Aim, design and setting
This clinical trial proposes a prospective, randomized, crossover trial in patients diagnosed with OSA and referred for MAD treatment. Patients will be recruited from the Multidisciplinary Apnea and Snoring Clinic of the Antwerp University Hospital (Edegem, Belgium).
This study aims to compare the optimal mandibular protrusion values obtained during three titration procedures in each individual patient performed in randomized order: 1) titration of the MAD in the home setting during 1 month based on both the physical limits of the patient’s mandibular protrusion and the resolution of subjective complaints, such as socially disturbing snoring and daytime somnolence, as currently used in routine clinical practice; 2) an overnight titration PSG using the RCMP with stepwise mandibular protrusion until respiratory events are reduced and 3) titration of the mandible during DISE using the RCMP until upper airway collapse at all collapsible levels is eliminated. The DISE-assisted titration will take on average 30 minutes with a maximum duration of 45 minutes and will be carried out by an Ear, Nose, Throat (ENT) surgeon experienced in DISE assisted by a dental sleep professional. After each type of titration, PSG-guided or DISE-assisted, respectively and in randomized order, the patient will use the MAD for 1 month in the obtained protrusion relative to the respective method. The subjective titration will also be done during a 1-month period.
A follow-up sleep study will be performed after each procedure for the evaluation of the efficacy of the MAD in terms of reduction of AHI. A washout interval of 1 week between the different test conditions is integrated in the protocol. The flowchart of the protocol is shown in Figure 1 and Figure 2.
Participants
Patients diagnosed with moderate to severe OSA and referred to the special care dentistry unit for treatment with an MAD will be recruited for participation in this study and will be asked for informed consent prior to the start of the study. To ensure accurately diagnosed OSA, all patients will need an initial baseline PSG of maximally 2 years old prior to the effective start of treatment, and show stable body weight (± 5 kg) since that PSG. No ENT surgery may be performed in eligible patients since the diagnostic PSG. An ENT examination, a dental screening, and an appraisal of inclusion and exclusion criteria (see below) will be performed.
Inclusion criteria
- Patients with moderate to severe OSA (obstructive apnea/hypopnea index (oAHI) ≥15/h)
- Age > 18 years
- PSG < 2 years old with stable body weight (+/- 5 kg) and no ENT surgery since the diagnostic PSG. If body weight changed significantly or ENT surgery is performed, a new diagnostic PSG is required to confirm the diagnosis of moderate to severe OSA.
- Normal clinical and radiological (incl. orthopantogram X-ray), periodontal and temporomandibular joint examination
- Subject is capable of giving informed consent
- No documented abuses (alcohol, drugs, …)
Exclusion criteria
- Edentulous patients
- Insufficient teeth to support MAD
- Active periodontal problems including tooth mobility
- Active temporomandibular joint dysfunction
- Limited maximum protrusive capacity (<6 mm)
- Limited vertical opening (<25 mm)
- Enlarged palatine tonsils (Friedman grade IV tonsils)
- Degenerative neuromuscular disorders
- Pregnancy
Study protocol
After inclusion, each patient will undergo three different titration procedures of the protrusive mandibular position, in a randomized order: subjective titration, RCMP titration during DISE, RCMP titration during PSG (see Figure 1).
In our study, a commercially available RCMP (MATRx™, Zephyr Sleep Technologies Inc., Calgary, Canada) will be used[21]. The RCMP uses dental trays filled with high viscosity impression material that fit retentively over the teeth to allow for progressive titration of the mandible during sleep, without arousing the patient. It consists of a controller that receives commands from the device software and, in turn, activates a stepping motor attached to dental trays in the patient’s mouth (Figure 3). The positioner (50 g; 62 mm × 41 mm × 20 mm) has two movable rods that connect to brackets extending anteriorly from the dental trays. The upper rod is driven by an internal linear actuator and attaches to the upper bracket. The lower rod is driven by a manually adjustable screw and connects to the lower bracket[21]. Before the PSG-guided or DISE-assisted titration is planned, the dental sleep professional will fit upper and lower disposable dental impression trays that attach to the RCMP positioner. During that visit, the dentist will record the habitual bite position, maximum retrusion and maximum protrusion as voluntarily performed during wakefulness. These measurements will be used to set the individual’s mandibular range of motion for the RCMP studies.
