful 
completion of the trial and prior to the regular follow up in the clinical sleep service. 

 
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7.3 Subject Selection 
 
Patients with obstructive sleep apnoea diagnosed by overnight polysomnography will be recruited in this 
trial. Obstructive sleep apnoea is defined as an AHI>5/hour plus symptoms of sleepiness 
(ESS>10points). The sample size calculation of n=60 patients is based on previously published data of 
the STAR trial (7) to detect a difference in the treatment arms with a Power of 95% and an alpha of 5% 
using the improvement in the AHI as an outcome parameter. 
 
Healthy volunteers will participate according to inclusion and exclusion criteria. The sample size 
calculation of n=        volunteers to record responses to different levels of electrical current. 
 
7.3.1 
Inclusion criteria 
 
Patients who have mild-moderate OSA (AHI 5-35/hour) will be included in this study if they fail to use 
or have been withdrawn from standard care (CPAP <4hours/night). We will include patients with a body 
mass index (BMI) of 18.5-32 kg/m2, without significant anatomical obstruction in the upper airway (e.g. 
normal sized tonsils). 
 
Apparently healthy volunteers, with BMI of 18.5-32 kg/m2 and without significant anatomical 
obstruction in the upper airway (e.g. normal sized tonsils). 
 
7.3.2 
Exclusion criteria  
 
We will exclude patients with no (AHI <5/h) or severe obstructive sleep apnoea (AHI>30/hour), 
exclusively postural sleep apnoea, isolated Rapid-Eye-Movement (REM) sleep associated OSA, patients 
who are cachectic (BMI <18.5 kg/m2) or very obese (BMI >32 kg/m2), hypercapnic patients (pCO2>6.5 
kPa) or those with other features of obesity hypoventilation syndrome (elevated bicarbonate, HCO3- 
>28mmol/L). Patients should not have enlarged tonsils (size 3-4), polyps and adenoids, neuromuscular 
disease, hypoglossal nerve palsy, abnormal pulmonary function tests, severe pulmonary hypertension, 
valvular heart disease, heart failure (New York Heart Association, NYHA III-IV), myocardial infarction 
and significant cardiac arrhythmias, uncontrolled hypertension, active psychiatric disease, co-existing 
non-respiratory sleep disorder, or significant metal implants or cardiac/other pacemakers. These criteria 
are consistent with our experience from previous trials using electrical stimulation in OSA and likely to 
define responders; these criteria are also consistent with experiences from trials using hypoglossal nerve 
stimulation (7-9). In addition, patients will need to be excluded if they have facial hair that affects the 
correct placement of the hydrogel patch, if they are unwilling to shave. Patients and volunteers with  
allergy to plasters or similar products will be excluded. 
7.3.3 
Criteria and procedures for subject withdrawal or discontinuation. 
 
Sample size estimation assumed 15-20% of patients would not provide end of study information that 
could be evaluated. If this rate is observed, data for some patients will be only partially observed. For 
patients who withdraw or drop out before the end of the study, the “no change assumption” will be used 
to impute the missing subsequent values. This may introduce a bias if the main reason for drop-out was 
deterioration. To examine this possibility, sensitivity analysis will be performed to assess the primary 

 
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efficacy outcome using different imputation methods including “best-case scenario” and “worst- case 
scenario” possible scores for the missing data. A second per protocol analysis, including only those 
subjects with complete follow-up data will also be performed. 
 
7.3.4 
Subject Enrolment  
 
Patients with OSA will be recruited from the Lane Fox Unit and the Sleep Disorders Centre at Guy’s & 
St Thomas’ NHS Foundation Trust where they are assessed in the Sleep Apnoea / CPAP clinics. The 
Lane Fox Unit runs daily outpatient clinics at the St Thomas’ site while the Sleep Disorders Centre has 
multiple clinics running Mondays-Fridays (am/pm) at Nuffield House at Guy’s. Currently, the Lane Fox 
Unit cares for >1,600 patients on home non-invasive ventilation and CPAP therapy while the Sleep 
Disorders Centre has >10,000 patients on their records using CPAP therapy. 
Patients will also be identified from the sleep clinics at the Royal Brompton Hospital and King’s College 
Hospital (PIC sites), but the study procedures will be undertaken at Guy’s & St Thomas’ Hospital. The 
direct care team will approach patients after consultation with the Consultant and hand out a Patient 
Information Sheet to discuss the study with them. Informed written consent will be taken after sufficient 
time to allow for information and questioning. Patients will then be offered a date to come to hospital 
within four weeks for the baseling assessment with overnight polysomnography. If the patient fulfills all 
inclusion and no exclusion criteria, follow up will be booked at 6- and 12-weeks following 
randomisation. Procedure on volunteers will take place at Lane Fox Unit. 
 
