Targeted Therapy for Sleep Apnoea: A Novel Personalised Approach

There are multiple arms in this project. In arm 1: up to 130 participants who are recommended mandibular advancement splint (MAS) therapy by their treating physician will be studied. Following a diagnostic sleep study, participants will complete a detailed physiological sleep study to define the key phenotypic causes of sleep apnoea according to critical closing pressure (Pcrit), Arousal threshold, Loop gain, Muscle responsiveness (PALM) scale phenotypic characterisation using simplified novel methodology and gold standard methodology described previously (Eckert et al, Am J Resp Crit Care Med, 2013, Terrill et al, Eur Resp J, 2015, Eckert Sleep Med Rev, 2018). Participants will be fitted with an Oventus custom-made MAS by the study dentist and treatment efficacy (apnoea/hypopnoea index [AHI]) will be assessed via overnight polysomnography. Each phenotypic trait will be compared between responders and non-responders. We will also use our recently developed novel predictive algorithm (Dutta et al, Annals of ATS, 2021) to predict treatment outcomes. Arm 2: aims to investigate the therapeutic efficacy (reduction in AHI) of mechanism-based targeted therapy (including combination therapy) to treat obstructive sleep apnoea (OSA) in incomplete responders (residual AHI> 10 events/h sleep) to MAS therapy alone. Specifically, incomplete responders (quantified during an in-laboratory treatment efficacy study) will return for one or more repeat sleep studies with targeted combination therapy based on Pcrit, Arousal threshold, Loop gain, Muscle responsiveness (PALM) scale phenotypic characterisation completed in arm 1 until the AHI is reduced to <10events/h sleep. Interventions include: 1) Expiratory positive airway pressure (EPAP) valves (8h sleep study) + positional therapy 2) O2 (4L/min via the nose, mouth or oronasally, 8h sleep study) 3) Zolpidem (10mg if <65y or 5mg if >65y, single dose, just prior to 8h sleep study, oral tablet) 4) Atomoxetine 80mg combined with oxybutynin 5mg (single doses), just prior to 8h sleep study, oral tablets 5) Continuous positive airway pressure (CPAP, titrated to eliminate respiratory events [2-20cmH2O], 8h sleep study) All participants in this arm will receive an EPAP valve + positional therapy (unless baseline Pcrit is <-3cmH2O in which case an EPAP valve alone will be delivered). In addition, interventions 2 to 4 will be added for those with unstable respiratory control (intervention 2), low arousal threshold (intervention 3), poor muscle responsiveness (intervention 4) one at a time based on PALM scale categorisation (if two or more traits are severely impaired the order of the interventions will be randomised). CPAP+MAS will be combined as a final option only if the other targeted interventions do not reduce the AHI to <10 events/h. Interventions will be delivered by the study investigators in-laboratory to ensure adherence for these acute, single night studies. For those who continue to use an EPAP valve after the study, comfort and tolerance will be assessed via telephone call and home sleep study 1 month after completion of the lab visits. Arm 3: in up to 40 participants who complete arm 1, a 1 to 1.5h MRI study will be performed by an investigator and a radiographer with and without MAS to provide mechanistic insight into how the MAS device works to change airway size and motion and assess the impact of route of breathing.