Comparison of titrable thermoplastic versus custom-made mandibular advancement device for the treatment of obstructive sleep apnoea

Open ArchivePublished:August 04, 2017DOI:https://doi.org/10.1016/j.rmed.2017.08.004

      Highlights

      • The use custom-made devices is recommended for mandibular advancement therapy of OSA.
      • Custom-made devices are expensive and a delay is required to manufacture the device.
      • A titrable thermoplastic device was effective in reducing OSA severity and symptoms.
      • 6-month adherence was high despite more dental discomfort than with a custom-made device.
      • A trial with a titrable thermoplastic device could be of interest prior to custome-made device.

      Abstract

      Backgound and objectives

      The disadvantages of custom-made mandibular advancement devices (MAD) for obstructive sleep apnoea (OSA) therapy are the cost and delay required to manufacture the device. This study aimed to evaluate the efficacy of a titrable, thermoplastic MAD compared to a custom-made MAD for OSA therapy.

      Methods

      In this prospective nonrandomized study, 158 patients with OSA from two French sleep centers were treated for 6 months with a titrable thermoplastic MAD (n = 86) or a custom-made MAD (n = 72). The primary outcome was the change in sleep-disordered breathing (SDB) severity.

      Results

      After adjustment for baseline values, age, body mass index and study site, no significant intergroup differences were observed between thermoplastic and custom-made MAD for the outcome of apnoea, hypopnoea and oxygen desaturation indices. No between treatment differences were observed for the outcome of subjective sleepiness, symptoms of snoring and fatigue, depressive symptoms, and quality of life. Thermoplastic MAD therapy was associated with higher side effects scores for tooth pain (p < 0.0001) and self-reported occlusal changes (p = 0.0069). Mean (SD) reported compliance was lower in the thermoplastic MAD group than in the custom-made MAD group (6.4 [0.2] vs 7.1 [0.1] h/night; p = 0.035).

      Conclusions

      This study demonstrates the efficacy of a titrable thermoplastic MAD in reducing SDB and related symptoms in patients with mild to severe OSA. Reported compliance at 6 months was high despite more dental discomfort than with custom-made MAD.

      Keywords

      Abbreviations:

      AHI (apnoea-hypopnoea index), AI (apnoea index), BMI (body mass index), CPAP (continuous positive airway pressure), ESS (Epworth Sleepiness Scale), MAD (mandibular advancement device), ODI (oxygen desaturation index), SF36 (Outcomes Study 36-item Short-Form), SDB (sleep-disordered breathing), T90 (sleep time with SaO2 <90%), VAS (visual analogue scale (VAS))

      1. Introduction

      Obstructive sleep apnoea (OSA) is a highly prevalent disease [
      • Peppard P.E.
      • Young T.
      • Barnet J.H.
      • Palta M.
      • Hagen E.W.
      • Hla K.M.
      Increased prevalence of sleep-disordered breathing in adults.
      ] characterized by recurrent episodes of partial or complete obstruction of the upper airway during sleep. Continuous positive airway pressure (CPAP), being the first line therapy for moderate to severe OSA, improves daytime alertness, health-related quality of life (HRQL) and reduces blood pressure [
      • McDaid C.
      • Griffin S.
      • Weatherly H.
      • Durée K.
      • van der Burgt M.
      • van Hout S.
      • Akers J.
      • Davies R.J.O.
      • Sculpher M.
      • Westwood M.
      Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea-hypopnoea syndrome: a systematic review and economic analysis.
      ,
      • Bratton D.J.
      • Gaisl T.
      • Wons A.M.
      • Kohler M.
      CPAP vs mandibular advancement devices and blood pressure in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. Observational prospective cohort studies indicate that regular CPAP therapy is also associated with a lower risk of driving-related accidents and cardiovascular events [
      • Antonopoulos C.N.
      • Sergentanis T.N.
      • Daskalopoulou S.S.
      • Petridou E.T.
      Nasal continuous positive airway pressure (nCPAP) treatment for obstructive sleep apnea, road traffic accidents and driving simulator performance: a meta-analysis.
      ,
      • Sánchez-de-la-Torre M.
      • Campos-Rodriguez F.
      • Barbé F.
      Obstructive sleep apnoea and cardiovascular disease.
      ]. However, among OSA patients in whom CPAP is recommended, approximately 40% are at risk of non-adherence especially if they have mild to moderate OSA [
      • Gagnadoux F.
      • Le Vaillant M.
      • Goupil F.
      • Pigeanne T.
      • Chollet S.
      • Masson P.
      • Humeau M.-P.
      • Bizieux-Thaminy A.
      • Meslier N.
      IRSR sleep cohort group, Influence of marital status and employment status on long-term adherence with continuous positive airway pressure in sleep apnea patients.
      ]. Mandibular advancement devices (MAD) have emerged as the main therapeutic alternative for OSA. Despite the superior efficacy of CPAP in reducing sleep-disordered breathing (SDB), most randomized trials comparing MAD and CPAP in OSA have reported similar heath outcomes in terms of sleepiness, neurobehavioral functioning, quality of life and blood pressure [
      • Bratton D.J.
      • Gaisl T.
      • Wons A.M.
      • Kohler M.
      CPAP vs mandibular advancement devices and blood pressure in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ,
      • Bratton D.J.
      • Gaisl T.
      • Schlatzer C.
      • Kohler M.
      Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: a network meta-analysis.
      ,
      • Sharples L.D.
      • Clutterbuck-James A.L.
      • Glover M.J.
      • Bennett M.S.
      • Chadwick R.
      • Pittman M.A.
      • Quinnell T.G.
      Meta-analysis of randomised controlled trials of oral mandibular advancement devices and continuous positive airway pressure for obstructive sleep apnoea-hypopnoea.
      ,
      • Phillips C.L.
      • Grunstein R.R.
      • Darendeliler M.A.
      • Mihailidou A.S.
      • Srinivasan V.K.
      • Yee B.J.
      • Marks G.B.
      • Cistulli P.A.
      Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea: a randomized controlled trial.
      ,
      • Gagnadoux F.
      • Fleury B.
      • Vielle B.
      • Pételle B.
      • Meslier N.
      • N'Guyen X.L.
      • Trzepizur W.
      • Racineux J.L.
      Titrated mandibular advancement versus positive airway pressure for sleep apnoea.
      ]. When MAD therapy is prescribed, practice guidelines also suggest with a low quality of evidence to use a custom, titratable MAD over non-custom devices [
      • Ramar K.
      • Dort L.C.
      • Katz S.G.
      • Lettieri C.J.
      • Harrod C.G.
      • Thomas S.M.
      • Chervin R.D.
      Clinical practice guideline for the treatment of obstructive sleep apnea and snoring with oral appliance therapy: an update for 2015.
      ]. However, potential disadvantages of these custom-made MAD are the cost and delay required to manufacture the device. In addition, not all patients benefit from MAD, and presently no method exists to predict the outcome prior to fabrication of the device [
      • Sutherland K.
      • Vanderveken O.M.
      • Tsuda H.
      • Marklund M.
      • Gagnadoux F.
      • Kushida C.A.
      • Cistulli P.A.
      Oral appliance treatment for obstructive sleep apnea: an update.
      ]. Thus, a trial with an inexpensive thermoplastic titrable MAD would be of great interest. A previous randomized cross-over trial found that a monobloc nonadjustable thermoplastic MAD with insufficient overnight retention was less effective that a custom-made MAD [
      • Vanderveken O.M.
      • Devolder A.
      • Marklund M.
      • Boudewyns A.N.
      • Braem M.J.
      • Okkerse W.
      • Verbraecken J.A.
      • Franklin K.A.
      • De Backer W.A.
      • Van de Heyning P.H.
      Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea.
      ]. The main requirement for a MAD to be effective is the adequate retention on the teeth while the patient is asleep [
      • Vanderveken O.M.
      • Van de Heyning P.
      • Braem M.J.
      Retention of mandibular advancement devices in the treatment of obstructive sleep apnea: an in vitro pilot study.
      ,
      • Braem M.
      In vitro retention of a new thermoplastic titratable mandibular advancement device.
      ]. The aim of this study was to evaluate the efficacy of a titrable, thermoplastic MAD compared to a custom-made MAD for mild to severe OSA therapy.