7.4 Procedures 
7.4.1 
Informed Consent 
 
A member of the direct clinical care team (Good Clinical Practice, GCP-trained) will take informed 
consent once the patients and the volunteers have had the opportunity to read and discuss the Patient 
Information Sheet with sufficient time. It will be clearly stated that the participant is free to withdraw 
from the study at any time without this affecting any future care and with no obligation to give the reason 
for withdrawal. 
Following sufficient time and the opportunity to question the (Co-)investigator or other independent 
parties to decide whether they will participate in the study written informed consent will then be obtained. 
A copy of the signed informed consent will be given to the participants.  The original signed form will be 
kept at the study site and a copy will be inserted in the medical notes.  
 
7.4.2 
Screening and Eligibility Assessment 
 
Patients with OSA will be recruited from the Lane Fox Unit and the Sleep Disorders Centre at Guy’s & 
St Thomas’ NHS Foundation Trust where they are assessed in the Sleep Apnoea / CPAP clinics. The 
Lane Fox Unit runs daily outpatient clinics at the St Thomas’ site while the Sleep Disorders Centre has 
multiple clinics running Mondays-Fridays (am/pm) at Nuffield House at Guy’s. Currently, the Lane Fox 
Unit cares for >1,600 patients on home non-invasive ventilation and CPAP therapy while the Sleep 
Disorders Centre has >10,000 patients on their records using CPAP therapy. 
Patients will also be identified from the sleep clinics at the Royal Brompton Hospital and King’s College 
Hospital (PIC sites), but the study procedures will be undertaken at Guy’s & St Thomas’ Hospital. The 
direct care team will approach patients after consultation with the Consultant and hand out a Patient 

 
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Information Sheet to discuss the study with them. Informed written consent will be taken after sufficient 
time to allow for information and questioning. Patients will then be offered a date to come to hospital 
within four weeks for the baseling assessment with overnight polysomnography. If the patient fulfills all 
inclusion and no exclusion criteria, follow up will be booked at 6- and 12-weeks following 
randomisation. 
 
7.4.3 
Baseline Assessments 
 
The initial assessment will include an overnight Sleep Study (Polysomnography, PSG). Patients will be 
assessed using the following parameters: 
 
a) Demographics 
i.  
Age 
ii.  
Gender 
iii.  
Height, Weight, Body-Mass-Index (BMI) 
iv.  
Neck circumference 
v.  
Waist, Hip, W:H ratio 
vi.  
Mallampati and Friedman Score 
vii.  
Basic lung function (spirometry: FEV1, FVC) 
viii. 
Blood pressure and heart rate 
ix. 
Medication use 
x. 
Number of pillows used 
 
b) Upper Airway and Carotides 
i.  
Mallampati and Friedman score 
ii.  
Response to transcutaneous electrical stimulation  
(visual inspection using endoscopy and ultrasound) 
  
c) Blood tests and blood pressure measurements 
i.  
Full blood count 
ii.  
Renal and hepatic profile 
iii.  
Thyroidal function tests 
iv.  
Ferritin 
v.  
HbA1c 
vi.  
BNP 
vii.  
Arterial or earlobe blood gas analysis  
 
 
 
 
 
 
 
 
(including pH, pO2, pCO2, HCO3-) 
viii. 
24-hour blood pressure measurement 
 
 d) Sleep study parameters, as measured by polysomnography 
i.  
AHI, 4%ODI  
ii.  
Total sleep time 
iii.  
Sleep onset 
iv.  
Sleep efficiency 
v.  
Diagnosis (obstructive, central, mixed sleep apnoea) 
vi.  
Posture in bed 

 
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vii.  
Different sleep stages 
viii.  
Snoring (total duration, intensity) 
ix.  
Neural respiratory drive (EMGpara) 
 
e) Symptom and Quality of Life scores 
i.  
Epworth Sleepiness Scale (ESS) 
ii.  
Stanford Sleepiness Scale (SSS) 
iii.  
European Quality of Life tool (EQ-5D) 
iv. 
Hospital Anxiety and Depression Scale (HADS) 
v.  
Functional Outcome of Sleep Questionnaire (FOSQ) 
vii.  
Qualitative overnight report 
viii. 
if available, spouse reporting snoring and sleep quality (Visual Analog Scales, ESS) 
 
During the COVID-19 pandemic assessments will be remotely (via telephone or videocall, a-c) or at 
home (d, e). For the home sleep studies multi-channel wearable sleep technology will be used (Apnea 
Link or NoxT3, ResMed, UK); the equipment can be couriered out and, upon return, cleaned and 
quarantined to avoid any risk associated with the COVID-19 virus. The patient will be provided with a 
manual how to use the equipment, the correct fitting will be explained via phone / videocall, and the 
provider’s teaching material will be made accessible online as well (additional information for the 
home-based sleep study and the instruction on how to use it are provided in the attached leaflet labelled 
“Home Sleep Study”, dated 22-11-2020, V1.0). 
 