Subjective titration
After fitting the MAD, there is a 1-month period during which patients titrate their MAD. Each patient will individually be instructed and trained to perform the actual titration of the MAD. In general, the degree of mandibular advancement is progressively increased until a significant improvement or resolution of symptoms occurs, or until the patient cannot tolerate any further advancement.
Titration during drug-induced sleep endoscopy (DISE) – DISE-assisted titration
The DISE will be performed by an 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[35].
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 (Figure 3). After the calibration, the RCMP-trays are fitted in edge-to-edge position to avoid excessive muscle tension. A flexible fiberoptic nasendoscope (Type ENF-GP, Olympus Europe GmbH, Hamburg, Germany) 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 mean effect site concentration). 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[36].
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 oxygen desaturations and snoring is reached.
If a stable upper airway without oxygen desaturation and snoring is noted, 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 fine-tuned in smaller steps (0.5 mm) 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 assessment.
If the DISE 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 DISE-assisted titration is inconclusive or scored as ‘predicted failure’, the MAD will be set at the most optimal protrusive position with the most open and stable upper airway following the medical doctor performing the DISE procedure. If the DISE procedure is inconclusive in the entire range of motion, the MAD will be set at 75% of maximal protrusion, in analogy with PSG-guided titration.
Titration during polysomnography (PSG) – PSG-guided titration
The mandibular protrusion titration PSG will be performed using the RCMP device, MATRx, during a standard type I full-night attended PSG. The PSG recordings and the scoring are performed using the AASM 2012 rules[8].
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 as explained above.
The titration procedure itself is previously described by Remmers et al[21]. Once in stage 2 sleep based on the PSG signals, the patient’s mandible will be protruded remotely in 0.5 mm steps in response to evidence of apneas and/or hypopneas. If an electroencephalographic (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, 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 described by Remmers et al.[21].
The patient should have 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 occurs. 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 sleep.
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. If the PSG-guided titration was scored as ‘inconclusive’ due to a lack of REM sleep, this will be incorporated in our database, but the MAD will be set at the most effective protrusive position found in non-REM sleep.
Sleep study
A level 1 sleep study will be planned at baseline and to assess the efficacy of the MAD treatment in the titrated positions. For the DISE-assisted and PSG-guided titration, the patients will use the MAD in the obtained protrusion during 1 month before the follow-up sleep study, while the subjective titration will be performed during a 1-month period directly followed by the follow-up sleep study (see also Figure 1).A wash-out period of at least one week is inserted between the polysomnographic evaluation of the protrusive position obtained during a titration procedure and the start of the next titration procedure.
The follow-up sleep study will be scored by an independent sleep technician that is blinded for the treatment phase.
The results of the different polysomnographic evaluations will be discussed with the patient by the multidisciplinary team, together with an interview about the patient’s experience about snoring and daytime sleepiness and possible side effects of MAD treatment.
Measurement of MAD adherence
A temperature-sensitive microsensor with on-chip integrated read-out electronics (Theramon®, Handels- und Entwicklungsgesellschaft, Handelsagentur Gschladt, Hargelsberg,Austria) will be embedded in the MAD at the upper right side. Objective compliance measurement is based on the assumption that the OA is worn when a temperature ≥35°C is recorded. At every follow-up visit, the objective MAD adherence will be collected.
Outcome measures
Primary outcome
The protrusive position that was predicted as the effective target protrusive position during each titration method (subjective titration, PSG-guided titration PSG and DISE-assisted titration) will be assessed and compared between the different titration methods.
Secondary outcomes
The efficacy of the MAD therapy will be assessed as a measure of treatment outcome by comparing the baseline AHI with the AHI under MAD therapy.
In addition, structured questionnaires to evaluate tolerance and side effects, subjective snoring, daytime sleepiness and fatigue will be completed by all patients at baseline and at follow-up evaluations.