      2. Methods

      This prospective nonrandomized study was conducted on the Institut de Recherche en Santé Respiratoire des Pays de la Loire [IRSR] sleep cohort [
      • Gagnadoux F.
      • Le Vaillant M.
      • Goupil F.
      • Pigeanne T.
      • Chollet S.
      • Masson P.
      • Humeau M.-P.
      • Bizieux-Thaminy A.
      • Meslier N.
      IRSR sleep cohort group, Influence of marital status and employment status on long-term adherence with continuous positive airway pressure in sleep apnea patients.
      ]. Approval was obtained from the University of Angers ethics committee and the “Comité Consultative sur le Traitement de l’Information en matière de Recherche dans le domaine de la Santé [C.C.T.I.R.S.] (07.207bis)”. The database is anonymous and complies with the restrictive requirements of the “Commission Nationale Informatique et Liberté [C.N.I.L.]”, the French information technology, and personal data protection authority. All patients included in the IRSR sleep cohort have given their written informed consent.

      2.1 Study population

      According to French clinical guidelines, MAD therapy is recommended as an appropriate first-line treatment option for mild to moderate OSA in patients without severe cardiovascular comorbidity or as a second line option in patients intolerant to CPAP [
      • Fleury B.
      • Cohen-Levy J.
      • Lacassagne L.
      • Buchet I.
      • Geraads A.
      • Pegliasco H.
      • Gagnadoux F.
      [Treatment of obstructive sleep apnea syndrome using a mandibular advancement device].
      ]. Between Jun 01, 2015 and January 25, 2017, consecutive OSA patients in whom MAD therapy was considered in two French sleep centers (University Hospital of Angers and Saint-Antoine Hospital of Paris, France) participating to the IRSR sleep cohort were offered the choice of being treated immediately with a custom-made MAD or starting with a trial of thermoplastic MAD.
      A flow diagram is presented in Fig. 1. Two hundred and twenty patients in whom MAD had been prescribed for at least 6 months were eligible for the study. None of these patients were on CPAP therapy during the study period. One hundred and twenty five patients had been treated with thermoplastic MAD and 95 had been treated by custome-made MAD. One hundred and fifty-eight patients were included in the analysis, 86 in the thermoplastic MAD group and 72 in the custom-made MAD group. The baseline characteristics of study participants are summarized in Table 1. Significant intergroup differences were observed for age, body mass index (BMI) and OSA severity. Patients treated with thermoplastic MAD were younger (p = 0.0039), had lower BMI (p = 0.0079) and had less severe OSA (p = 0.0022 for AHI and 0.0445 for sleep time with SaO2 <90%).
      Fig. 1
      Fig. 1Flow diagram of subjects during the study.
      Abbreviations: MAD, mandibular advancement device; OSA, obstructive sleep apnoea.
      Table 1Baseline characteristics of study participants.
      All patientsThermoplastic MADCustom-made MADp value
      Custom-made versus thermoplastic MAD.
      N1588672
      Age, years54.0 (11.6)51.6 (12.3)56.9 (10.0)0.0039
      BMI, kg/m226.6 (3.7)25.9 (3.4)27.5 (3.9)0.0079
      Women, %34.232.636.10.6391
      Hypertension, %
      Custom-made versus thermoplastic MAD.
      17.513.222.40.1762
      Diabetes, %4.84.45.20.8416
      Dyslipidemia, %9.50.013.30.3471
      Current smoker, %28.627.829.70.8396
      Epworth sleepiness score9.6 (5.4)9.9 (5.6)9.4 (5.2)0.5674
      Q2DA depression score2.9 (3.2)3.1 (3.4)2.6 (3.0)0.3792
      VAS for snoring intensity274.5 (211.8)255.1 (210.8)296.1 (212.2)0.2407
      Clinic systolic BP, mmHg127.7 (11.8)126.7 (12.8)128.2 (11.4)0.6358
      Clinic diastolic BP, mmHg79.0 (11.2)78.5 (12.0)79.2 (11.0)0.8157
      Apnoea-hypopnoea index,n27.3 (18.2)23.2 (15.1)32.2 (20.3)0.0022
      Apnoea index,n8.2 (12.9)7.0 (10.3)10.5 (16.6)0.2388
      3% ODI,n22.3 (19.6)19.9 (18.6)25.0 (20.4)0.1072
      T90,%4.7 (12.4)2.8 (7.9)7.0 (15.8)0.0445
      OSA severity
       Mild OSA, %25.329.120.80,2357
       Moderate OSA, %32.339.523.60.0330
       Severe OSA, %42.431.455.60.0022
      Data are expressed as mean (standard deviation) or percentages.
      Abbreviations: MAD, mandibular advancement device, BMI, body mass index; VAS, 0–10 visual analog scale; BP, blood pressure; ODI, oxygen desaturation index; T90, time spent with SaO2 <90%; OSA, obstructive sleep apnoea.
      a Custom-made versus thermoplastic MAD.

