Combined Upper-airway and Breathing Control Therapies for Obstructive Sleep Apnea

Pre-specified primary analysis for Aim 1 is the change in AHI with combination treatment versus oral appliance alone (%reduction versus placebo; including hypopnea events without desaturation/arousals).

Aim 2 seeks to identify subgroups of patients that have the greatest reduction in AHI (responders) with each treatment (post-hoc). We will use baseline physiological measures of the four traits causing OSA (collapsibility, responsiveness, loop gain, arousal threshold) to determine which characteristics predict responses to each intervention (leave-one-out support vector machine modeling). Clinical measures of the same traits will be estimated from the placebo night to confirm that responses can be predicted with clinically-available data. We will also test whether responders to oral appliances have a greater response to oxygen than oral appliance non-responders (and vice-versa), to address whether responders to both treatments are similar or different.

• Oral appliance (Device), also known as Mandibular advancement device: An oral appliance (dental mouthpiece) will be used to improve upper airway patency. Patients who do not have their own custom dental oral appliance (various brands, commonly Herbst/Somnomed) will be provided with a device (BluePro, BlueSom) for the duration of the study. Patients will also be administered sham (room air) at 4 L/min via nasal cannula.
• Oxygen (Drug), also known as Supplemental inspired oxygen: Supplemental oxygen will be delivered at 4 L/min via nasal cannula to improve ventilatory control stability.
• Oral appliance plus oxygen (Other), also known as Combination therapy: Both treatments will be administered simultaneously.
• No treatment (Other), also known as Sham: Subjects will not wear an oral appliance, and will be administered sham (room air) at 4 L/min via nasal cannula.

Primary outcomes

• Change in apnea hypopnea index (AHI), percent of baseline. [Single night]: Primary test is difference between combination therapy and oral appliance

Secondary outcomes

• Change in frequency of arousals, percent of baseline. [Single night]: Primary test is difference between combination therapy and oral appliance
• Patient reported sleep quality (visual analog scale) [Single night]: Primary test is difference between combination therapy and oral appliance
• Morning minus evening systolic blood pressure [Single night]: Primary test is difference between combination therapy and oral appliance
• Morning minus evening diastolic blood pressure [Single night]: Primary test is difference between combination therapy and oral appliance

Sex: All, ages: 21 Years to 79 Years

Inclusion Criteria:

* Diagnosed OSA or suspected OSA based on snoring

Exclusion Criteria:

* Severe co-morbidities (cardiovascular, renal, lung disease, neurological), including:

Congestive heart failure, Neurological conditions that may affect sleep or breathing (e.g. neuromuscular diseases e.g. myasthenia gravis; neurodegenerative diseases e.g. Alzheimer's/Parkinson's)

* Medications that will substantially affect respiration, including opioids, barbiturates, theophylline, doxapram, acetazolamide, pseudoephedrine
* Claustrophobia
* Insomnia and other non-respiratory sleep disorders
* Inability to sleep supine
* Contraindications to oral appliances, including insufficient teeth to support the device, periodontal problems inducing tooth mobility, active temporomandibular joint disorder
* Allergy to lidocaine or oxymetazoline HCl

• Results publication: Hynes DJ, Mann DL, Landry SA, Joosten SA, Edwards BA, Hamilton GS. Night-to-night variability in obstructive sleep apnea severity, the physiological endotypes, and the frequency of flow limitation. Sleep. 2025 Apr 11;48(4):zsae295. doi: 10.1093/sleep/zsae295. PMID 39688178

• Scott A Sands, PhD, Principal investigator, Brigham and Women's Hospital
• Bradley A Edwards, PhD, Principal investigator, Monash University

NIH grants: R01HL128658