Rescue Pharmacotherapy for Obstructive Sleep Apnea

(RescOSA Trial)

Recruiting in Boston (>99 mi)

Overseen By David Andrew Wellman, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Brigham and Women's Hospital

Must be taking: Acetazolamide, Atomoxetine, Trazodone

Must not be taking: Opioids, Benzodiazepines, SSRIs, SNRIs

Disqualifiers: Central sleep apnea, COPD, Pregnancy, others

Compensation: Varies

Number of Visits: 1

Duration: 1 night

70 Participants Needed

Trial Summary

What is the purpose of this trial?

Persistent obstructive sleep apnea (OSA) is common in people treated with mandibular advancement device (MAD) or hypoglossal nerve stimulation (HGNS). For most patients, these treatments are the last line of defense. If MAD or HGNS do not work, then patients are left to suffer the consequences of undertreated OSA. In this study, the investigators want to test the addition of a drug treatment to their regimen. Endotypes will be targeted pharmacologically with one of the following drugs: acetazolamide for a high loop gain, atomoxetine-plus-eszopiclone for poor pharyngeal muscle compensation, or trazodone for a low arousal threshold. This aim is expected to provide treatment strategies for rescuing non-responders to MAD or HGNS therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as those that stimulate or depress breathing (like opioids and benzodiazepines) and SSRIs/SNRIs. If you are on any of these, you would need to stop them to participate in the trial.

What evidence supports the effectiveness of the drug combination including acetazolamide and atomoxetine for treating obstructive sleep apnea?

Research indicates that acetazolamide can reduce the severity of obstructive sleep apnea (OSA) by lowering the apnea-hypopnea index, which measures breathing interruptions during sleep. Additionally, atomoxetine combined with certain other drugs has shown modest improvements in upper airway function and reduced sleepiness in OSA patients. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Acetazolamide and eszopiclone have been studied for safety in various conditions. Acetazolamide is considered safe for improving sleep at high altitudes, while eszopiclone is approved for long-term treatment of insomnia and has been tested in over 2700 adults and elderly subjects, showing a generally safe profile. ^{1 6 7 8 9}

How does the drug acetazolamide differ from other treatments for obstructive sleep apnea?

Acetazolamide is unique because it is a medication that can be used to treat obstructive sleep apnea (OSA) at high altitudes, where other treatments like CPAP (continuous positive airway pressure) may not be practical. It works by altering the body's acid-base balance, which can help improve breathing during sleep, especially in situations where traditional therapies are not feasible. ^{4 5 10 11 12}

Eligibility Criteria

This trial is for individuals with persistent obstructive sleep apnea (OSA) who haven't found relief through mandibular advancement device (MAD) or hypoglossal nerve stimulation (HGNS). Participants must have a residual AHI of ≥15 events/hr despite these treatments. People with certain medical conditions, including severe liver or kidney issues, specific heart problems, glaucoma, and those on conflicting medications like SSRIs/SNRIs are excluded.

Inclusion Criteria

My sleep apnea treatment with a device hasn't reduced my symptoms enough.

Exclusion Criteria

I do not have any unstable major health conditions.

I do not have heart, liver, kidney issues, glaucoma, priapism, and I'm not pregnant/breastfeeding or have mental health issues that trazodone could worsen.

I have a sleep disorder like restless legs, narcolepsy, or unusual behaviors during sleep.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pharmacotherapy based on their specific OSA endotype, including drugs such as acetazolamide, atomoxetine-plus-eszopiclone, or trazodone

1 night

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Acetazolamide
• Atomoxetine and eszopiclone
• Placebo
• Trazodone

Trial Overview The study tests whether adding one of several drugs—acetazolamide, atomoxetine-plus-eszopiclone, trazodone—or a placebo can improve OSA in patients unresponsive to MAD or HGNS. Each drug targets different physiological traits contributing to OSA such as high loop gain or low arousal threshold.