      2.2 Device fitting and titration

      A customizable, titratable, thermoplastic MAD (BluePro®; BlueSom, France), with sufficient retention forces to resist mouth opening forces [
      • Braem M.
      In vitro retention of a new thermoplastic titratable mandibular advancement device.
      ], was evaluated in the present study (Fig. 2A). Two titrable custom-made MADs with proven clinical efficacy in treating OSA [
      • Phillips C.L.
      • Grunstein R.R.
      • Darendeliler M.A.
      • Mihailidou A.S.
      • Srinivasan V.K.
      • Yee B.J.
      • Marks G.B.
      • Cistulli P.A.
      Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea: a randomized controlled trial.
      ,
      • Gagnadoux F.
      • Pépin J.-L.
      • Vielle B.
      • Bironneau V.
      • Chouet-Girard F.
      • Launois S.
      • Meslier N.
      • Meurice J.-C.
      • Nguyen X.-L.
      • Paris A.
      • Priou P.
      • Tamisier R.
      • Trzepizur W.
      • Goupil F.
      • Fleury B.
      Impact of mandibular advancement therapy on endothelial function in severe obstructive sleep apnea.
      ] were used in the study: 63 patients were treated with the AMO® device (SomnoMed, France) and 9 with the Somnodent® device (SomnoMed, France) (see Fig. 2B and C). All patients were fitted with the chosen MAD by a qualified dentist. The same MAD titration procedure was used for thermoplastic and custom-made MADs. As previously described, once fitted with the device, patients underwent an acclimatization period during which the mandible was incrementally advanced by 1-mm steps every 1 or 2 weeks until symptom relief or the maximum comfortable limit of advancement was achieved [
      • Gagnadoux F.
      • Pépin J.-L.
      • Vielle B.
      • Bironneau V.
      • Chouet-Girard F.
      • Launois S.
      • Meslier N.
      • Meurice J.-C.
      • Nguyen X.-L.
      • Paris A.
      • Priou P.
      • Tamisier R.
      • Trzepizur W.
      • Goupil F.
      • Fleury B.
      Impact of mandibular advancement therapy on endothelial function in severe obstructive sleep apnea.
      ].
      Fig. 2
      Fig. 2Mandibular advancement devices (MADs) used in the study; (A) BluePro® (BlueSom, France) thermoplastic MAD, (B) AMO® (SomnoMed, France) custom-made MAD and (C) SomnoDent® (SomnoMed, France) custom-made MAD.

      2.3 Outcomes and follow-up

      All outcomes were assessed at baseline and after 6 months of MAD therapy. Outcome assessors were unaware of the device assignment. The primary outcome was the change in SDB severity as assessed by the apnoea-hypopnoea index (AHI), the apnoea index (AI), the 3% oxygen desaturation index (ODI) and the sleep time with SaO2 <90% (T90) between baseline and after 6 months of thermoplastic or custom-made MAD. Secondary outcome measures included changes in daytime sleepiness, depressive symptoms, HRQL, clinical symptoms of OSA, treatment side effects and compliance. Daytime sleepiness was evaluated by the Epworth Sleepiness Scale (ESS) [
      • Johns M.W.
      A new method for measuring daytime sleepiness: the Epworth sleepiness scale.
      ]. Symptoms of depression were assessed with the Pichot QD2A depression score [
      • Gagnadoux F.
      • Le Vaillant M.
      • Goupil F.
      • Pigeanne T.
      • Chollet S.
      • Masson P.
      • Bizieux-Thaminy A.
      • Humeau M.-P.
      • Meslier N.
      IRSR Sleep Cohort Group*, Depressive symptoms before and after long-term CPAP therapy in patients with sleep apnea.
      ]. HRQL was evaluated with a validated French-language version of the Medical Outcomes Study 36-item short-form (SF36) [
      • Perneger T.V.
      • Leplège A.
      • Etter J.F.
      • Rougemont A.
      Validation of a French-language version of the MOS 36-item short form health survey (SF-36) in young healthy adults.
      ]. Outcome of OSA symptoms, global treatment satisfaction, and reported side effects were assessed at 6-month follow-up using previously described specific questionnaires [
      • Gagnadoux F.
      • Fleury B.
      • Vielle B.
      • Pételle B.
      • Meslier N.
      • N'Guyen X.L.
      • Trzepizur W.
      • Racineux J.L.
      Titrated mandibular advancement versus positive airway pressure for sleep apnoea.
      ,
      • Gagnadoux F.
      • Pépin J.-L.
      • Vielle B.
      • Bironneau V.
      • Chouet-Girard F.
      • Launois S.
      • Meslier N.
      • Meurice J.-C.
      • Nguyen X.-L.
      • Paris A.
      • Priou P.
      • Tamisier R.
      • Trzepizur W.
      • Goupil F.
      • Fleury B.
      Impact of mandibular advancement therapy on endothelial function in severe obstructive sleep apnea.
      ]. Reported compliance was assessed through a diary during the 6 months of treatment with thermoplastic or custom-made MAD. Each night, patients recorded the number of hours that the device was used. A mean reported daily use over the study period was then calculated.

      2.4 Sleep recordings

      At baseline all patients underwent type III overnight respiratory recordings (CID 102 LX, Cidelec, Sainte-Gemmes sur Loire, France) with continuous recording of arterial oxygen saturation, nasal-oral airflow, chest and abdominal wall motion, and body position [
      • Gagnadoux F.
      • Le Vaillant M.
      • Goupil F.
      • Pigeanne T.
      • Chollet S.
      • Masson P.
      • Bizieux-Thaminy A.
      • Humeau M.-P.
      • Meslier N.
      IRSR Sleep Cohort Group*, Depressive symptoms before and after long-term CPAP therapy in patients with sleep apnea.
      ]. Respiratory events were scored manually using recommended criteria [
      • Berry R.B.
      • Budhiraja R.
      • Gottlieb D.J.
      • Gozal D.
      • Iber C.
      • Kapur V.K.
      • Marcus C.L.
      • Mehra R.
      • Parthasarathy S.
      • Quan S.F.
      • Redline S.
      • Strohl K.P.
      • Davidson Ward S.L.
      • Tangredi M.M.
      American academy of sleep medicine, rules for scoring respiratory events in sleep: update of the 2007 AASM manual for the scoring of sleep and associated events. Deliberations of the sleep apnea definitions task force of the american academy of sleep medicine.
      ]. At 6 months, SDB severity was evaluated under thermoplastic or custom-made MAD with either type III overnight respiratory recording (n = 120) or overnight pulse oximetry (n = 38) using Nonin 8500 M (Nonin Medical Inc. Plymouth, MN, USA) with calculation of the ODI and T90 [
      • Fleury B.
      • Rakotonanahary D.
      • Petelle B.
      • Vincent G.
      • Pelletier Fleury N.
      • Meyer B.
      • Lebeau B.
      Mandibular advancement titration for obstructive sleep apnea: optimization of the procedure by combining clinical and oximetric parameters.
      ].