7.4.4 
Randomisation 
 
Randomisation and Home Treatment 
Following the baseline assessment patients’ degree of sleep apnoea will be reviewed and, if eligible, 
patients will be randomized into active treatment or usual care (CPAP). The active treatment will be 
domiciliary transcutaneous electrical stimulation at night using a medical device while the usual care 
group will receive ongoing CPAP therapy. 
 
Randomisation will involve assigning a unique patient number in sequential, ascending chronological 
order. This number will be a two-digit number prefixed by “R” (e.g. R01, R02 etc) and will be used to 
identify the treatment order the patient was randomised to. Treatment assignment will be determined 
according to a computer generated randomisation list prepared by an individual not directly involved in 
subject assessments. 
 
7.4.5 
Subsequent assessments 
 
Bi-weekly Telephone Contacts 
All patients will receive bi-weekly phone calls to encourage usage of the device and discuss problems 
with the treatment. Patients will be asked about comfort and adverse events / serious adverse events. The 
following parameters will be assessed: 
 
i.  
Epworth Sleepiness Scale (ESS) 
ii.  
Stanford Sleepiness Scale (SSS) 
iii.  
European Quality of Life tool (EQ-5D) 

 
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iv.  
Functional Outcome of Sleep Questionnaire (FOSQ) 
vii.  
Comfort (analogue scale, 0-10 points) 
 
Follow up at 6-weeks 
At six weeks, patients will be followed in the outpatient clinic at the Lane Fox Unit / Sleep Disorders 
Centre. The following assessments will be made (for more details see above): 
 
a) Demographics  
b) Blood tests  
c) Symptom and Quality of Life scores 
d) Usage and compliance with medical device and treatment 
i.  
the total usage (hours) and usage per night (hours)  
ii.  
subjective comfort with the device (Visual Analogue Scale) 
iii.  
comfort and AE / SAE 
iv.  
usage of number of hydrogel patches 
e) Nocturnal pulse oximetry on treatment at home (will be returned via mail) 
 
At this stage, the patients will be educated on the device/CPAP again and encouraged to continue with 
its usage. 
 
During the COVID-19 pandemic assessments will be remotely (via telephone or videocall, a-d) or at 
home (e). For the home sleep studies multi-channel wearable sleep technology will be used (Pulse 
Oximetry or Apnea Link or NoxT3, ResMed, UK); the equipment can be couriered out and, upon return, 
cleaned and quarantined to avoid any risk associated with the COVID-19 virus. The patient will be 
provided with a manual how to use the equipment, the correct fitting will be explained via phone / 
videocall, and the provider’s teaching material will be made accessible online as well (additional 
information for the home-based sleep study and the instruction on how to use it are provided in the 
attached leaflet labelled “Home Sleep Study”, dated 22-11-2020, V1.0). 
 
 
Follow up at 12-weeks 
At 12-week follow up the patients will be invited to attend the Lane Fox Unit / Sleep Disorders Centre 
for another overnight polysomnography. The assessment will repeat the following measurements (for 
more details see above): 
 
i) Demographics 
ii) Upper Airway 
iii) Blood tests and blood pressure measurement. 
iv) Sleep study parameters, as measured using a polysomnography 
v) Symptom and Quality of Life scores 
vi) Usage and compliance of Treatment (for more details see 6.6)  
 
Patients will be given a debriefing by the study team and individual study reports can be requested at 
this stage, they will be provided once the entire analysis has been completed. Qualitative data will be 
recorded for a potential later multi-centre trial.  
 
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at home (iv). For the home sleep studies multi-channel wearable sleep technology will be used (Apnea 
Link or NoxT3, ResMed, UK); the equipment can be couriered out and, upon return, cleaned and 
quarantined to avoid any risk associated with the COVID-19 virus. The patient will be provided with a 
manual how to use the equipment, the correct fitting will be explained via phone / videocall, and the 
provider’s teaching material will be made accessible online as well (additional information for the 
home-based sleep study and the instruction on how to use it are provided in the attached leaflet labelled 
“Home Sleep Study”, dated 22-11-2020, V1.0). 
 
