In this prospective randomized cross-over trial, 3 different titration procedures will be compared:

1. titration of the mandibular advancement device (MAD) in the home setting based on both the physical limits of the patient's mandibular protrusion and the resolution of subjective complaints, as currently often used in routine clinical practice;
2. an overnight titration PSG using the remotely controlled mandibular positioner (RCMP) with stepwise mandibular protrusion until respiratory events are reduced and
3. incremental protrusion of the mandible during DISE using the RCMP until upper airway collapse at all collapsible levels is eliminated.

The aim of this study is to prospectively compare the target protrusion, as well as the treatment outcome in terms of treatment efficacy, of the 3 different titration protocols.

After inclusion, each patient will undergo three different titration procedures of the protrusive mandibular position or target protrusion for the MAD treatment, in a randomized order: subjective titration, titration during DISE, titration during PSG.

1. Subjective titration:

   After fitting the MAD, there is a 1-month period during which the patients get used to wearing the device and titrate the MAD based on improvement of subjective complaints. The actual mechanism of titration will be individually trained with each patient.

2. Titration during drug-induced sleep endoscopy (DISE) - DISE-assisted titration:

   The DISE will be performed by an ear-nose-throat (ENT)surgeon experienced in DISE in order to visualize the dose-dependent effect of the mandibular protrusion on the upper airway collapsibility. The DISE is performed in a semi-dark and silent operating theatre with the patient lying in supine position. The different collapsible levels of the upper airway that can be investigated during DISE are the palate (velopharynx), the oropharynx, the tongue base, the hypopharynx and the epiglottis. The degree of collapse at each level is reported as none, partial or complete. The pattern of the pharyngeal collapse during the obstructive events are classified as concentric, anteroposterior and/or laterolateral. Upon connection of the RCMP to a dedicated laptop, calibration of the actual versus the software-guided protrusion is verified using the RCMP ruler and proprietary developed software, to rule out day-to-day variation caused by environmental factors such as room temperature or humidity. This procedure ensures the mandibular displacement to be read out correctly from the ruler present at the upper tray fitted over the tooth arcs. After the calibration, the RCMP-trays are fitted in edge-to-edge position to avoid excessive muscle tension. A flexible fibreoptic nasendoscope will be introduced by the ENT surgeon in the awake patient to evaluate the awake upper airway state. Thereafter, sedation will be induced by intravenous administration of midazolam (bolus injection of 1.0 to 2.0 mg) and propofol using a target-controlled infusion system (2.0 to 3.0 μg/mL). The transition to unconsciousness similar to stage 2 sleep is aimed at and examined by assuring absence of patients' eyelash reflex after stimulation by means of a gentle brush. Findings are noted using a uniform upper airway scoring system evaluating level of snoring, presence of apneas and degree of oxygen saturation, degree and configuration of obstruction(s) and the level of upper airway collapse. When target sedation is reached, examined by assuring absence of patients' eyelash reflex after stimulation by means of a gentle brush, the RCMP will be remotely protruded in increments of 2 mm in response to the visualized upper airway collapse at the different collapsible levels until a stable upper airway together with absence of desaturations and snoring is reached. If a stable upper airway in absence of snoring is noted, oxygen desaturation and apneas are evaluated, and the mandible will be remotely retruded for 1 mm. If the upper airway remains stable, further so-called 'reversed titration' will continue. This approach will be repeated until the effective target protrusive position can be determined, defined as the minimal mandibular threshold position corresponding to a stable upper airway in the absence of snoring, oxygen desaturation and apneas. When a stable upper airway is reached, the titration procedure will be continued in 0.5 mm steps, to be as precise as possible. After every protrusive or retrusive movement the RCMP protrusion will be checked on the RCMP ruler versus the protrusion measured by the software, assuring correct positioning of the mandible during the upper airway evaluation.

3. Titration during polysomnography (PSG):

At the start of the PSG, the participant's dental trays are attached to the mandibular positioner of the RCMP device, and the positioner is calibrated to the PSG system using the device software. The titration procedure that will be used in this study is previously described. Once asleep, the patient's mandible will be protruded remotely in 0.5 mm steps in response to evidence of apneas and/or hypopneas. If an EEG arousal occurs, no further advancement will be attempted until stable sleep resumes. Stepwise mandibular protrusion will continue until respiratory events are reduced to normal in all sleep stages, and in both supine and lateral position, or until maximal protrusion is reached. Afterwards, an independent researcher will score the PSG together with body position and mandibular position signals and will predict success or failure with MAD therapy based on the predetermined interpretative rules. The patient needs to have rapid eye movement (REM) sleep for ≥ 5 minutes in the supine position or in the lateral position, if REM in supine position was not observed. All REM cycles will be evaluated to identify a minimum 5 minutes' interval where ≤ 1 respiratory event occurred. If this is the case, the PSG will be scored as predicted MAD success for that protrusive position. If not, the PSG will be judged to predict therapeutic failure. The predicted effective target protrusive position is the minimum protrusive position that is associated with ≤ 1 respiratory event per 5-minutes REM interval. If the PSG is scored as predicted success, the predicted effective target protrusive position is provided to the dentist to start MAD therapy in that position. If the PSG is scored as predicted failure, an alternative position equal to 75% of maximal protrusion is provided.

A polygraphic evaluation of the MAD efficacy will be planned after each titration procedure. Furthermore, the patients will be asked to fill out questionnaires regarding snoring, daytime sleepiness (Epworth Sleepiness Scale, ESS), fatigue (Checklist Individual Strength, CIS20R) and side effects of the MAD treatment.

A wash-out period of one week is inserted between the polygraphic evaluation of the protrusive position obtained during a titration procedure and the start of the next titration procedure.

Inclusion Criteria:

• Patients with moderate to severe obstructive sleep apnea (OSA) (obstructive AHI (oAHI) ≥ 15/h)
• BMI < 30 kg/m²
• Age > 18 year
• PSG < 2 years old with stable body weight (+/- 5 kg), no ENT surgery since most recent PSG and stable clinical condition
• Normal clinical and radiological (incl. OPG), periodontal en temporomandibular joint examination
• Subject is capable of giving informed consent
• No documented abuses (alcohol, drugs, …)

Exclusion Criteria:

• Edentulous patients
• Insufficient teeth to support the mandibular advancement device
• Active periodontal problems including tooth mobility
• Active temporomandibular joint dysfunction
• Limited maximum protrusive capacity (<6 mm)
• Limited vertical opening (<25 mm)
• Enlarged palatine tonsils (Grade IV tonsils)
• Degenerative neuromuscular disorders
• Pregnancy or willing to become pregnant