Efficacy of a Novel MAD in OSA

The MAD in study features a novel monobloc device including a tongue retainer, a suction cavity to push the tongue down onto the mouth floor, thus preventing its lifting towards the hard palate, which improves retro lingual dimensions. Its design requires the presence of only four occlusal points, allowing for a direct anchorage onto the mandibular bone, thus reducing the risk for occlusal changes, tooth loosening and the development of an anterior cross bite, which represent the major long-term adverse effects of oral appliances.

MADs, as well as CPAP, represent the first choice treatment for mild-to-moderate OSAH. In several countries, as well as in Switzerland, health insurances cover the costs of MAD production in patients with mild-to-moderate OSAH or in severe OSAH patients who did not tolerate CPAP previously (as specified in the federal Mittel und Gegenständeliste (MiGeL), Position L 23.26.01.00.1).

Three main novelties justify the experimentation of this new MAD: a monobloc design, the combination with a tongue retainer and a potential future lower cost of production compared to the devices available on the market today.

The device will be designed, manufactured and used under the conditions and for the purposes intended. Thus, it will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons. Any risks, which may be associated with its intended use, constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety.

The administration of the device will proceed according to both the essential requirements of the European directives concerning medical devices (Annex I and X of directive 93/42/EEC) and the clinical practice standards and guidelines provided by the AASM and AASDM. These include the obtainment of alginate impression of both jaws and an interocclusal record, with the mandible at 50% of its maximal protrusive position. Since no single standard titration protocol is available, progressive mandibular advancement will be conducted according to the best available medical standard.

Monocentric, prospective, open-label, interventional, exploratory pilot study.

Patients aged 18-65 years who received a video-polysomnographic diagnosis of mild-to-moderate OSA (AHI between 5/h and 30/h) within three months will be screened and recruited at the Sleep and Epilepsy Center in Lugano. An ENT evaluation including a Müller maneuver and a calculation of the Mallampati Score must have been performed in order to rule out significant ENT comorbidities (See Section 7.1 Eligibility Criteria).

At Visit 1 (week 1: 7+3 days), performed by either Prof. Manconi or Dr. Chiaro, inclusion and exclusion criteria will be checked. Eligible patients will be included in the study.

Proof that a video-polysomnographic diagnosis of mild-to-moderate OSA was reached and that significant oropharyngeal disease was ruled out by means of fibro endoscopic evaluation, performed by a trained Ear, Nose \& Throat (ENT) specialist in the last three months will be obtained.

During the visit, overall sleep quality and excessive daytime sleepiness will be evaluated by means of the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) (See Appendix 2).

At any time within Visit 1 and 2, (weeks 1 to 2, 14+3 days), the patient will undergo a head-CT scan. Patients will be scheduled for a CT scan of the oropharynx region at the Radiology Department of the Ospedale Civico of Lugano. CT scans (CT Siemens SOMATOM Definition Edge).will be performed in awake supine patients with their heads in a neutral position and will be repeated in the same session with and without the MAD. Subsequently, post-processing measurements of the upper airway will be calculated with a dedicated CT workstation.

At Visit 2 (week 2: 7+3 days), subjects will undergo odontological evaluation, performed by Dr Ciocco. This includes a first general clinical evaluation, the obtainment of alginate dental impressions (Blueprint creme, dust-free alginate impression material, manufactured by Dentsply® DeTrey GmbH 78467 Konstanz, Germany) with dental impression trays, the calculation of the dental facebow with an occlusal fork and of the bite with dental wax casts.

Weeks 3 to 4 (14+3 days) are the timeframe allotted to medical device production, which will be carried out by Mr Frigerio. Dental impressions will be modelled into chalk casts. Both casts will be then fixed on a dental articulator, so that different orthodontic measures can be calculated and the BVL will be produced out of resin (Palapress, powder+ liquid, Heraeus Kulzer GmbH, Grüner Weg 11, D-63450 Hanau) directly on the chalk casts, obtained from the patient's dental impression.

Once roughly finished, the two splints will be held together by means of an integrated advancement system composed by two stainless steel positioning holding screws (one left, one right) two serrated housing nuts (one left, one right), both produced by Leone SPA, Sesto Fiorentino, Italy, as well as two Dolder® system bars (one male, one female, two per side), produced by Cendres+Metaux SA, Biel/Bienne, Switzerland. This coupling system enables the horizontal (forwards) sliding of the lower splint on the upper splint, thus allowing mandibular advancement. The metal and resin parts are glued together with a primer produced by SHOFU Dental GmbH, Ratingen, Germany.

The BVL also features a tongue retainer, which will be completed by small holes on its anterior part in order to allow enhanced breathing and saliva excretion.

The BVL will then be finished, perfected and polished. A unique identification number and the BVL trademark will be printed on the BVL.

See Appendix 1 for technical and commercial details regarding used materials and their related available safety data.

At visit 3 (week 5-6: 7+3 days): the BVL will be then administered at 50% of mandibular advancement by Dr Ciocco, based on calculations of the patient's maximal mandibular protrusion. Immediate tolerability and side effects (i.e: myofacial pain, temporo-mandibular tension) will be checked by means of a semi-structured self-administered questionnaire (See Appendix 3) and duly noted.

If the patient experiences important side effects at this stage, he will discontinue the study.

At Visit 4 (week 7: 7+3 days), Dr Ciocco will perform further mandibular advancement to 60% of the calculated maximal mandibular protrusion by activating the integrated advancement system. Tolerability, side effects and compliance will be assessed by means of a semi-structured self-administered questionnaire (See Appendix 3) and duly noted.

At Visit 5 (week 8: 7+3 days), Dr Ciocco will perform further mandibular advancement to 70% of the calculated maximal mandibular protrusion by again activating the integrated advancement system. Tolerability, side effects and compliance will be assessed by means of a semi-structured self-administered questionnaire (See Appendix 3) and duly noted.

At Visit 6 (week 9 to 10, 14+3 days), the patient will undergo VPSG recording and a head-CT scan. Patients will be scheduled for a CT scan of the oropharynx region at the Radiology Department of the Ospedale Civico of Lugano. CT scans (CT Siemens SOMATOM Definition Edge).will be performed in awake supine patients with their heads in a neutral position and will be repeated in the same session with and without the MAD. Subsequently, post-processing measurements of the upper airway will be calculated with a dedicated CT workstation. At this point, tolerability, side effects and compliance will be assessed by means of a semi-structured self-administered questionnaire (See Appendix XXX) and duly noted.

If, at any point from MAD administration (Visit 3) to achievement of 70% mandibular protrusion (Visit 5), any serious side effect occurs, the patient will stop mandibular advancement and return to the previous level of mandibular protrusion, at which no side effects were experienced. He or she will then proceed directly to VPSG and Head-CT and then leave the study.

At the final evaluation (Visit 7, week 11), the patient will meet with the investigator again. PSQI and ESS will be administered to assess overall sleep quality and daytime sleepiness. Overall tolerability, side effects and compliance will be assessed by means of a semi-structured self-administered questionnaire (See Appendix 3) and duly noted. The custom-made MAD will be left with the patient free of charge.

We plan to include 20 study subjects. This study does not comply study groups, comparators or placebo. All subjects will receive treatment with MAD. For each patient, as described above, we plan a study duration of a maximum of 11 weeks. A shorter duration is foreseen for subjects who cannot reach a 70% mandibular advancement because of TMJ tension or for dropouts.