7.5 Definition of End of Trial  
 
The trial finishes with the 12-week follow up assessment. The patients will then be referred back to 
standard care to be followed up in the outpatient setting at the Lane Fox Unit / Sleep Disorders Centre, 
the Royal Brompton Hospital or King’s College Hospital, as appropriate. 
 
7.6 Discontinuation/ Withdrawal of Participants from Study Treatment 
 
Each participant has the right to withdraw from the study at any time without providing a reason.  In 
addition, the investigator may discontinue the study at any time if considered necessary for one of the 
following reasons:  
• Ineligibility (either arising during the study or retrospectively), 
• Disease progression which requires discontinuation of the study or inability to continue to 
comply with study procedures, 
• Consent withdrawn, 
• Lost to follow up. 
• The reason for withdrawal will be recorded, including ‘no reason given’, in the case report forms 
(CRF).   
 
7.7 Source Data 
 
Source documents are original documents, data, and records from which participants’ CRF data are 
obtained.  These include, but are not limited to, hospital records (from which medical history and 
previous and concurrent medication and sleep apnoea treatment may be summarised into the CRF), 
clinical and office charts and software (e.g. Somnologica / Alice). 
 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g., there is no 
other written or electronic record of data). In this study the CRF will be used as the source document for 
stable patients recruited into the study. All documents will be stored safely on password-protected 
systems in locked rooms at the Lane Fox Unit Clinical Research Facility. Only the research team will 
have access to the data. Rooms are locked and computers are password protected. On all study-specific 
documents, other than the signed consent, the participant will be referred to by the study participant 
number/code, not by name. Data are stored for the duration of the study (3 years) and then archived (for 
at least another 5 years). 
 

 
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8 Statistical Considerations 
 
Sample size 
We performed a sample size analysis based on the previous trial by Strollo et al  (11) using hypoglossal 
nerve stimulation in sleep apnoea. A total of 46 patients would need enter this two-treatment parallel-
design study. This sample size achieves 90% power to detect a clinically important difference of at least 
12.3 units (h-1) between the null hypothesis that both group means are 32.0 (h-1) and the alternative 
hypothesis that the mean of the trial treatment group is 19.7 (h-1) with estimated group standard 
deviations of 11.8 (h-1) and with a significance level of 5%.These calculations were based on 1000 
Monte Carlo samples from normal distributions and using a two-sided Mann-Whitney Test. To adjust 
for the unknown distribution of the primary outcome and based on the lower bound for the asymptotic 
relative efficiency of the Mann-Whitney U test, we have increased the sample size by a further 15% to 
54. Considering our experience with previous studies over this time period we need to account for 
dropouts and loss-to-follow up of between 15-20%. We therefore propose to study a total sample size of 
68, 34 in each group, patients for this study. 
 
Statistical Methods  
Statistical analysis will compare the respective outcome parameters (primary outcome: AHI; secondary 
outcome: ESS, 4%ODI, compliance in hours usage/night, comfort) between active stimulation and the 
control group. Full statistical description will be provided and for each of the variables analysed, 
univariate descriptive statistics will present an overview of the data. Continuous variables will be 
presented as median and interquartile range (IQR), unless otherwise stated. For categorical variables, 
frequency counts and percentages will be presented as summary statistics for the subgroups of interest. 
To compare study groups, we will use the Wilcoxon and paired t-test for continuous paired variables, 
and the χ2 test for categorical variables. The primary outcome parameters (AHI) will be analysed using 
the Mann-Whitney test between treatment groups (active stimulation) and control group (CPAP). 
Similar analyses will be conducted for secondary outcomes. The trial follows up each patient for at least 
12 weeks and some patients will be inevitably lost to follow-up. Sample size estimation assumed 20% of 
patients would not provide end of study information that could be evaluated. If this rate is observed, data 
for many patients will be only partially observed. For patients who withdraw or drop out before the end 
of the study, the “no change assumption” will be used to impute the missing subsequent values. This 
may introduce a bias if the main reason for drop-out was deterioration. To examine this possibility, 
sensitivity analysis will be performed to assess the primary efficacy outcome using different imputation 
methods including “best-case scenario”, and “worst- case scenario” possible scores for the missing data 
as well as Markov Chain Monte Carlo Multiple Imputation. A second per protocol analysis, including 
only those subjects with complete follow-up data will also be performed. All analyses will be performed 
using StataTM version 12. Differences will be considered significant at p<0.05. 
9 Data Management 
9.1 Data to be collected 
 
Direct access will be granted to authorised representatives from the sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
 

 
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9.2 Data handling and record keeping 
 
