Pharmacological Intervention for Symptomatic Snoring

Study Overview
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Brief Summary
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Currently, there is no pharmacological intervention capable of maintaining airway patency for the treatment of snoring and airflow limitation during sleep. Here we study the effect of pharmacological stimulation of the pharyngeal muscles on snoring severity, in a randomized quadruple-blind, crossover study.

Detailed Description
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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.

Official Title
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Pharmacological Intervention for Symptomatic Snoring

Conditions
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Snoring

Intervention / Treatment
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* Drug: SAS2094AH and SAS2094BH
* Drug: SAS2094AL and SAS2094BL
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Enrollment Age 18-79 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 80 dB); 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active H<br>Participants will take SAS2094AL and SAS2094BH for 3 days, then SAS2094AH and SAS2094BH for 7 days. | Drug: SAS2094AH and SAS2094BH<br>* SAS2094AH and SAS2094BH for 7 days, preceded by SAS2094AL and SAS2094BH for 3 days.<br>|
| Active Comparator: Active L<br>Participants will take SAS2094AL and SAS2094BL for 10 days | Drug: SAS2094AL and SAS2094BL<br>* SAS2094AL and SAS2094BL for 10 days<br>|
| Placebo Comparator: Placebo<br>Participants will take placebo for 10 days. | Drug: Placebo<br>* Placebo for 10 days. Capsules will mimic active treatments.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Snoring intensity | mean tracheal snoring sound intensity (tracheal microphone), decibels | 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Snoring frequency | snoring frequency (tracheal microphone), snores per hour of total sleep time | 1 week | 
| Snoring Self-Evaluation Scale | frequency, loudness, disruption, bothersome, 5-point scales | 1 week | 
| Snoring Bed-Partner Evaluation Scale | frequency, loudness, disruption, bothersome, 5-point scales | 1 week | 
| Flow-limitation frequency | breaths per hour (nasal pressure airflow shape) | 1 week | 
| Flow-limitation severity | flow:drive ratio (nasal pressure airflow shape), % | 1 week | 
| Visual-Analog Scale for Sleep Quality | 0-10 scale | 1 week | 
| Mean oxygen saturation | Percentage | 1 week | 
| Stage 1 Sleep | %Total sleep time | 1 week | 
| Arousal index | events per hour of total sleep time | 1 week | 
| Visual-Analog Scale for Treatment Satisfaction | 0-10 scale | 1 week | 
| Epworth Sleepiness Scale | units on a scale | 1 week | 
| Functional Outcomes of Sleep Questionnaire | 30 items, units on a scale | 1 week | 
| Would you keep using this medication? | Yes/No | 1 week |