SLEEPINESS - a Search for a Biomarker of Excessive Daytime Sleepiness in Severe Obstructive Sleep Apnoea - An Explorative Study

2.1 Background Sleep quality and quantity is essential for a healthy life. One prominent spoiler of good sleep quality is sleep fragmentation duo to sleep disordered breathing like obstructive sleep apnoea (OSA). A recent global estimation of OSA prevalence estimated that close to 1 billion people suffer from OSA. With a global population of advancing age and increasing obesity the global OSA prevalence seems at a rise.

The health-related consequences of OSA are many; Surge towards metabolic syndrome and an increased cardiovascular risk is well established within the scientific literature. But very invalidating is the inability to obtain restorative sleep through the night and its daytime fellow excessive daytime sleepiness (EDS) which is a key feature for some OSA patient. This reduces quality of life, work ability and general cognitive function as well as driving performance. Furthermore EDS has been is linked to increased comorbidity and mortality.

The American Academy of Sleep Medicine (AASM) defines EDS as "the inability to maintain wakefulness and alertness during the major waking episodes of the day, with sleep occurring unintentionally or at inappropriate times almost daily for at least three months"

3 Study design - overview 3.1 Description of study design This study is an exploratory study in severe OSA patients with EDS defined as an ESS \> 10 to record ultra-long-term EEG data with a subcutaneous EEG electrode 6 weeks prior to starting CPAP treatment and 6 weeks after initiation of CPAP treatment. The scope is to detect and quantify episodes of sleep phenomena during normal daytime and study CPAP related sleep rehabilitation.

The hypothesis is that the recordings will show episodes of daytime lapses into sleep both registered by the subject but also episodes of EEG recordings with sleep phenomena that will not be registered by the subject. We hypothesise that CPAP treatment will decrease the quantity of these events in a dose dependant manner. Can this be used as a biomarker for EDS in OSA patients? Is this biomarker stable for patients who do not experience a reduction in ESS when they start CPAP? Will the reduction in EEG recorded sleep phenomenons follow a reduction in other sleepiness scores or sleepiness related cognitive performance? The study period will be running over a period of approximately 4 months from inclusion to completion of the study. The subject enrolled will follow the ordinary patient flow for new referrals within the sleep clinic. The participation in the study will not postpone the timeframe within the OSA patient normally starts CPAP treatment.

Subjects will be recruited after a new referral to the sleep clinic with a diagnosis of OSA and ESS \> 10 and screened according to criteria of inclusion and exclusion. Eligible subjects will be enrolled and will start CPAP treatment within the ordinary waiting time to start OSA treatment. Up to 25 subjects are planned to be enrolled to ensure 15 subjects completing the study.

The subjects will start the study by a full PSG test followed by a MSLT. If the result of these test is in conflict with the criteria of inclusion and exclusion the subject will be excluded from the further study.

The subjects will have the UNEEG™ SubQ implanted (the implant) (see "24-7 EEG™ SubQ") and after approximately 10 days of healing, the study subjects will start wearing the 24/7 EEG™ SubQ as much as possible the following 12 weeks. Two secondary PSG will be performed after implantation. The first prior to OSA treatment initiation and the second after treatment initiation.

Sleep diary, subjective sleepiness scores and cognitive test During the study period the subjects will be asked to complete a sleep diary with registration of episodes of daytime napping (intended and unintended).

Subjects will be asked to fill out subjective scores of sleepiness (e.g. Epworth and Karolinska sleepiness scale) on a daily basis during the study period as well as completing a simple cognition test on a tablet or telephone such as a psychomotor vigilance task test (PVT) lasting 3-10 minutes.

Subjects will be invited to participate in scientific semi-structured interviews focusing on the everyday life burden of chronic sleepiness in relation to obstructive sleep apnea and the treatment related rehabilitation from chronic sleepiness.

This study will be conducted in accordance with this investigational plan, ethics committee requirements, the Declaration of Helsinki and applicable local governmental regulations.

5.5 Withdrawal criteria The subject may withdraw at will at any time without explanation. The subjects may be withdrawn from the study at the discretion of the investigator due to a safety concern or if judged non-compliant with the study procedures.

Subjects must be withdrawn from the study for any of the following reasons:

1. Included in the study in violation with any of the inclusion and/or exclusion criteria. 2. The subjects may be withdrawn from the study at the discretion of the investigator due to a safety concern or if judged non-compliant with the study procedures.

Withdrawal will not impact any treatment or follow-up of the subject. Although a subject is not obliged to give his/her reason(s) for withdrawal, the investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.

6 Methods and assessments

This clinical trial will consist of 7 visits from inclusion to completion. The visits are labeled as the following and the specific study activities and visits will be described in details below.

1. Inclusion 2. Pre-PSG and MSLT 3. Implantation 4. Start-up 5. PSG 6. 6 week recording, START CPAP 7. PSG 8. 12 weeks recording and device explantation 9. Follow-up, end of study This clinical trial will take place at Zealand University Hospital Department of Otorhinolaryngology and Maxillofacial Surgery (Køge) Department of Neurology, Roskilde All activities will be under the responsibility of the principal investigator.