      2.5 Statistical analysis

      Continuous variables were described as mean (standard deviation [SD]) or mean (95% confidence interval, [CI]) for variables with a normal distribution and as median (interquartile range [IQR]) for variables with a non-normal distribution. Normality of distribution was assessed using the Kolmogorov–Smirnov test. Normal variables were analyzed using an unpaired t-test for intergroup difference and a paired t-test for intragroup difference. Linear regression analysis was used to adjust for baseline values and potential covariates. Non-normal variables were analyzed using the Mann-Whitney test for intergroup difference and the rank-signed Wilcoxon test for intragroup difference. The Chi-square test and Fisher's exact test were used for categorical variables, as appropriate. All reported p-values were two-sided. A p-value less than or equal to 0.05 was considered to indicate statistical significance. All statistical analyses were performed with SAS software (SAS/STAT Package 2002–2003 by SAS Institute Inc. Cary, NC, USA).

      3. Results

      3.1 Primary outcome

      A significant decrease in AHI, AI and ODI was observed with both thermoplastic and custom-made MAD therapies. No significant change was observed in the 2 groups for T90. After adjustment for baseline values, age, BMI and study site, no significant intergroup differences were observed between thermoplastic and custom-made MAD therapies regarding the outcomes of AHI, AI, ODI and T90 (Table 2). No significant adjusted intergroup differences were observed between the 2 devices when changes in AHI were expressed as Δ outcome values as defined as [(baseline value - 6-months follow-up value)/baseline value] * 100 (Table 2). Treatment responses according to AHI reduction under thermoplastic and custom-made MAD are presented in Fig. 3. A complete treatment response (AHI reduced by = 50% to less than 5) was obtained in 34.6% of patients treated with thermoplastic MAD versus 26.2% in the custom-made MAD group (p = 0.32). The rate of partial response (AHI reduced by = 50% to but ≥ 5) was 34.6% in the thermoplastic MAD group versus 35.4% the in the custom-made MAD group (p = 0.92). A treatment failure (AHI reduced by <50%) occurred in 30.8% of patients treated with thermoplastic MAD versus 38.4% in the custom-made MAD group (p = 0.39).
      Table 2Effects of thermoplastic mandibular advancement device (MAD) vs custom-made MAD device on sleep-disordered breathing severity.
      Thermoplastic MADCustom-made MADAdjusted intergroup differences
      Adjusted for baseline value, age and body mass index and study site.


      Mean (95%CI)
      Baseline6 months follow-upBaseline6 months follow-up
      AHI,n
      Data from 120 patients with type III overnight respiratory recording at 6 months (55 in the thermoplastic MAD group and 65 in the custom-made MAD group).
      23.2 (1.6)7.9 (1.1)
      p < 0.001 versus baseline.
      32.2 (2.4)13.2 (1.5)
      p < 0.001 versus baseline.
      2.4 (−1.3; 6.0)
      ΔAHI, %
      Data from 120 patients with type III overnight respiratory recording at 6 months (55 in the thermoplastic MAD group and 65 in the custom-made MAD group).
      ,
      Changes in AHI are presented as Δ outcome values as defined by [(baseline value - 6-months follow-up value)/baseline value] * 100.
      57.7 (36.5)57.0 (34.3)7.8 (−6.4; 21.9)
      AI,n
      Data from 120 patients with type III overnight respiratory recording at 6 months (55 in the thermoplastic MAD group and 65 in the custom-made MAD group).
      7.0 (1.2)1.5 (0.6)
      p < 0.05 versus baseline.
      10.5 (2.5)2.5 (0.6)
      p < 0.001 versus baseline.
      0.9 (−0.6; 2.3)
      ODI,n19.9 (2.1)8.5 (0.8)
      p < 0.001 versus baseline.
      25.0 (2.4)12.9 (1.3)
      p < 0.001 versus baseline.
      1.6 (−1.5; 4.6)
      T90,%2.8 (0.9)2.8 (0.9)7.0 (1.9)5.5 (1.4)0.3 (−3.2; 3.8)
      Data are expressed as mean (standard deviation), or mean (95% confidence interval [CI]).
      Abbreviations: AHI, apnoea-hypopnoea index; AI, apnoea index; ODI, 3% oxygen desaturation index; T90; time spent with SaO2 <90%,%.
      a Adjusted for baseline value, age and body mass index and study site.
      b p < 0.001 versus baseline.
      c Data from 120 patients with type III overnight respiratory recording at 6 months (55 in the thermoplastic MAD group and 65 in the custom-made MAD group).
      d p < 0.05 versus baseline.
      e Changes in AHI are presented as Δ outcome values as defined by [(baseline value - 6-months follow-up value)/baseline value] * 100.
      Fig. 3
      Fig. 3Treatment response for thermoplastic (n = 55) and custom-made mandibular advancement device (MAD) (n = 65) where complete response equals apnea-hypopnea index (AHI) reduced by = 50% to less than 5, partial response equals AHI reduced by = 50% but still ≥5, and failure equals AHI reduced by <50%.

      3.2 Secondary outcomes

      As shown in Table 3, the ESS improved significantly after both thermoplastic and custom-made MAD. A significant improvement of the QD2A depression score was also observed in the thermoplastic MAD group. After adjustment for baseline values, baseline AHI, age, BMI and study site, there was no between treatment difference for the outcome of sleepiness, depressive symptoms, the overall mental and physical component scores and most subscale measures of HRQL. No significant correlations were observed between changes in AHI and changes in SF36 Physical Component Summary (p = 0.5) or Mental Component Summary (p = 0.5). As shown in Table 4, thermoplastic and custom-made MAD therapies for six months were associated with a similar improvements in snoring, fatigue and sleepiness complaints. The global treatment satisfaction was also similar in the 2 groups. However, thermoplastic MAD therapy was associated with significantly higher side effects scores for tooth pain (p < 0.0001) and self-reported occlusal changes (p = 0.0069). Reported daily use of the device was also significantly lower in the thermoplastic MAD group than in the custom-made MAD group (p = 0.035).
      Table 3Effects of thermoplastic mandibular advancement device (MAD) vs custom-made MAD device on daytime sleepiness, depressive symptoms and health-related quality of life (HRQL) questionnaires.
      Thermoplastic MADCustom-made MADAdjusted intergroup differences
      Adjusted baseline value, baseline AHI, age, body mass index and study site.