The participants will be identified by a study specific participants number and/or code in any database. 
The name and any other identifying detail will NOT be included in any study data electronic file.  The 
research team will be adhering to Data Protection Act 1998. The data will be collected by the clinical 
research fellow and controlled by the CI/PI on site, as well as in the quarterly data management meetings 
with the trial statistician. Records will be kept and archived for 10 years in the Lane Fox Unit CRF. 
10 Deviations from clinical investigation plan 
 
A deviation is considered a departure from the conditions and principles of GCP in connection with that 
trial; or the CIP relating to that trial, as amended from time to time. The Investigator shall not deviate 
from this CIP except in situations that affect the subject’s rights, safety and well-being, or the scientific 
integrity of the clinical investigation.  All CIP deviations shall be recorded and reported to the sponsor 
as agreed. A deviation log shall be maintained by the study site. Deviations shall be reported to the REC 
and the regulatory authorities if required by national regulations. All deviations will be included, as 
required in the final study report.  
11 Device accountability 
The Investigators conducting studies in which investigational devices will be used must follow 
regulations for device storage, accountability, dispensing/administration and record-keeping.  
Investigators will demonstrate understanding of the handling and control of investigational test articles 
by reviewing this policy and developing a written plan or procedure for ensuring these regulations are 
met.  
Receipt and Inventory of Study Devices  
This section applies to those study devices the investigator dispenses/administers to the study subject. 
The investigator (or designated research team member) is responsible for ensuring that the following 
sections are fully documented and complete. Upon receipt (preferably within 2 working days, but 
definitely prior to dispensing) of the study device:  
- Conduct an inventory of the shipment to ensure that the information on the packing slip matches 
exactly with what has been sent to the site, to include the receipt date, lot numbers, device type, batch 
number, code mark, and quantity.  
- Identify and document the name of the person who received the shipment of devices as well as their 
role on the protocol.  
- Discrepancies must be promptly (usually within 2-3 working days) reported to the Sponsor/Supplier of 
the device.  
- Documentation of this shipment inventory including the above information must be maintained by the 
principal investigator or designee.  

 
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Documentation for the Regulatory Binder  
Copies of the following documents must be retained:  
• The shipping inventory, packing slips and document inventory in the regulatory binder.  
• Accountability log (most Sponsors will issue/supply a device accountability log).  
 
Labelling of study devices  
Study devices are pre-labeled.  
- Do not re-label, deface, or change in any way without prior written permission of the Sponsor.  
- It is highly recommended that an additional label may be placed on the study device or packaging, if 
space and the design of the device permits, to include the study staff contact name/number, but ONLY if 
the Sponsor agrees in writing prior to doing so.  
 
Principal Investigator Responsibilities 
The Principal Investigator must be aware of applicable regulations and at a minimum, include the 
following on the label (if allowed by the sponsor) or on the packaging: 
• Name of device 
• Model number 
• Serial number 
• Manufacturer name 
• Study staff contact name/number  
 
Storage of Study Devices 
The Principal Investigator is responsible for establishing and maintaining appropriate access controls for 
essential and appropriate research personnel. The access controls must include, at a minimum, the 
following areas: 
• Develop procedures for verifying physical access 
• Store the study device in a secure environment to include locks on doors and controlled access. 
• Establish equipment control both into and out of the research site. 
• Develop Security Incident Procedures to report any privacy breaches 
• Assess any privacy risks anticipated and develop methods to avoid those risks 
• Develop data backup, storage, and emergency mode procedures, if applicable.  
• Ensure the study device is stored at the appropriate temperature, and maintain a storage area 
temperature log, if appropriate.  
 
Study Device Dispensing 
- The Principal Investigator shall permit an investigational device to be used only with subjects under 
their personal supervision or under the supervision of a properly trained sub-investigator responsible to 
the Principal Investigator.  
- The Principal Investigator shall not permit an investigational device to be used with subjects who are 
not under their personal supervision or not under the supervision of a properly trained sub-investigator 
responsible to the principal investigator.  
 