Participant Groups

Group I: Interventional arm Active Control 3 Interventions

This is a two arm study. Patients will receive only one of the following drugs based on their altered sleep apnea trait. Patients with decreased arousal threshold will undergo treatment with placebo or Trazodone 100 mg in random order (one pill before 30 minutes before bedtime), patients with decreased pharyngeal muscle responsiveness will undergo treatment with placebo or Atomoxetine 80 mg + Eszopiclone 3 mg in random order (one pill before 30 minutes before bedtime), patients with increased loop gain will undergo treatment with placebo or Acetazolamide 500 mg in random order (one pill before 30 minutes before bedtime).

Group II: Placebo Placebo Group 1 Intervention

This is a two arm study. Patients will receive only one of the following drugs based on their altered sleep apnea trait. Patients with decreased arousal threshold will undergo treatment with placebo or Trazodone 100 mg in random order (one pill before 30 minutes before bedtime), patients with decreased pharyngeal muscle responsiveness will undergo treatment with placebo or Atomoxetine 80 mg + Eszopiclone 3 mg in random order (one pill before 30 minutes before bedtime), patients with increased loop gain will undergo treatment with placebo or Acetazolamide 500 mg in random order (one pill before 30 minutes before bedtime).

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Findings from Research

The combination of atomoxetine and trazodone (Ato-Trazo) significantly reduced the apnea-hypopnea index in patients with obstructive sleep apnea (OSA), indicating improved severity of the condition, with a reduction from 18.2 to 7.4 events per hour (P = .024).

Unlike previous treatments, Ato-Trazo did not lower the arousal threshold, suggesting it may be better tolerated by patients, although it worsened self-reported sleep quality and further studies are needed to optimize dosage and identify the best patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. Corser, B., Eves, E., Warren-McCormick, J., et al.[2023]

In a study of 18 adults with obstructive sleep apnea (OSA), the combination of atomoxetine and trazodone significantly reduced the apnea-hypopnea index (AHI) and improved other sleep parameters compared to placebo, indicating better respiratory function during sleep.

The A-T combination also led to fewer apneas, less oxygen desaturation, and reduced respiratory arousals, suggesting it could be a viable alternative treatment for patients who struggle with standard OSA therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study. Shahbazi, M., Heidari, R., Tafakhori, A., et al.[2023]

In a study involving 10 participants with severe obstructive sleep apnea (OSA), the combination of atomoxetine with solifenacin improved upper airway function, reducing the frequency of obstructive apneas and increasing oxygen levels during sleep, although it did not significantly change overall OSA severity compared to placebo.

The combination of atomoxetine with biperiden reduced next-day sleepiness, indicating potential benefits for alertness, but overall, both combinations had modest effects compared to previous findings with atomoxetine and oxybutynin, suggesting that the choice of antimuscarinic agent can influence treatment outcomes for OSA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity. Aishah, A., Lim, R., Sands, SA., et al.[2023]

A systematic review of 58 randomized controlled trials involving 1710 patients found that while some drugs, like acetazolamide, showed a small reduction in the apnoea-hypopnoea index (AHI), the overall efficacy of pharmacotherapy for obstructive sleep apnoea (OSA) remains limited.

Despite some drugs demonstrating potential benefits, the effects were generally small and not clinically significant, indicating that there is currently insufficient evidence to recommend any pharmacotherapy for OSA, and no large-scale phase-III trials have been conducted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of pharmacotherapy for OSA in adults: A systematic review and network meta-analysis. Gaisl, T., Haile, SR., Thiel, S., et al.[2020]

Acetazolamide has been established as the most effective medication for treating sleep apnea syndrome (SAS), outperforming other pharmacological options.

Other therapeutic approaches for SAS, including nasal CPAP, dental appliances, and surgeries, have not shown satisfactory effects when acetazolamide is not included in the treatment plan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Drug therapy for sleep apnea syndrome]. Takahashi, Y., Shimizu, T.[2013]

Insomnia is a common issue for patients with chronic obstructive pulmonary disease (COPD), and treating it effectively is crucial for their overall care.