      Mean (95%CI)
      Baseline6 months follow-upBaseline6 months follow-up
      Sleepiness
      ESS9.9 (0.6)7.2 (0.6)
      p < 0.001 versus baseline.
      9.4 (0.6)6.5 (0.5)
      p < 0.001 versus baseline.
      0.8 (−0.6; 2.1)
      ΔESS, %
      Changes in ESS are presented as Δ outcome values as defined as [(baseline value - 6-months follow-up value)/baseline value]* 100.
      16.1 (7.5)26.0 (5.0)2.7 (−17.6; 23.0)
      ESS≥11,%48.121.7
      p < 0.001 versus baseline.
      41.215.9
      p < 0.01 versus baseline.
      0.1 (−0.1; 0.2)
      Depression
      QD2A3.1 (0.4)2.4 (0.4)
      p < 0.05 versus baseline.
      2.6 (0.4)2.3 (0.4)0.5 (−0.8; 1.8)
      Q2DA≥7,%16.78.312.511.30.1 (−0.1; 0.2)
      HRQL
      SF36 PCS50.8 (0.2)50.8 (1.9)51.0 (0.2)50.7 (0.3)
      p < 0.05 versus baseline.
      −0.3 (−1.0; 0.4)
      SF36 MCS47.7 (0.6)48.2 (5.1)47.5 (0.5)48.3 (0.7)
      p < 0.05 versus baseline.
      1.2 (−0.6; 2.9)
      SF36 BP67.7 (3.1)74.3 (2.8)
      p < 0.05 versus baseline.
      73.8 (3.0)68.5 (3.2)
      p < 0.05 versus baseline.
      12.3 (3.8; 20.7)
      SF36 VT50.3 (2.3)57.1 (2.3)
      p < 0.01 versus baseline.
      50.0 (2.2)57.3 (2.4)
      p < 0.01 versus baseline.
      4.7 (−2.5; 11.8)
      SF36 GH66.4 (2.2)68.6 (2.3)66.2 (1.9)66.4 (2.4)2.9 (−3.2; 8.9)
      SF36 MH67.0 (2.0)68.6 (2.2)64.9 (2.0)68.6 (2.5)
      p < 0.05 versus baseline.
      4.4 (−1.8; 10.7)
      SF36 PF89.1 (1.6)90.4 (1.8)87.3 (2.4)86.9 (2.5)3.6 (−2.5; 9.7)
      SF36 RE82.2 (3.8)81.5 (3.8)72.7 (4.6)80.8 (4.1)3.4 (−9.7; 16.6)
      SF36 RP73.0 (4.0)76.6 (4.5)79.2 (4.3)84.1 (3.9)3.0 (−9.8; 15.8)
      SF36 SF73.2 (2.8)75.4 (2.7)72.7 (2.9)75.5 (3.1)6.5 (−2.0; 15.0)
      Data are expressed as mean (standard deviation), median [interquartile range], mean (95% confidence interval [CI]), or percentages.
      Abbreviations: ESS, Epworth sleepiness scale; QD2A, Pichot depression scale; PCS, Physical Component Summary; MCS, Mental Component Summary; BP, bodily pain; VT, energy/vitality; GH, general health; MH, mental health; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning.
      a Adjusted baseline value, baseline AHI, age, body mass index and study site.
      b p < 0.001 versus baseline.
      c p < 0.01 versus baseline.
      d p < 0.05 versus baseline.
      e Changes in ESS are presented as Δ outcome values as defined as [(baseline value - 6-months follow-up value)/baseline value]* 100.
      Table 4Symptoms of obstructive sleep apnoea (OSA), global treatment satisfaction, perceived side effects and self reported compliance after 6 months of treatment with thermoplastic mandibular advancement device (MAD) vs custom-made MAD.
      Thermoplastic MADCustom-made MADp value
      Snoring
       Markedly reduced, %48.132.60.4725
       Reduced, %34.645.7
       Unchanged, %11.513.0
       Increased, %5.88.7
       Not applicable, %39.536.0
      Fatigue
       Markedly reduced, %13.618.50.5026
       Reduced, %43.951.9
       Unchanged, %31.820.4
       Increased, %10.69.3
       Not applicable, %23.325.0
      Sleepiness
       Markedly reduced, %26.233.30.6569
       Reduced, %37.739.6
       Unchanged, %26.216.7
       Increased, %9.810.4
       Not applicable, %29.033.3
      Side-effects scores
      Patients were asked to give a score from 0 to 3 (0, absent; 1, mild; 2, moderate; 3, severe) for each side-effect of oral appliance therapy. A global side-effects score from 0 to 18 was then calculated.
       Jaw pain0.4 (0.1)0.3 (0.1)0.6931
       Tooth pain1.3 (0.1)0.6 (0.1)<0.0001
       Muscle stiffness1.3 (0.1)1.1 (0.1)0.2366
       Dry mouth0.9 (0.1)0.9 (0.1)0.9138
       Hypersalivation0.5 (0.1)0.7 (0.1)0.2621
       Self-reported occlusal changes1.0 (0.1)0.5 (0.1)0.0069
       Global score6.0 (0.6)4.5 (0.5)0.0503
      Global treatment satisfaction
      Global treatment satisfaction was assessed using a 0–10 visual analog scale.
      6.9 (0.3)7.1 (0.3)0.5831
      Self-reported compliance
       Use rate, h/night6.4 (0.2)7.1 (0.1)0.0035
       Compliant users, %
      Use rate≥ 4 h/night.
      95.5100.00.0946
      Data are expressed as percentages, mean (standard deviation) or median [interquartile range].
      a Patients were asked to give a score from 0 to 3 (0, absent; 1, mild; 2, moderate; 3, severe) for each side-effect of oral appliance therapy. A global side-effects score from 0 to 18 was then calculated.
      b Global treatment satisfaction was assessed using a 0–10 visual analog scale.
      c Use rate≥ 4 h/night.