Documentation of Study Device Use 
The investigator must create and maintain an access log to document the following:  
• 
Each time the study device is dispensed/used  
• 
Where it is dispensed/used to  
• 
Whom it is dispensed/used  

 
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• 
And the date and signature or initials of the person dispensing/using the study device (plus any 
other information dictated by the study protocol).  
• 
 
Documentation of Return/Destruction of the Study Device  
- The Principal Investigator must verify:  
• 
All documentation regarding receipt, storage, dispensing, return of used  
containers, and accountability is complete and accurate.  
• 
An explanation of why and how many device units have been returned to the  
sponsor, repaired, or otherwise disposed of must he noted. When a device is  
disposed of, the identification of the person who doing so must also be noted.  
• 
Devices obtained from a Sponsor for the specific purpose of a research study must be returned to 
Sponsor. Only with the written authorization (i.e. in the protocol or other written 
correspondence) of the Sponsor may the investigator discard the device on site, or retain the 
device.  
• 
Unused study devices that include individually identifiable health information must not be 
transferred to other investigators without sponsor approval or an authorization from the study 
subject.  
• 
Unused study devices without individually identifiable health information must not be 
transferred to other investigators, used for animal research, or dispensed to non-study patients 
unless written consent is obtained from the Sponsor/Provider of the device.  
12 Statements of compliance 
12.1 Declaration of Helsinki, International Standards and national regulations  
 
The clinical investigation shall be conducted in accordance with the ethical principles of the Declaration 
of Helsinki, ISO 14155 and all other applicable device and UK regulations.  
12.2 Approvals 
The clinical investigation shall not commence recruitment until all REC, Health Research Authority 
(HRA), other regulatory (if applicable) and confirmation of local capacity and capability is received. All 
additional requirements imposed by the REC, HRA  or regulatory authority will be followed.  
12.3 Funding and Insurance 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If any patients are 
harmed whilst taking part in a clinical trial as a result of negligence on the part of a member of the study 
team this liability cover would apply. 
Non-negligent harm is not covered by the NHS indemnity scheme. Guy’s and St Thomas’ NHS Trust, 
therefore, cannot agree in advance to pay compensation in these circumstances. In exceptional 
circumstances an ex-gratia payment may be offered. However, legislation now requires any GMC 
registered medical professional  to hold a valid indemnity cover. 
 

 
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13 Monitoring 
 
There will be quarterly meetings of the trial steering committee (Chief Investigator, Principal 
Investigators and Clinical Research Fellow) as well as Data Monitoring meetings every 6-
months (Chief Investigator, Statisticians, Clinical Research Fellow). 
 
Case Report Forms (CRFs) will be completed by the investigator and/or his/her delegates 
within 1 working days of the study visit. All data from the examinations and investigations listed 
in section 7.4 will be transferred to media provided by the sponsor and collected at the time of 
CRF collection.  
 
The sponsor will perform interim monitoring. The sponsor will schedule interim monitoring visits 
with advance notice and confirm the scheduling of the visit with the study site. The sponsor 
representative should meet with the investigator at each monitoring visit.  
 
The investigator(s) / institution(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents. Trial participants 
are informed of this during the informed consent discussion.  Participants will consent to 
provide access to their medical notes. 
 
The sponsor representative shall perform the following activities at each monitoring visit; 
 
• 10% of source verification 
• Essential document review 
• Deviation review 
• Adverse event review 
 
At the conclusion of the monitoring visit, the sponsor representative shall write a monitoring 
report detailing the activities performed during the visit with recommendations for action items 
and study site action. A follow-up letter to the study site detailing these recommendations and 
actions will be sent to the investigator.  
 
13.1 Confidentiality 
 
All data will be handled in accordance with the UK Data Protection Act 1998. The CRFs will not bear 
the subject’s name or other personal identifiable data. The subject’s initials, date of birth and trial 
identification number, will be used for identification. Subjects will be assigned a trial identification 
number by the study site sequentially starting with 1 upon enrolment into the study. The study site will 
maintain a master Subject Identification Log.  
 
13.2 Record keeping and archiving 
 
Archiving will be authorised by the Sponsor following submission of the end of study report. Chief 
Investigators are responsible for the secure archiving of essential trial documents as per their trust 

 
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policy. All essential documents will be archived for at least 5 years after completion of trial. Destruction 
of essential documents will require authorisation from the Sponsor.   
 
14 Adverse events, adverse device effects and device deficiencies 
14.1 Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. 
Note 1: This definition includes events related to the investigational medical device 
or the comparator 
Note 2: This definition includes events related to the procedures involved 
Note 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices 
Adverse Device Effect 
(ADE) 
Adverse Event related to the use of an investigational device.  
Note 1: This definition includes AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational device 
Note 2: This definition includes any event resulting from use error or from 
intentional misuse of the investigational medical device 
Serious Adverse Event 
(SAE) 
Any adverse event that: 
• 
Led to death, 
• 
Led to serious deterioration in the health of the subject, that either resulted in  
• a life-threatening illness or injury, or 
• a permanent impairment of a body structure or a body function, or 
• in-patient or prolonged hospitalisation, or 
• medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function, 
• 
Led to foetal distress, foetal death or a congenital anomaly or birth defect 
Note 1: Planned hospitalisation for a pre-existing condition, or a procedure required 
by the CIP, without serious deterioration in health is not considered a SAE.  
Serious Adverse Device 
Effect (SADE) 
An ADE that has resulted in any of the consequences characteristic of an SAE 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
An SADE which by its nature, incidence, severity or outcome has not been identified 
in the current version of the risk analysis report.  
Device Deficiency (DD) 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. 
Note 1: this includes malfunctions, use errors, and inadequate labelling 
 
