Combination Therapy to Treat Sleep Apnea
Condition: Sleep Apnea, Obstructive
MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive
Study type: Interventional

Summary: 
      In Obstructive sleep apnea (OSA), the upper airway closes over and over again during sleep.
      This leads to disrupted sleep (waking up during the night), daytime sleepiness, and an
      increased risk for developing high blood pressure. Currently, the best treatment for
      obstructive sleep apnea is sleeping with a mask that continuously blows air into the nose
      (i.e. Continuous positive airway pressure [CPAP] treatment). While CPAP treatment stops the
      upper airway from closing in most people, many people have difficulty sleeping with the mask
      in place and therefore do not use the CPAP treatment. This research study is being conducted
      to learn whether using a combination of therapies (i.e. a sedative and oxygen therapy) will
      improve OSA severity by altering some of the traits that are responsible for the disorder.
    

Detailed description: 
      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).
    

Intervention name(s): Placebo pill; Sedative; Room air; Oxygen
Intervention type(s): Drug; Drug; Other; Other
Intervention description(s): Subjects will receive a sugar pill (in combination with room air) during their placebo arm studies; Subjects will receive eszopiclone (in combination with medical oxygen) during their treatment arm studies; Subjects will receive room air (in combination with a sugar pill) during their placebo arm studies; Subjects will receive medical grade oxygen (in combination with eszopiclone) during their treatment arm studies
Other intervention name(s): sugar pill; Lunesta
Intervention MeSH terms: Hypnotics and Sedatives
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science