During all study related activities the subjects will be insured by the patient insurance of Zealand University Hospital (Patienterstatningen).

Patient related information described in the following will be obtained by medical interviewing and will be confirmed for data source identification reasons by a look up in the subject's patient file.

6.1 Description of study activities and procedures

6.1.10 EEG recording device for ultra-long-term EEG recordings The ultra-long-term (\>2 weeks) EEG recordings will be made using the 24/7 EEG™ SubQ, a CE approved device manufactured by UNEEG™ Medical A/S, Nymøllevej 6, 3540 Lynge, Denmark.

The electrode will be implanted behind the ear with the electrode positioned over the temporal lobe. The side is chosen at the one that the patient most often do not sleep on. The subjects will be instructed in mounting and using of 24/7 EEG™ SubQ (according to the instruction for use) every night during sleep in the study period. The subjects will asked to create an event by double-tapping the power button on the logger twice when they intentionalley take a nap. The subjects will asked to create an event by double-tapping the power once when the recognice they wake up from an unintended nap.

The implantation and explanation of the device, postoperative assessment and suture removal will take place at the Department of Otorhinolaryngology and Maxillofacial Surgery (Køge).

6.1.1 PSG and MSLT The PSG will be mounted by trained personnel on a study site and performed according to the AASM criteria for PSG mock-up. The PSG night recordings will be made in an outpatient setting where the subject sleep in their own home. The day after the subjects will meet on site for the MSLT. The MSLT study protocol will follow the AASM guideline. Thereafter the PSG equipment will be demounted. The PSG/MSLT recordings will be performed with CE approved equipment. The PSG and MSLT data analysis will be conducted by a trained sleep technician according to the AASM criteria and evaluated by a physician with expertise in sleep medicine. The clinically relevant results of the PSG and MSLT will be given to the subject by a medical doctor at the following in-site visit. If the results of the PSG is in violation with the inclusion criteria the subject must be excluded from the study before implantation of the subcutaneous EEG devise.

6.1.2 Sleep diary The study subjects should fill out the sleep diary every evening prior to going to bed focusing on episodes during the day with all experienced episodes of daytime sleeping or dozing off. The study subjects will be asked to mark every episode as either intentional napping (I) or unintentional napping (U) in the sleep diary.

6.1.3 Photo of implant area Photos of the area where the implant is located will be taken at visit 3 and 6. The photos will be taken at different angles and distances in combination with one or more fiducial markers. The photos will be taken such that facial recognition is not possible.

6.1.4 Patient-reported outcome measures and Cognitive test During the study period the study subjects will be asked to perform Patient-reported outcome measures (PROM) evaluating sleepiness symptoms on a daily basis(e.g. 08:00; 11:00, 15:00, 19:00, 22:00). Measures like the Epworth Sleepiness Scale (ESS), a 4-point likert scale where the subject rates the likelihood of them dozing of or falling asleep and the Karolinska Sleepiness Scale (KSS), a 9 point scale raging from 1 "extremely alert" to 9 "very sleepy, great effort to keep alert, fighting sleep" will be used. In relation to the sleepiness PROM the subjects will be asked to perform a simple cognitive test measuring cognition processes like reaction time and alertness. The PROM and the cognitive test takes approximately 5-10 minutes to perform. The data collection for these data will be performed on a tablet or smartphone and supported by a data collection service like www.carp.cachet.dk.

CARP Cognition Package - Copenhagen Research Platform (CARP) (cachet.dk) Here the relevant cognitive test can also be found called "Reaction Time".

6.1.5 Actigraphy During the study period the study subjects will be asked to wear an actigraphy unit measuring gross motor activity. The unit will be a wristwatch-like device for monitoring physical rest/activity.

6.1.6 Interview During the study period the study subjects will be invited to participate in interviews focusing on sleepiness symptoms in relation to everyday life before and after treatment initiation.

6.2 Other baseline assessments 6.2.1 Demographics

The following demographics will be recorded at visit 1 and recorded in the case report form CRF: * Date of birth * Sex * Height * Weight * Profession * Preferred sleeping position * Preferred sleep duration and time of the day

6.3 Description of study visits Recruitment and information visit New referrals to the sleep clinic that is fund eligible to the study inclusion criteria (age \> 18y, severe OSA and ESS \> 10) will be contacted and asked permission to send study information. Patients will be asked to contact the clinic if they find the study interesting and would like to hear more. Interested patient will be invited to an information visit and will be informed about the opportunity to bring a close relative.

At the individual information visit the information will be given in a simple language and by an undisturbed medical doctor (field-investigator). The oral information will be according to the information given in the "Deltagerinformation\_SLEEPINESS" and will take place in a private office. The subjects will be given the opportunity to ask questions regarding the study. Subjects will be given the informed consent form. Subjects will be given a minimum of 3 days reflection time to consider participation. If subjects decide to participate they will sign and

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