An adverse event does not include: 
• 
Medical or surgical procedures; the condition that leads to the procedure is an adverse event. 
• 
Pre-existing disease, conditions, or laboratory abnormalities present at the start of the study that do not 

 
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worsen in frequency or intensity. 
• 
The disease being studied or signs/symptoms associated with the disease unless more severe than 
expected for the subject’s condition. 
14.2 Safety Reporting requirements and timelines 
 
Term 
Reporter 
Reported to 
Reporting Timeline from 
awareness of the event 
Adverse Event (AE) 
Investigator 
Sponsor 
As agreed with sponsor 
Adverse Device Effect 
(ADE) 
Investigator 
Sponsor/Manufacturer 
As agreed with sponsor 
Serious Adverse Event 
(SAE)/ Serious Adverse 
Device Effect (SADE) 
Investigator 
Sponsor 
Immediately, no more than 24hrs 
of becoming aware of the event   
Investigator/Sp
onsor 
MHRA1 
 within 2 calendar days of 
becoming aware of the event. 
Updates within 7 calendar day.  
Investigator/Sp
onsor 
MHRA Adverse Incident 
Centre 
On CE marked devices 
 
1 SAEs indicating immediate risk of death, serious injury or serious illness and that require prompt remedial action for other 
patients/subjects, users or other persons or a new finding to it 

 
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Term 
Reporter 
Reported to 
Reporting Timeline from awareness 
of the event 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
Investigator 
 
Sponsor 
 
Immediately, no more than 24 
hours 
CI/Sponsor 
MHRA/REC 
Within 15 calendar days of the CI 
becoming aware of the event 
Urgent Safety 
Measures (USM) 
CI/Sponsor 
REC 
(i) 
Immediately-By telephone 
(ii) 
Within 3 days-Notice in 
writing setting out reasons 
for the USM and plan for 
further action 
Device Deficiency (DD) 
Investigator 
Sponsor 
 
Immediately, no more than 24 
hours of becoming aware of the 
event 
 
Sponsor 
 
NCA 
7 calendar days 
 
Only reportable if the event may 
have led to an SAE if; 
• 
suitable action had not 
taken 
• 
intervention had not been 
made 
• 
if circumstances had been 
less fortunate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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14.3 Assessments of adverse events 
 
Each adverse event will be assessed for the following criteria: 
14.3.1 Severity  
Category 
Definition 
Mild 
The adverse event does not interfere with the subjects daily routine, and does 
not require intervention; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the subjects routine, or 
requires intervention, but is not damaging to health; it causes moderate 
discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is clearly 
damaging to health 
Note: A severity rating of severe does not necessarily categorise the event as 
an SAE. 
14.3.2 Seriousness 
Seriousness as defined for an SAE in section 14.1.  
14.3.3 Causality 
The assessment of relationship of adverse events to the study procedure and the investigational device will be a 
clinical decision based on all available information at the time of the completion of the case report form. The 
following categories will be used to define the causality of the adverse event: 
 
Category 
Definition 
Yes 
There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the event 
occurred within a reasonable time after procedure). However, the influence of 
other factors may have contributed to the event (e.g. the patient’s clinical 
condition, other concomitant events). 
No 
There is no evidence of any causal relationship. 
 
14.3.4 Expectedness 
 
Category 
Definition 
Expected 
An adverse event that is consistent with the information about the device 
listed in the Investigator Brochure or clearly defined in this CIP. 
Unexpected 
An adverse event that is not consistent with the information about the device 
listed in the Investigator Brochure  
 
The reference document to be used to assess expectedness against the intervention is the IB. The CIP will be 
used as the reference document to assess disease related and/or procedural expected events.  

 
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14.4 
Procedures for recording and reporting Adverse Events and Device Deficiencies 
14.4.1 Investigator responsibilities:  
All AEs and SAEs will be recorded in the medical records and CRF following consent. 
 
All SAEs will need to be reported to the sponsor on a SAE form unless stated in the CIP that some expected SAEs 
will not be reported to the sponsor, with a justification as to why they will not be reported.   
 
For patients on the control arm of a trial, SAEs may not have to be reported to the sponsor but will be recorded 
in the CRF and medical records. 
 