      4. Discussion

      This study showed no significant difference in treatment efficacy between thermoplastic and custom-made MADs, whether in terms of reduction of SDB severity or symptom relief. Self-reported treatment compliance was high and only slightly lower with the thermoplastic MAD group. Although global treatment satisfaction was not statistically different, global side-effects score were higher in patients treated with a thermoplastic MAD, mainly because of tooth pain and self-reported occlusal changes.
      Numerous prefabricated MADs are currently commercialized, ranging from ready-to-use non-customizable, non-adjustable devices to more sophisticated, thermoplastic, partially customized (the so called “boil and bite” appliances) devices. However, practice guidelines to date still strongly recommend the use of a custom-made MAD over non-custom devices [
      • Ramar K.
      • Dort L.C.
      • Katz S.G.
      • Lettieri C.J.
      • Harrod C.G.
      • Thomas S.M.
      • Chervin R.D.
      Clinical practice guideline for the treatment of obstructive sleep apnea and snoring with oral appliance therapy: an update for 2015.
      ]. Among thermoplastic devices evaluated in the literature, those without chairside impressions and/or customized design were found to be poorly effective and uncomfortable, leading to poor compliance and treatment discontinuation [
      • Quinnell T.G.
      • Bennett M.
      • Jordan J.
      • Clutterbuck-James A.L.
      • Davies M.G.
      • Smith I.E.
      • Oscroft N.
      • Pittman M.A.
      • Cameron M.
      • Chadwick R.
      • Morrell M.J.
      • Glover M.J.
      • Fox-Rushby J.A.
      • Sharples L.D.
      A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO).
      ,
      • Johal A.
      • Haria P.
      • Manek S.
      • Joury E.
      • Riha R.
      Ready-made versus custom-made mandibular repositioning devices in sleep apnea: a randomized clinical trial.
      ]. The thermoplastic MAD evaluated in our study was partly customized and was fitted by a qualified dentist, following careful examination to assess contra-indications. Chairside impressions of the thermoplastic material resulted in a customization of a pre-fabricated device, which was immediately available to the patient, in contrast with custom-made devices, which often take several weeks to be manufactured. Titration and follow-up evaluations were conducted along the same guidelines for the thermoplastic MAD and the custom-made device. Clearly, this adds to the process length but ensures suitable fitting and retention, and consequently proper tolerance and efficacy of the appliance, as already shown with other devices [
      • Marty M.
      • Lacaze O.
      • Arreto C.D.
      • Pierrisnard L.
      • Bour F.
      • Chéliout-Héraut F.
      • Simonneau G.
      Snoring and obstructive sleep apnea: objective efficacy and impact of a chairside fabricated mandibular advancement device.
      ,
      • Friedman M.
      • Pulver T.
      • Wilson M.N.
      • Golbin D.
      • Leesman C.
      • Lee G.
      • Joseph N.J.
      Otolaryngology office-based treatment of obstructive sleep apnea-hypopnea syndrome with titratable and nontitratable thermoplastic mandibular advancement devices.
      ].
      Discrepant findings were obtained in previous studies evaluating the impact of ready-made or partially customized MADs on SDB and related symptoms. The TOMADO randomized trial compared non-adjustable “boil and bite” thermoplastic appliances with a custom-made MAD for the treatment of mild OSA [
      • Quinnell T.G.
      • Bennett M.
      • Jordan J.
      • Clutterbuck-James A.L.
      • Davies M.G.
      • Smith I.E.
      • Oscroft N.
      • Pittman M.A.
      • Cameron M.
      • Chadwick R.
      • Morrell M.J.
      • Glover M.J.
      • Fox-Rushby J.A.
      • Sharples L.D.
      A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO).
      ]. All devices reduced AHI compared with no treatment but compliance was lower with the self-moulded device, which was the least preferred treatment at trial exit. Friedman et al. [
      • Friedman M.
      • Hamilton C.
      • Samuelson C.G.
      • Kelley K.
      • Pearson-Chauhan K.
      • Taylor D.
      • Taylor R.
      • Maley A.
      • Hirsch M.A.
      Compliance and efficacy of titratable thermoplastic versus custom mandibular advancement devices.
      ] found that a custom-made device achieved higher rates of objective improvement and cure of OSA than a thermoplastic MAD. Self-reported adherence was present in 54% of patients on thermoplastic MAD versus 65% on custom-made MAD. At 6 months, only one third of patients on thermoplastic MAD were still considered adherent, compared to 51% in the other group. Using the same thermoplastic device Vanderveken et al. [
      • Vanderveken O.M.
      • Devolder A.
      • Marklund M.
      • Boudewyns A.N.
      • Braem M.J.
      • Okkerse W.
      • Verbraecken J.A.
      • Franklin K.A.
      • De Backer W.A.
      • Van de Heyning P.H.
      Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea.
      ] found that thermoplastic MAD was completely or partially effective in 31% of patients versus 60% for the custom-made MAD. In a recent randomized study, Johal et al. [
      • Johal A.
      • Haria P.
      • Manek S.
      • Joury E.
      • Riha R.
      Ready-made versus custom-made mandibular repositioning devices in sleep apnea: a randomized clinical trial.
      ] reported a response rate of only 24% with a thermoplastic MAD versus 64% in the custom-made arm. While these studies are difficult to compare due to marked differences in devices and study designs, titration of mandibular advancement appears to be an important factor of treatment success [
      • Lettieri C.J.
      • Paolino N.
      • Eliasson A.H.
      • Shah A.A.
      • Holley A.B.
      Comparison of adjustable and fixed oral appliances for the treatment of obstructive sleep apnea.
      ,
      • Dieltjens M.
      • Vanderveken O.M.
      • de Heyning P.H.V.
      • Braem M.J.
      Current opinions and clinical practice in the titration of oral appliances in the treatment of sleep-disordered breathing.
      ].
      Common side effects of MAD therapy include mucosal dryness, hyper salivation, tooth discomfort, temporal mandibular joint and muscle pain, tooth movement and self-reported occlusal changes [
      • Ramar K.
      • Dort L.C.
      • Katz S.G.
      • Lettieri C.J.
      • Harrod C.G.
      • Thomas S.M.
      • Chervin R.D.
      Clinical practice guideline for the treatment of obstructive sleep apnea and snoring with oral appliance therapy: an update for 2015.
      ,
      • Sutherland K.
      • Vanderveken O.M.
      • Tsuda H.
      • Marklund M.
      • Gagnadoux F.
      • Kushida C.A.
      • Cistulli P.A.
      Oral appliance treatment for obstructive sleep apnea: an update.
      ,
      • Marklund M.
      • Franklin K.A.
      • Persson M.
      Orthodontic side-effects of mandibular advancement devices during treatment of snoring and sleep apnoea.
      ]. Although open trials with thermoplastic devices showed mild side effects [
      • Marty M.
      • Lacaze O.
      • Arreto C.D.
      • Pierrisnard L.
      • Bour F.
      • Chéliout-Héraut F.
      • Simonneau G.
