Pharmacological Intervention for Symptomatic Snoring

Two active interventions are being studied and compared against placebo. Participants will
therefore be randomized to one of six possible sequences. Washout periods will be 1 week.

Effects of interventions on outcomes will be assessed using mixed effect model analyses: we
will quantify the effect of active treatment 1 (referenced to placebo), the effect of active
treatment 2 (referenced to placebo), adjusting for effects of time (period number), carryover
effects, and baseline values (fixed effects). Participants are considered random effects.

Primary outcome is based on significance of active intervention 1 versus placebo.

Inclusion Criteria for Enrollment

- Age 21-79 yrs

- Self-reported habitual snoring ("most of the time" or "all of the time" on Snoring
Self-Evaluation Scale)

- Sleep-related symptoms defined by any of the following*:

- Visual-Analog Scale for Sleep Quality ≤7/10 ("reduced sleep quality")

- Epworth Sleepiness Scale ≥10 ("excessive daytime sleepiness")

- Functional Outcomes of Sleep Questionnaire <18 ("reduced sleep-related quality of
life").

- Presence of a bed-partner who is able to provide feedback to the participant on
snoring (Snoring Bed-Partner Evaluation Scale)

- The intention of these criteria is to enable participants with a broad range of
possible snoring symptoms to be included. We note that the Visual-Analog Scale
for Sleep Quality is, on average, approximately 7/10 in patients with sleep
apnea; thus, we consider a value at or below 7 to indicate "reduced sleep
quality".

Exclusion Criteria for Enrollment

- Known obstructive sleep apnea (OSA, except "mild")

- Current treatment for OSA or snoring (continuous positive airway pressure, oral
appliances, supplemental oxygen)

- Use of medications expected to stimulate or depress respiration (including opioids,
barbiturates, acetazolamide, doxapram, almitrine, theophylline, 4-hydroxybutanoic
acid).

- Use of similar medications to the study drugs.

- Conditions likely to affect obstructive sleep apnea physiology: neuromuscular disease
or other major neurological disorder, heart failure (also below), or any other
unstable major medical condition.

- Respiratory disorders other than sleep disordered breathing:

o chronic hypoventilation/hypoxemia (awake oxygen saturation < 92% by oximetry) due to
chronic obstructive pulmonary disease or other respiratory conditions.

- Other sleep disorders: periodic limb movements (periodic limb movement arousal index >
10/hr), narcolepsy, or parasomnias.

- Contraindications to the study drugs, including:

- clinically-significant kidney disorders (eGFR<60 ml/min/1.73m2)

- clinically-significant liver disorders

- clinically-significant cardiovascular conditions

- severe hypertension (systolic blood pressure above 180 mmHg or diastolic
below 110 mmHg measured at baseline)

- cardiomyopathy (left ventricular ejection fraction, LVEF<50%) or heart
failure

- advanced atherosclerosis

- history of cerebrovascular events

- history of cardiac arrhythmias e.g., atrial fibrillation, QT prolongation

- other serious cardiac conditions

- myasthenia gravis

- pregnancy/breast-feeding

We will not make new measurements of eGFR, LVEF or document their presence/absence for each
participant.

Criteria for Randomization

After the baseline visit, the following criteria need to be met to continue participation:

- Participants with AHI≥15 events/hr (moderate-to-severe OSA, hypopneas based on a 30%
reduction in flow, accompanied by either a 3% oxygen desaturation or scored
EEG-arousal) on the baseline study night, will not continue further participation
after the baseline visit.

- Participants must exhibit evidence of snoring during the baseline sleep study for
further participation (mean tracheal sound intensity, Leq, exceeding 70 dB,
approximately the loudness of normal speech at 3 ft); the precise cutoff will be pilot
tested in ongoing protocols (where snoring is routinely measured).

Thus, strictly, the study population will include patients with symptomatic habitual
snoring, with or without mild OSA (i.e. AHI<5 and 5≤AHI<15). We note that studies in
patients with moderate-to-severe OSA have already been performed (AHI>15), and further
studies in this population are in progress. The inclusion of "mild OSA" will prevent a gap
in the inclusion criteria for the investigation of the current intervention.