Tiagabine to Enhance Slow Wave Sleep in Patients With Sleep Apnea

Study Overview
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Brief Summary
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Obstructive sleep apnea (OSA) is common and has major health implications but treatment options are limited. Interestingly, the severity of OSA is profoundly reduced in deep sleep (called slow wave sleep), potentially via an increase in the stimulus required to arouse from sleep. Here the investigators test the idea that the medication called tiagabine improves slow wave sleep and reduces OSA severity. The investigators will also test whether tiagabine raises the arousal threshold (more negative esophageal pressure), and whether detailed OSA phenotyping characteristics can predict the improvement in OSA severity with this intervention.

Detailed Description
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The current study tests the primary hypothesis that tiagabine improves sleep apnea severity in patients with moderate-to-severe sleep apnea (apnea hypopnea index measured in supine non-REM sleep; hypopneas defined by 3% desaturation or arousal). The investigators test three secondary hypotheses that tiagabine: increases the proportion of total sleep time in slow wave sleep raises the non-REM arousal threshold (more negative esophageal pressure) via (1). is preferentially effective in patients whose OSA phenotype predicts that an increase in the arousal threshold is sufficient to resolve OSA versus those without such favorable physiology. Favorable physiology is defined here as having a low ventilatory drive at which stable breathing is theoretically feasible (stable Vdrive is <100% above eupneic ventilatory drive) due to any combination of a high upper airway muscle response, good passive anatomy (high Vpassive), and low steady-state loop gain (see Owens RL et al SLEEP 2014; Wellman A et al J Appl Physiol 2011, 2013; Eckert DJ et al 2013 AJRCCM).

Official Title
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Inducing Slow Wave Sleep to Treat Obstructive Sleep Apnea

Conditions
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Sleep Apnea, Obstructive

Intervention / Treatment
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* Drug: Tiagabine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed OSA (moderate-to-severe; apnea hypopnea index >15 events/hr) Exclusion Criteria: History of seizures

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: Tiagabine<br>Tiagabine PO 12 mg before sleep | Drug: Tiagabine<br>* GABA reuptake inhibitor<br>* Other names: Gabitril;|
| Placebo Comparator: Placebo<br>Placebo PO before sleep | Drug: Placebo<br>* Placebo comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apnea Hypopnea Index (AHI) | Number of apneas + hypopneas per hour of sleep. Hypopnea criteria: reduction in 30% of baseline flow plus 3% desaturation or arousal. | 1 night | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Slow Wave Sleep (% Total Sleep Time) | Fraction of sleep spent in stage N3 | 1 night | 
| Arousal Threshold (Esophageal Pressure Swing) | The arousal threshold was quantified as the mean of all the nadir negative esophageal pressure swings immediately preceding an arousal at the end of an obstructive apnea or hypopnea during both placebo and tiagabine nights. | 1 night | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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arousal threshold, phenotype, tiagabine, slow wave sleep