Traditional benzodiazepines may worsen respiratory function in COPD patients, so alternative treatments like non-benzodiazepine receptor agonists (e.g., eszopiclone, zolpidem) and melatonin receptor agonists (e.g., ramelteon) are being considered for safer management of insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypnotic use for insomnia management in chronic obstructive pulmonary disease. Roth, T.[2009]

Eszopiclone, approved in the U.S. in 2004, is an effective treatment for insomnia and has been studied for its use in patients with conditions like obstructive sleep apnea, highlighting its versatility in managing sleep disorders.

The review discusses safety concerns, including its effects on taste (dysgeusia) and potential impacts on memory and cognitive functions, which are important considerations for its use in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eszopiclone: an update on its use in insomnia. Owen, RT.[2017]

Acetazolamide, temazepam, zolpidem, and zaleplon are supported by available data as effective and safe options for improving sleep at high altitudes, based on a review of pharmacologic interventions.

Diazepam should be avoided at high altitude due to the risk of hypoventilation, while other common sleep medications like eszopiclone and diphenhydramine, though not specifically studied at altitude, are likely safe based on their known effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Which medications are safe and effective for improving sleep at high altitude? Luks, AM.[2018]

Eszopiclone (Lunesta) is an FDA-approved short-acting hypnotic agent effective for treating insomnia, with a duration of effect lasting up to 6 hours, which helps improve sleep maintenance and reduce nocturnal awakenings.

Clinical trials involving over 2700 adult and elderly subjects demonstrated that eszopiclone is effective for both sleep onset and maintenance, and it showed enhanced efficacy when combined with fluoxetine in patients with insomnia and major depressive disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone--Sepracor. [2018]

Acetazolamide significantly improves sleep apnea at high altitudes by reducing the Apnea-Hypopnea Index (AHI) and increasing nocturnal oxygenation, particularly in healthy trekkers compared to those with obstructive sleep apnea (OSA).

A daily dose of 250 mg of acetazolamide may be as effective as higher doses for healthy individuals, suggesting a potential optimal therapeutic dose for treating sleep apnea in high-altitude conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of acetazolamide on sleep apnea at high altitude: a systematic review and meta-analysis. Liu, HM., Chiang, IJ., Kuo, KN., et al.[2018]

Treatment-emergent central sleep apnoea (TECSA) can occur in about 8% of patients using CPAP for obstructive sleep apnoea, but it often resolves on its own in 60% to 80% of cases.

In a case study of a 74-year-old man, adding acetazolamide to CPAP treatment effectively resolved his TECSA, suggesting that acetazolamide may be a beneficial adjunct therapy for patients with significant symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-emergent central sleep apnoea managed by CPAP with adjunctive acetazolamide: A case report. Kwok, CT., Wong, KC., Kwok, CL., et al.[2022]

In a study involving 45 patients with obstructive sleep apnea (OSA), acetazolamide significantly improved oxygen levels and reduced breathing disturbances at high altitudes compared to a placebo, indicating its potential as an alternative treatment when CPAP is not used.

Acetazolamide not only enhanced nocturnal oxygen saturation and reduced apnea/hypopnea indices but also improved sleep quality and prevented high blood pressure during altitude exposure, suggesting it stimulates ventilation effectively in OSA patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. Nussbaumer-Ochsner, Y., Latshang, TD., Ulrich, S., et al.[2017]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Efficacy of pharmacotherapy for OSA in adults: A systematic review and network meta-analysis. [2020]

5. Japan pubmed.ncbi.nlm.nih.gov

[Drug therapy for sleep apnea syndrome]. [2013]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Hypnotic use for insomnia management in chronic obstructive pulmonary disease. [2009]

7. Spain pubmed.ncbi.nlm.nih.gov

Eszopiclone: an update on its use in insomnia. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Which medications are safe and effective for improving sleep at high altitude? [2018]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone--Sepracor. [2018]

10. England pubmed.ncbi.nlm.nih.gov

The effect of acetazolamide on sleep apnea at high altitude: a systematic review and meta-analysis. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Treatment-emergent central sleep apnoea managed by CPAP with adjunctive acetazolamide: A case report. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. [2017]