Combination Therapy to Treat Sleep Apnea

Obstructive sleep apnea (OSA) is characterized by repetitive collapse or 'obstruction' of
the pharyngeal airway during sleep. These obstructions result in repetitive hypopneas/apneas
and intermittent hypoxia/hypercapnia, as well as surges in sympathetic activity. Such
processes disturb normal sleep and impair neurocognitive function, often resulting in
excessive daytime sleepiness and decreased quality of life. Furthermore, OSA is associated
with cardiovascular morbidity and mortality, making OSA a major health concern.

Current evidence suggests that OSA pathogenesis involves the interactions of at least four
physiological traits comprising 1) the pharyngeal anatomy and its propensity towards
collapse 2) the ability of the upper airway dilator muscles to activate and reopen the
airway during sleep (i.e. neuromuscular compensation), 3) the arousal threshold from sleep
(i.e. the propensity for hypopneas/apneas to lead to arousal and fragmented sleep) and 4)
the stability of the ventilatory feedback loop (i.e. loop gain). Continuous positive airway
pressure (CPAP) is the most common treatment for OSA but it is often poorly tolerated; only
~50% of patients diagnosed with OSA continue therapy beyond 3 months. Given this limitation,
alternative approaches have been tested and have generally focused on the use of oral
appliances, surgery, and more recently pharmacological agents.

However, these alternate therapies, when used alone as monotherapy, rarely abolish OSA
completely. This is not that surprising given that these treatments focus primarily on
correcting only one trait and ignore the fact that the pathogenesis of OSA is
multi-factorial. Thus the investigators hypothesize that some patients could be treated
without CPAP if more than one trait is targeted (i.e., the investigators take a
multi-factorial treatment approach). Such a multi-factorial approach is not unusual in
Medicine. Many disorders such as diabetes, asthma, hypertension, cancer and congestive heart
failure are treated with more than one medication or modality. In our view, giving CPAP to
all OSA patients is like treating every diabetic with insulin, or every asthmatic with oral
steroids - these treatments, like CPAP, are poorly tolerated and ignore the complexity of
the underlying biology.

The investigators recently published a technique that measures the four traits using
repeated 'drops' in CPAP levels during sleep. Each trait is measured in a way that allows
model-based predictions of the presence/absence of OSA. With this technique the
investigators demonstrated in a small group of CPAP-treated OSA subjects that decreasing the
sensitivity of the ventilatory feedback loop (i.e. reducing loop gain) by approximately 50%
with either acetazolamide or oxygen reduces the apnea/hypopnea index (AHI) by half.
Interestingly, our model allowed us to make the prediction that if, in addition to an agent
that reduces loop gain, the investigators also gave a drug that increases the arousal
threshold by at least 25%, then the investigators could potentially abolish OSA (rather than
just reduce its severity by 50%). This is of great interest given that the investigators
already have shown than eszopiclone increases the arousal threshold by approximately 30% and
is associated with an improvement in the AHI. However, to date there has been no study
examining the combination of an agent that reduces loop gain (i.e. oxygen) with one that
increases the arousal threshold (i.e. eszopiclone) as a treatment for OSA.

To determine the effect of combination therapy on each of the four traits and how they
contribute to our model prediction of OSA, as well as on apnea severity. Specifically the
investigators will assess:

1. The physiological traits responsible for OSA:

1. Pharyngeal anatomy and its propensity towards collapse

2. The ability of the upper airway dilator muscles to activate and reopen the airway
during sleep (i.e. neuromuscular compensation)

3. Arousal threshold from sleep (i.e. the propensity for hypopneas/apneas to lead to
arousal and fragmented sleep).

4. Stability of the ventilatory control system feedback loop (i.e. loop gain)

2. The severity of OSA (apnea-hypopnea index (AHI), percent of time with unstable
breathing, sleep quality)

STUDY DESIGN:

A single-blinded randomized control design will be used. Initially, participants will be
randomized to either the treatment or placebo arm where they will have both a clinical and
research polysomnography (PSG); these initial PSGs constitute what will be referred to as
VISIT 1 (see outcome measures). The purpose of the clinical PSG is to determine the severity
of OSA (i.e. AHI). The research PSG will measure the 4 physiological OSA traits.

During the treatment arm, in both PSGs (i.e. clinical and research) participants will be
given eszopiclone (3mg by mouth) to take before bed and be placed on oxygen throughout the
night. During the placebo arm, subjects will be given a placebo to take before bed and
placed on room air while they sleep. Participants will then have at least a 1-week washout
period and cross over to the other arm of the study whereby the clinical and research PSG
will be repeated; these studies constitute what will be referred to asVISIT 2 (see outcome
measures).

Inclusion Criteria:

- Ages 18 - 79 years

- Documented OSA (AHI > 10 events/hr Non rapid eye movement sleep supine)

- If treated then, current CPAP use (>4 hrs CPAP/night for > 2 months)

Exclusion Criteria:

- Any uncontrolled medical condition

- Any other sleep disorder (Periodic leg movement syndrome, restless legs syndrome,
insomnia, etc.)

- Use of medications known to affect sleep/arousal, breathing, or muscle physiology

- Allergy to lidocaine or Afrin

- Claustrophobia

- Alcohol consumption within 24 hours of PSG