      Snoring and obstructive sleep apnea: objective efficacy and impact of a chairside fabricated mandibular advancement device.
      ,
      • Banhiran W.
      • Kittiphumwong P.
      • Assanasen P.
      • Chongkolwatana C.
      • Metheetrairut C.
      Adjustable thermoplastic mandibular advancement device for obstructive sleep apnea: outcomes and practicability.
      ,
      • Tsuda H.
      • Almeida F.R.
      • Masumi S.
      • Lowe A.A.
      Side effects of boil and bite type oral appliance therapy in sleep apnea patients.
      ], most comparative trials found that tolerance and overnight retention were lower with thermoplastic than custom-made devices [
      • Vanderveken O.M.
      • Devolder A.
      • Marklund M.
      • Boudewyns A.N.
      • Braem M.J.
      • Okkerse W.
      • Verbraecken J.A.
      • Franklin K.A.
      • De Backer W.A.
      • Van de Heyning P.H.
      Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea.
      ,
      • Quinnell T.G.
      • Bennett M.
      • Jordan J.
      • Clutterbuck-James A.L.
      • Davies M.G.
      • Smith I.E.
      • Oscroft N.
      • Pittman M.A.
      • Cameron M.
      • Chadwick R.
      • Morrell M.J.
      • Glover M.J.
      • Fox-Rushby J.A.
      • Sharples L.D.
      A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO).
      ,
      • Johal A.
      • Haria P.
      • Manek S.
      • Joury E.
      • Riha R.
      Ready-made versus custom-made mandibular repositioning devices in sleep apnea: a randomized clinical trial.
      ,
      • Friedman M.
      • Hamilton C.
      • Samuelson C.G.
      • Kelley K.
      • Pearson-Chauhan K.
      • Taylor D.
      • Taylor R.
      • Maley A.
      • Hirsch M.A.
      Compliance and efficacy of titratable thermoplastic versus custom mandibular advancement devices.
      ]. Most patients expressed preference for the custom-made device in cross-over trials [
      • Vanderveken O.M.
      • Devolder A.
      • Marklund M.
      • Boudewyns A.N.
      • Braem M.J.
      • Okkerse W.
      • Verbraecken J.A.
      • Franklin K.A.
      • De Backer W.A.
      • Van de Heyning P.H.
      Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea.
      ,
      • Johal A.
      • Haria P.
      • Manek S.
      • Joury E.
      • Riha R.
      Ready-made versus custom-made mandibular repositioning devices in sleep apnea: a randomized clinical trial.
      ]. Our study showed higher side effect scores with the thermoplastic MAD than in the custom-made group although global satisfaction was not different between the 2 groups. One can hypothesize that the high retention properties of the BluePro® thermoplastic MAD [
      • Braem M.
      In vitro retention of a new thermoplastic titratable mandibular advancement device.
      ] contributed to its therapeutic efficacy but also resulted to greater tooth discomfort and a slightly lower reported compliance.
      We acknowledge a number of limitations of the present study. While outcome assessors were unaware of the device assignment, this was not a randomized trial. Patients treated with the thermoplastic MAD presented several baseline characteristics that have been associated with better treatment outcomes on MAD therapy including younger age, lower BMI and less severe OSA [
      • Lettieri C.J.
      • Paolino N.
      • Eliasson A.H.
      • Shah A.A.
      • Holley A.B.
      Comparison of adjustable and fixed oral appliances for the treatment of obstructive sleep apnea.
      ]. However, no intergroup differences were observed between thermoplastic and custom-made MAD for SDB reduction and symptom relief after adjustment for these confounding factors. Among 158 included patients, only 120 had available AHI data obtained by type III overnight respiratory recording at 6 months. However, all patients had available data on nocturnal hypoxemia which have been found to be more strongly correlated to heath ouctomes than the AHI [
      • Kendzerska T.
      • Gershon A.S.
      • Hawker G.
      • Leung R.S.
      • Tomlinson G.
      Obstructive sleep apnea and risk of cardiovascular events and all-cause mortality: a decade-long historical cohort study.
      ,
      • Tkacova R.
      • McNicholas W.T.
      • Javorsky M.
      • Fietze I.
      • Sliwinski P.
      • Parati G.
      • Grote L.
      • Hedner J.
      European Sleep Apnoea Database study collaborators, Nocturnal intermittent hypoxia predicts prevalent hypertension in the European Sleep Apnoea Database cohort study.
      ]. Another potential limitation of the present study is that the comparison between thermoplastic and custom-made devices was mainly based on questionnaires with no cardiovascular outcomes. Symptoms and quality of life are major therapeutic targets in OSA patients. Excessive daytime sleepiness, depressive symptoms and quality of life were evaluated by validated and widely used questionnaires [
      • Johns M.W.
      A new method for measuring daytime sleepiness: the Epworth sleepiness scale.
      ,
      • Gagnadoux F.
      • Le Vaillant M.
      • Goupil F.
      • Pigeanne T.
      • Chollet S.
      • Masson P.
      • Bizieux-Thaminy A.
      • Humeau M.-P.
      • Meslier N.
      IRSR Sleep Cohort Group*, Depressive symptoms before and after long-term CPAP therapy in patients with sleep apnea.
      ,
      • Perneger T.V.
      • Leplège A.
      • Etter J.F.
      • Rougemont A.
      Validation of a French-language version of the MOS 36-item short form health survey (SF-36) in young healthy adults.
      ]. Reported side effects were scored with questionnaires previously used in randomized controlled trials [
      • Gagnadoux F.
      • Fleury B.
      • Vielle B.
      • Pételle B.
      • Meslier N.
      • N'Guyen X.L.
      • Trzepizur W.
      • Racineux J.L.
      Titrated mandibular advancement versus positive airway pressure for sleep apnoea.
      ,
      • Gagnadoux F.
      • Pépin J.-L.
      • Vielle B.
      • Bironneau V.
      • Chouet-Girard F.
      • Launois S.
      • Meslier N.
      • Meurice J.-C.
      • Nguyen X.-L.
      • Paris A.
      • Priou P.
      • Tamisier R.
      • Trzepizur W.
      • Goupil F.
      • Fleury B.
      Impact of mandibular advancement therapy on endothelial function in severe obstructive sleep apnea.
      ]. However, as thermoplastic MAD therapy was associated with significantly higher side effects scores for tooth pain and self-reported occlusal changes, temporomandibular disorders and craniofacial changes related to thermoplastic versus custom-made devices therapy should be objectively measured in future comparative studies [
      • Marklund M.
      • Franklin K.A.
      • Persson M.
      Orthodontic side-effects of mandibular advancement devices during treatment of snoring and sleep apnoea.
      ,
      • Doff M.H.J.
      • Veldhuis S.K.B.
      • Hoekema A.
      • Slater J.J.R.H.
      • Wijkstra P.J.
      • de Bont L.G.M.
      • Stegenga B.
      Long-term oral appliance therapy in obstructive sleep apnea syndrome: a controlled study on temporomandibular side effects.
      ]. We acknowledge that cardiovascular outcomes have emerged as a therapeutic objective in patients with OSA. A recent review and meta-analysis concluded that both CPAP and MAD therapies were associated with reductions in blood pressure with no statistically significant difference between these therapies regarding blood pressure outcomes [
