Sleep Apnea, Obstructive
Conditions
Keywords
arousal threshold, phenotype, tiagabine, slow wave sleep
Brief summary
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
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: 1. increases the proportion of total sleep time in slow wave sleep 2. raises the non-REM arousal threshold (more negative esophageal pressure) via (1). 3. 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).
Interventions
DRUGTiagabine
GABA reuptake inhibitor
DRUGPlacebo
Placebo comparator
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed OSA (moderate-to-severe; apnea hypopnea index \>15 events/hr)
Exclusion criteria
* History of seizures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apnea Hypopnea Index (AHI) | 1 night | Number of apneas + hypopneas per hour of sleep. Hypopnea criteria: reduction in 30% of baseline flow plus 3% desaturation or arousal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Slow Wave Sleep (% Total Sleep Time) | 1 night | Fraction of sleep spent in stage N3 |
| Arousal Threshold (Esophageal Pressure Swing) | 1 night | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Analyzed Participants All patients who were randomized, completed both study nights and were included in the analysis | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | All Analyzed Participants |
|---|---|
| Age, Continuous | 58 years |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 0 / 14 | 0 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 |
Outcome results
Primary
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.
Time frame: 1 night
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tiagabine | Apnea Hypopnea Index (AHI) | 39.1 events/hour |
| Placebo | Apnea Hypopnea Index (AHI) | 40.8 events/hour |
p-value: >0.5Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 1 night
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tiagabine | Arousal Threshold (Esophageal Pressure Swing) | -27.6 cmH2O |
| Placebo | Arousal Threshold (Esophageal Pressure Swing) | -26.5 cmH2O |
Secondary
Slow Wave Sleep (% Total Sleep Time)
Fraction of sleep spent in stage N3
Time frame: 1 night
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tiagabine | Slow Wave Sleep (% Total Sleep Time) | 8.3 % total sleep time |
| Placebo | Slow Wave Sleep (% Total Sleep Time) | 8.8 % total sleep time |