Clinical trial NCT02264353: The Impact of Arousal Threshold in Obstructive Sleep Apnea
Official title: The Impact of Arousal Threshold in Obstructive Sleep Apnea: Donepezil's Effects on the Arousal Threshold and on the Apnea Hypopnea Index
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Obstructive Sleep Apnea
Keywords: Obstructive
Sleep Apnea
Arousal threshold
Donepezil
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
First posted: 2014-10-15
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Apnea Hypopnea Index (AHI)
timeFrame: 14 days (during overnight sleep study after donepezil or placebo is given)
Secondary outcomes:
measure: Respiratory Arousal Threshold
timeFrame: 14 days (during overnight sleep study after donepezil or placebo is given)
Other outcomes:
measure: Loop Gain
timeFrame: 14 days (during overnight sleep study after donepezil or placebo is given)
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
Study officials:
affiliation: University of California, San Diego
name: Robert Owens, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Li Y, Orr J, Jen R, Sands SA, DeYoung P, Smales E, Edwards B, Owens RL, Malhotra A. Is there a threshold that triggers cortical arousals in obstructive sleep apnea. Sleep. 2019 Jun 11;42(6):zsz047. doi: 10.1093/sleep/zsz047.
citation: Li Y, Owens RL, Sands S, Orr J, Moraes W, DeYoung P, Smales E, Jen R, Malhotra A. The Effect of Donepezil on Arousal Threshold and Apnea-Hypopnea Index. A Randomized, Double-Blind, Cross-Over Study. Ann Am Thorac Soc. 2016 Nov;13(11):2012-2018. doi: 10.1513/AnnalsATS.201605-384OC.