Obstructive Sleep Apnea
Conditions
Keywords
Obstructive, Sleep Apnea, Arousal threshold, Donepezil
Brief summary
The investigators hypothesis is that obstructive sleep apnea (OSA) patients with a low arousal threshold may wake up too early during a respiratory event, before upper airway muscles can be activated to achieve stable ventilation. Thus, strategies to manipulate the respiratory arousal threshold could potentially improve the quality of sleep and sleep disordered breathing. Agents that raise arousal threshold are therefore likely to benefit some patients with OSA. The overall goal of this project is to determine the importance of the arousal threshold in OSA, determine which patients might benefit from a raised arousal threshold, and test this hypothesis by using pharmacological manipulation of the arousal threshold to achieve this goal.
Detailed description
This study is a pilot study. The investigators will test whether donepezil has important effects on the arousal threshold and on the apnea hypopnea index. Donepezil is a cholinesterase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of symptoms of Alzheimer's disease. Eligible participants will undergo overnight polysomonography as described below and will receive either donepezil (10 mg immediately prior to sleep) or placebo (in random order) followed roughly 14 days later with placebo or donepezil. This aim will allow us to test the impact of donepezil on the apnea hypopnea index. The study plans to enroll approximately 30 subjects. The change in apnea hypopnea index as well as arousal thresholds/upper airway mechanics will be compared in the donepezil groups with the placebo group.
Interventions
DRUGDonepezil
Donepezil 10mg before sleep
DRUGplacebo
One piece of placebo before sleep
Sponsors
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Ages 18-70 years * sleep study (with apnea hypopnea index\>5) * Diagnosis of obstructive sleep apnea
Exclusion criteria
* Any known unstable cardiac (apart from treated hypertension), pulmonary (including asthma), renal, neurologic (including epilepsy), neuromuscular, or hepatic disease. * Susceptible to stomach ulcers. * Pregnant women or Nursing mothers * Using positive airway pressure (PAP) therapy over one week or longer * Body weight \<55kg * History of hypersensitivity to Afrin, Lidocaine and/or Donepezil * History of bleeding diathesis and/or gastrointestinal bleeding. * Use of any medications that may affect sleep or breathing. * A psychiatric disorder, other than mild depression; e.g. schizophrenia, bipolar disorder, major depression, panic or anxiety disorders. * Substantial cigarette (\>5/day), alcohol (\>3oz/day) or use of illicit drugs. * More than 10 cups of beverages with caffeine (coffee, tea, soda/pop) per day. * Deprived from sleep in the recent one week * Desaturations to below 70% lasting greater than 10 seconds in duration per event in the sleep study (without Oxygen).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apnea Hypopnea Index (AHI) | 14 days (during overnight sleep study after donepezil or placebo is given) | The Apnea-Hypopnea Index or Apnoea-Hypopnoea Index (AHI) is an index used to indicate the severity of sleep apnea. It is represented by the number of apnea and hypopnea events per hour of sleep. The apneas (pauses in breathing) must last for at least 10 seconds and be associated with a decrease in blood oxygenation. A higher AHI value indicates more severe sleep apnea |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Respiratory Arousal Threshold | 14 days (during overnight sleep study after donepezil or placebo is given) | Arousal Threshold was measured as the average nadir epiglottic airway pressure immediately before electroencephalogram (EEG) arousal. It was measured with an epiglottic pressure catheter. The epiglottic catheter/balloon is linked in a pressure catheter inserted through the de-congested, anesthetized nostril and the tip of the catheter located at hypopharyngeal area. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Loop Gain | 14 days (during overnight sleep study after donepezil or placebo is given) | The sensitivity of the ventilatory control system (loop gain) was quantified by fitting a simplified mathematical model to the spontaneous ventilatory pattern of obstructive sleep apnea (OSA). The sensitivity of the ventilatory control system (loop gain) was quantified by fitting a simplified mathematical model to the spontaneous ventilatory pattern of OSA 21. Loop gain is reflected in the size of the ventilatory overshoot following a ventilatory perturbation (hypopnea/apnea), where loop gain = response/disturbance. Ventilatory fluctuations are estimated using the square-root transformed nasal pressure waveform. Loop gain was reported as the ventilatory response to a 1 cycle/min disturbance (LG1); a value of LGn\>1 yields periodic central apnea. Calculations were performed using MATLAB |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants who were randomized to receive either Donepezil 10mg tablet or Placebo tablet (matching Donepezil 10mg) before sleep | 41 |
| Total | 41 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants |
| Age, Continuous | 51.6 years STANDARD_DEVIATION 11.1 |
| Apnea Hypopnea Index (AHI)>5 events/hr; lowest Oxygen Saturation (SaO2)>70% | 41 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 33 Participants |
| Region of Enrollment United States | 41 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 41 |
| other Total, other adverse events | 0 / 41 | 2 / 41 |
| serious Total, serious adverse events | 0 / 41 | 0 / 41 |
Outcome results
Primary
Apnea Hypopnea Index (AHI)
The Apnea-Hypopnea Index or Apnoea-Hypopnoea Index (AHI) is an index used to indicate the severity of sleep apnea. It is represented by the number of apnea and hypopnea events per hour of sleep. The apneas (pauses in breathing) must last for at least 10 seconds and be associated with a decrease in blood oxygenation. A higher AHI value indicates more severe sleep apnea
Time frame: 14 days (during overnight sleep study after donepezil or placebo is given)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Apnea Hypopnea Index (AHI) | 50.0 events/hour | Standard Deviation 23.4 |
| Placebo | Apnea Hypopnea Index (AHI) | 51.8 events/hour | Standard Deviation 27.4 |
p-value: 0.576t-test, 2 sided
Secondary
Respiratory Arousal Threshold
Arousal Threshold was measured as the average nadir epiglottic airway pressure immediately before electroencephalogram (EEG) arousal. It was measured with an epiglottic pressure catheter. The epiglottic catheter/balloon is linked in a pressure catheter inserted through the de-congested, anesthetized nostril and the tip of the catheter located at hypopharyngeal area.
Time frame: 14 days (during overnight sleep study after donepezil or placebo is given)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Donepezil | Respiratory Arousal Threshold | -18.0 cm H20 |
| Placebo | Respiratory Arousal Threshold | -18.9 cm H20 |
p-value: 0.394Wilcoxon (Mann-Whitney)
Other Pre-specified
Loop Gain
The sensitivity of the ventilatory control system (loop gain) was quantified by fitting a simplified mathematical model to the spontaneous ventilatory pattern of obstructive sleep apnea (OSA). The sensitivity of the ventilatory control system (loop gain) was quantified by fitting a simplified mathematical model to the spontaneous ventilatory pattern of OSA 21. Loop gain is reflected in the size of the ventilatory overshoot following a ventilatory perturbation (hypopnea/apnea), where loop gain = response/disturbance. Ventilatory fluctuations are estimated using the square-root transformed nasal pressure waveform. Loop gain was reported as the ventilatory response to a 1 cycle/min disturbance (LG1); a value of LGn\>1 yields periodic central apnea. Calculations were performed using MATLAB
Time frame: 14 days (during overnight sleep study after donepezil or placebo is given)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Loop Gain | 0.55 Unitless | Standard Deviation 0.15 |
| Placebo | Loop Gain | 0.58 Unitless | Standard Deviation 0.16 |
p-value: 0.089t-test, 2 sided