The degree of daytime sleepiness will be assessed using the Epworth Sleepiness Scale (ESS)[37]. A standard 10-point visual analogue scale (VAS) for the scoring of snoring as assessed by the bed partner will be used only in patients who have a bed partner that is able to report the snoring intensity. This VAS is ranging from 0 to 10 with 0 equaling no snoring and 10 causing the bed partner to leave the room or sleep separately[38]. Heavy snoring will be defined as a VAS snoring index of at least 7. Fatigue severity will be measured by the Checklist Individual Strength (CIS20R)[36]. The CIS20R and more specific its subscale on fatigue is a standardized and validated questionnaire that consists of eight items scored on a seven-point Likert scale. The scores range from 8 (normal fatigue) to 56 (most severe fatigue). A score of 26 or lower indicates a normal energy level, scores between 27 to 35 indicate mild fatigue and a score of 36 or higher indicates severe fatigue.
For all secondary outcomes, non-inferiority of RCMP titration with PSG compared to RCMP titration with DISE will be assessed. Additionally, differences between subjective titration and both RCMP titration protocols will be investigated.
Statistics
Sample size calculation
The primary endpoint of this study protocol is to assess equivalence of the protrusive position obtained with the three titration protocols. We need 65 patients to have 80% power to show equivalence of two procedures with an equivalence margin of 1.6 and a standard deviation of 3.7. These numbers are based on the results of Civelek et al[12]. The significance level of 0.05 will be Bonferroni corrected to 0.0167, to account for comparing three titration protocols.
For every patient dropping out of the study before the first visit, an extra patient will be recruited. Based on previous studies, dropout rate is anticipated to be around 20%, so we expect to include 78 patients in total.
Statistical analyses
The primary end point and all continuous secondary end points will be analyzed using a linear mixed effects model with period, sequence and procedure as fixed effects, and patient nested within sequence as a random effect. For response rate, a logistic mixed effects model with the same specifications will be used. The response rate will be defined as a decrease in AHI of at least 50% compared to baseline or an AHI under treatment of < 15 events/hour. Posthoc comparisons will be made based on these models, correcting for multiple testing by means of Bonferroni-Holm stepdown correction.
Non-inferiority of PSG compared to DISE will be judged based on the confidence intervals obtained from the mixed effects models. When the lower limit of the confidence interval falls above the predefined non-inferiority margin, non-inferiority will be concluded. Non-inferiority margin for percent change in AHI from baseline will be set at 10%. For change in VAS for snoring, ESS, CIS20R and its fatigue subscale the margin is considered respectively 1, 2, 5 and 10 points. Additionally, differences between subjective titration and both RCMP titration protocols will be investigated for all the secondary endpoints.
If more than 20% of all information regarding one endpoint is missing, a sensitivity analysis will be conducted for this endpoint by using multiple imputation. Results of the original analysis will be interpreted in the light of these sensitivity analyses.
Randomization
This study design will lead to six different sequences of titration procedures (Table 1). The patients will be randomly allocated to one of the six possible sequences of titration procedures. To ensure that the groups are of approximately the same size, block randomisation will be used. The allocation sequence will be automatically generated and will be stratified by OSA severity (moderate/severe), gender and body mass index (BMI < 26 kg/m²; 26 ≤ BMI < 30 kg/m²; 30 kg/m² ≤ BMI).
Table 1: Overview of the six possible titration sequences in this study protocol.
Sequence 1
|
subjective titration
|
RCMP titration PSG
|
RCMP titration DISE
|
Sequence 2
|
subjective titration
|
RCMP titration DISE
|
RCMP titration PSG
|
Sequence 3
|
RCMP titration PSG
|
subjective titration
|
RCMP titration DISE
|
Sequence 4
|
RCMP titration PSG
|
RCMP titration DISE
|
subjective titration
|
Sequence 5
|
RCMP titration DISE
|
subjective titration
|
RCMP titration PSG
|
Sequence 6
|
RCMP titration DISE
|
RCMP titration PSG
|
subjective titration
|
RCMP: Remotely controlled mandibular positioner; PSG: type 1 polysomnography; DISE: drug-induced sleep endoscopy