      • Bratton D.J.
      • Gaisl T.
      • Wons A.M.
      • Kohler M.
      CPAP vs mandibular advancement devices and blood pressure in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. However, lowering blood pressure was not a major therapeutic objective in our population since only 17.5% of patients were hypertensive at inclusion. Whether OSA therapies have the power to reduce the incidence of late cardiovascular events has not been demonstrated yet [
      • Yu J.
      • Zhou Z.
      • McEvoy R.D.
      • Anderson C.S.
      • Rodgers A.
      • Perkovic V.
      • Neal B.
      Association of positive airway pressure with cardiovascular events and death in adults with sleep apnea: a systematic review and meta-analysis.
      ]. Many studies have correlated endothelial dysfunction with the incidence of cardiovascular events in at-risk patients [
      • Flammer A.J.
      • Anderson T.
      • Celermajer D.S.
      • Creager M.A.
      • Deanfield J.
      • Ganz P.
      • Hamburg N.M.
      • Lüscher T.F.
      • Shechter M.
      • Taddei S.
      • Vita J.A.
      • Lerman A.
      The assessment of endothelial function: from research into clinical practice.
      ]. Endothelial function assessment has also a potential value in identifying responders and non responders to therapy [
      • Flammer A.J.
      • Anderson T.
      • Celermajer D.S.
      • Creager M.A.
      • Deanfield J.
      • Ganz P.
      • Hamburg N.M.
      • Lüscher T.F.
      • Shechter M.
      • Taddei S.
      • Vita J.A.
      • Lerman A.
      The assessment of endothelial function: from research into clinical practice.
      ]. Previous observational studies reported a beneficial effect of MAD therapy for 2–12 months on endothelial function [
      • Lin C.-C.
      • Wang H.-Y.
      • Chiu C.-H.
      • Liaw S.-F.
      Effect of oral appliance on endothelial function in sleep apnea.
      ,
      • Itzhaki S.
      • Dorchin H.
      • Clark G.
      • Lavie L.
      • Lavie P.
      • Pillar G.
      The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function.
      ,
      • Ciccone M.M.
      • Favale S.
      • Scicchitano P.
      • Mangini F.
      • Mitacchione G.
      • Gadaleta F.
      • Longo D.
      • Iacoviello M.
      • Forleo C.
      • Quistelli G.
      • Taddei S.
      • Resta O.
      • Carratù P.
      Reversibility of the endothelial dysfunction after CPAP therapy in OSAS patients.
      ]. However, being uncontrolled with no sham device group, these studies were not accounting for the influence of confounders like lifestyle and dietary modifications on endothelial function [
      • Flammer A.J.
      • Anderson T.
      • Celermajer D.S.
      • Creager M.A.
      • Deanfield J.
      • Ganz P.
      • Hamburg N.M.
      • Lüscher T.F.
      • Shechter M.
      • Taddei S.
      • Vita J.A.
      • Lerman A.
      The assessment of endothelial function: from research into clinical practice.
      ]. Conversely, a recent multicenter randomized controlled trial showed that treating severe OSA with MAD for 2 months reduces SDB and related symptoms, but has no impact on peripheral endothelial function [
      • Gagnadoux F.
      • Pépin J.-L.
      • Vielle B.
      • Bironneau V.
      • Chouet-Girard F.
      • Launois S.
      • Meslier N.
      • Meurice J.-C.
      • Nguyen X.-L.
      • Paris A.
      • Priou P.
      • Tamisier R.
      • Trzepizur W.
      • Goupil F.
      • Fleury B.
      Impact of mandibular advancement therapy on endothelial function in severe obstructive sleep apnea.
      ]. Further studies are required to determine whether MAD therapy of OSA may improve cardiovascular outcomes. We also acknowledge the lack of objective measurement of treatment compliance in the present study. However, several studies demonstrated a high agreement between self reported and objectively measured compliance on effective MAD therapy [
      • Gagnadoux F.
      • Pépin J.-L.
      • Vielle B.
      • Bironneau V.
      • Chouet-Girard F.
      • Launois S.
      • Meslier N.
      • Meurice J.-C.
      • Nguyen X.-L.
      • Paris A.
      • Priou P.
      • Tamisier R.
      • Trzepizur W.
      • Goupil F.
      • Fleury B.
      Impact of mandibular advancement therapy on endothelial function in severe obstructive sleep apnea.
      ,
      • Vanderveken O.M.
      • Dieltjens M.
      • Wouters K.
      • De Backer W.A.
      • Van de Heyning P.H.
      • Braem M.J.
      Objective measurement of compliance during oral appliance therapy for sleep-disordered breathing.
      ,
      • Dieltjens M.
      • Braem M.J.
      • Vroegop A.V.M.T.
      • Wouters K.
      • Verbraecken J.A.
      • De Backer W.A.
      • Van de Heyning P.H.
      • Vanderveken O.M.
      Objectively measured vs self-reported compliance during oral appliance therapy for sleep-disordered breathing.
      ]. Finally, the relatively short duration of follow-up in the present study does not allow drawing any conclusion regarding long-term treatment efficacy and side effects of the two types of MAD. However, this drawback is irrelevant if the use of thermoplastic MAD is considered for a short duration trial prior to the fabrication of a custom-made device. Furthermore, recent meta-analyses addressing the impact of MAD therapy on SDB and related symptoms reported significant changes for studies duration from to 2–12 weeks [
      • Bratton D.J.
      • Gaisl T.
      • Schlatzer C.
      • Kohler M.
      Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: a network meta-analysis.
      ,
      • Sharples L.D.
      • Clutterbuck-James A.L.
      • Glover M.J.
      • Bennett M.S.
      • Chadwick R.
      • Pittman M.A.
      • Quinnell T.G.
      Meta-analysis of randomised controlled trials of oral mandibular advancement devices and continuous positive airway pressure for obstructive sleep apnoea-hypopnoea.
      ].

      5. Conclusion

      This study demonstrates the efficacy of a titrable thermoplastic MAD in reducing SDB and related symptoms in patients with mild to severe OSA. Reported compliance at 6 months was high despite more dental discomfort than with custom-made MAD.

      Financial support

      This work was funded by the Institut de Recherche en Santé Respiratoire (IRSR) des Pays de la Loire (9 rue du landreau - BP 77132 - 49071 Beaucouzé cedex, France). The content of this manuscript is solely the responsibility of the authors.

      Acknowledgements

      Author contributions: F.G., M.L.V. and S.L. conceived the study, analyzed the data and drafted the manuscript; X.L.N., P.P., N.M., A.E., J.D.K.D., C.F., B.V., M.L.,W.T. contributed to the acquisition of data, revised the manuscript critically for important intellectual content, and approved the final version to be submitted.
      The authors thank Wissam Boucenna, Sandra Girard and Christelle Gosselin for their help with trial administration, monitoring, and coordination, as well as data management.
      BlueSom, France, provided the thermoplastic appliances free of charge but had no involvement in the design of the study, the analysis of data or drafting of the manuscript.

      Conflict of interest

      This was not an industry-supported study. The authors have indicated no financial conflicts of interest.

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