The Chief or Principal Investigator will complete the sponsor’s serious adverse event form and the form will be 
emailed to the sponsor R&D@gstt.nhs.uk immediately (or within 24 hours but certainly no later than 24 hours) 
of his / her becoming aware of the event. The Chief or Principal Investigator will respond to any SAE queries 
raised by the sponsor as soon as possible 
 
You may choose not to report EXPECTED SAEs to the sponsor for example if they are expected to occur on a 
regular basis and offer no further new information to your safety profile. These events must continue to be 
recorded in the source data and CRF, however you may state that you will not complete an SAE form and 
forward it to the sponsor.  
 
All deaths will be reported to the sponsor irrespective of whether the death is related to disease progression, 
the device, or an unrelated event. These reports will be provided immediately (or within 24hours) upon 
notification.  
 
The investigator shall keep detailed records of all adverse events and device deficiencies relating to the clinical 
trial which are reported to them by trial participants or users. The investigator shall document all relevant 
information on sponsor provided AE logs, SAE forms and DD forms.  
 
All SAEs, SADEs and USADEs should be reported to R&D@gstt.nhs.uk  
 
14.5 Reporting of all Adverse Events and Device Deficiencies: Investigator and Sponsor 
responsibilities 
 
Investigator responsibilities shall be as per section 14.4. The sponsor shall keep detailed records of all adverse 
events and device deficiencies relating to the clinical trial which are reported to them by the trial investigators. 
The sponsor shall ensure that all relevant information about a reportable event which occurs during the course 
of this clinical trial in the United Kingdom is reported as soon as possible to the MHRA, and the relevant ethics 
committees per their reporting requirements and according to the timelines in section 14.2. Any additional 
relevant information should be sent within the same time frame as the initial report. The Sponsor is responsible 
for informing the appropriate regulatory authorities, ethics committees and other investigators of any 
reportable events that have occurred with the study device in any clinical investigation according to the 
guidelines set forth by either the REC of record or regulatory authority in the country where the clinical 
investigation is taking place.  

 
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14.5.1 Annual Safety Reports 
There is no requirement for an additional Annual Safety Report to the REC or MHRA.  
14.5.2 Progress reports 
Progress reports will be submitted to the REC as per the REC requirements. The chief investigator will prepare 
the progress reports. 
 
14.6 Foreseeable adverse events and anticipated adverse device effects 
 
Transcutaneous electrical neuro-stimulation (TENS) has been used for many years and its effects are 
well established. Potential adverse events could include: 
 
• skin irritation 
• pain 
However, having tested this method over >10 years, including a previous randomised controlled trial 
(TESLA trial, published 2016 in THORAX) we have not experienced any severe adverse events. TENS 
machines are considered to be safe in use for labour related pain in pregnant women. 
15 Vulnerable population 
 
No vulnerable population will be selected for recruitment into this trial. 
16 Suspension or premature termination of the clinical investigation 
 
Each participant has the right to withdraw from the study at any time without providing a reason.  In 
addition, the investigator may discontinue the study at any time if considered necessary for one of the 
following reasons:  
• Ineligibility (either arising during the study or retrospectively), 
• Disease progression which requires discontinuation of the study or inability to continue to 
comply with study procedures, 
• Consent withdrawn, 
• Lost to follow up. 
• The reason for withdrawal will be recorded, including ‘no reason given’, in the case report forms 
(CRF).   
Premature termination of the clinical investigation will be reported to the relevant authorities. 
 
17 Publication policy 
 
The data used from the study will be published in an agreed international and peer-reviewed journal by 
the research team. The data may also be presented at relevant conferences in poster or spoken form as 
agreed. 
 

 
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Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-
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Steier J, Martin A, Harris J, Jarrold I, Pugh D, Williams A. Predicted relative prevalence estimates for 
obstructive sleep apnoea and the associated healthcare provision. Thorax. 2014;69(4):390-2. 
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Steier J, Seymour J, Rafferty GF, Jolley CJ, Solomon E, Luo YM, et al. Continuous transcutaneous 
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Pengo MF, Xiao S, Ratneswaran C, Reed K, Shah N, Chen T, et al. Randomised sham-controlled trial 
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Pengo MF, Steier J. Emerging technology: electrical stimulation in obstructive sleep apnoea. J 
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Eastwood PR, Barnes M, Walsh JH, Maddison KJ, Hee G, Schwartz AR, et al. Treating obstructive 
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Schwartz AR, Barnes M, Hillman D, Malhotra A, Kezirian E, Smith PL, et al. Acute upper airway 
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