Rescue Pharmacotherapy for Obstructive Sleep Apnea
(RescOSA Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
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
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.12345
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.16789
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.45101112
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.
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Trial 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 (Other)
- Atomoxetine and eszopiclone (Other)
- Placebo (Other)
- Trazodone (Other)
Trial OverviewThe 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
2Treatment groups
Active Control
Placebo Group
Group I: Interventional armActive Control3 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: PlaceboPlacebo Group1 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).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Sleep Disorders Research Program Brigham and Women's HospitalBoston, MA
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Who Is Running the Clinical Trial?
Brigham and Women's HospitalLead Sponsor
References
Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. [2023]Pharmacotherapy for obstructive sleep apnea (OSA) regained consideration after the discovery that atomoxetine and oxybutynin greatly reduced OSA severity. However, atomoxetine and oxybutynin reduced the arousal threshold and may therefore be poorly tolerated in patients with OSA and disturbed sleep. As a result, we tested the combination of atomoxetine plus 2 hypnotics in patients with OSA. The effects of atomoxetine plus: (1) trazodone (Ato-Trazo) and (2) lemborexant vs placebo on apnea-hypopnea index, hypoxic burden, arousal threshold, and total sleep time were assessed. Drug safety was also ascertained, together with the effect of the combinations on other OSA traits, self-reported sleep quality, and next-day alertness.
The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study. [2023]we aimed to compare the effects of atomoxetine and trazodone (A-T) in combination with placebo in patients with obstructive sleep apnea (OSA).
Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity. [2023]The combination of the noradrenergic agent atomoxetine plus the antimuscarinic oxybutynin has recently been shown to improve upper airway physiology and reduce obstructive sleep apnea (OSA) severity. However, the effects of different antimuscarinics when combined with atomoxetine is limited. This study aimed to determine the effects of atomoxetine combined with two different antimuscarinics with varying M-subtype receptor selectivity on OSA severity and upper airway physiology. Ten people with predominantly severe OSA completed a double-blind, randomized, placebo-controlled, cross-over trial. Participants completed three overnight in-laboratory sleep studies after either 80 mg atomoxetine + 5 mg solifenacin succinate (ato-sol) or 80 mg atomoxetine + 2 mg biperiden hydrochloride (ato-bip) or placebo. OSA severity, ventilatory stability (loop gain), respiratory-arousal threshold (via epiglottic manometry), next-day subjective sleepiness [Karolinska Sleepiness Scale (KSS)], and alertness were compared between conditions. Neither drug combination altered the apnea/hypopnea index versus placebo (P = 0.63). Ato-sol caused a shift toward milder respiratory events with reduced frequency of obstructive apneas (13 ± 14 vs. 22 ± 17 events/h; means ± SD, P = 0.04) and increased hypopneas during nonrapid eye movement (NREM) (38 ± 21 vs. 24 ± 18 events/h, P = 0.006) with improved nadir oxygenation versus placebo (83 ± 4 vs. 80 ± 8%, P = 0.03). Both combinations reduced loop gain by ∼10% versus placebo; sleep efficiency and arousal threshold were unaltered. Ato-bip reduced next-day sleepiness versus placebo (KSS = 4.3 ± 2.2 vs. 5.6 ± 1.6, P = 0.03). Atomoxetine + biperiden hydrochloride reduces perceived sleepiness, and atomoxetine + solifenacin modestly improves upper airway function in people with OSA but to a lesser extent versus recently published atomoxetine + oxybutynin (broad M-subtype receptor selectivity) findings. These results provide novel mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.NEW & NOTEWORTHY In contrast to recent findings of major reductions in OSA severity when atomoxetine is combined with a nonspecific antimuscarinic, oxybutynin (broad M-subtype receptor selectivity), addition of solifenacin succinate (M2 and M3 muscarinic receptor selectivity) or biperiden (M1 muscarinic receptor selectivity) with atomoxetine had modest effects on upper airway function during sleep, which provide mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.
Efficacy of pharmacotherapy for OSA in adults: A systematic review and network meta-analysis. [2020]Pharmacotherapy represents a desirable potential therapeutic alternative for patients with obstructive sleep apnoea (OSA). We aimed to summarize evidence on the efficacy of pharmacotherapy in adults with OSA and delineate the underlying mechanisms. Seven databases were systematically screened for randomised controlled trials (RCTs) from their inception to September 2018. According to a pre-registered study protocol (PROSPERO-ID-CRD42018086446) network meta-analysis was performed to obtain intervention effects on the apnoea-hypopnoea-index (AHI) based on data extracted from published reports. We identified 58 RCTs (n = 1710 patients) investigating 44 different drugs or drug-combinations. Interventions were classified into seven pathomechanism-groups and summarized narratively. A meta-analysis of 17 trials for seven drugs (acetazolamide, donepezil, mirtazapine, ondansetron, paroxetine, protriptyline, theophylline) indicated a small effect for acetazolamide (mean difference in AHI -9.6/h [-17.7; -1.4]; p = 0.02). In the network meta-analysis (I2 = 50%) nine drugs (tramazoline, liraglutide, spironolactone/furosemide, acetazolamide, dronabinol, zonisamide, phentermine, spironolactone, and ondansetron/fluoxetine) significantly lowered the AHI compared to placebo. Although some trials indicate favorable outcomes, these results are only valid for distinctive OSA-phenotypes or were not clinically significant. The effect sizes were small, the majority of trials were not adequately powered. There is currently insufficient evidence to recommend any pharmacotherapy for OSA and no phase-III trials are available.
[Drug therapy for sleep apnea syndrome]. [2013]The number of patients suffering from sleep apnea syndrome(SAS) have been increased. In recent years, many therapeutic approaches such as nasal CPAP, dental appliance, upper airway surgery, pharmacological agents, have been used for the treatment of SAS. The various drugs(acetazolamide, some tricyclic antidepressant, progesterone, theophylline, aminophylline and so on) have been used for pharmacotherapy of SAS. Acetazolamide have been established as the best medication. But all approaches without acetazolamide, could not shown their satisfactory effects on SAS. In this article, drug therapy for SAS is described.
Hypnotic use for insomnia management in chronic obstructive pulmonary disease. [2009]Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and morbidity worldwide. Because of the chronic nature of the disease, optimal care for patients includes successful treatment of comorbidities that accompany COPD, including insomnia. Insomnia symptoms and associated disruption of sleep are prevalent in COPD patients but treatment with traditional benzodiazepines may compromise respiratory function. This review summarizes the efficacy and safety consideration of current drugs available for the treatment of insomnia in COPD patients including benzodiazepines, non-benzodiazepine receptor agonists such as eszopiclone, zolpidem, and zaleplon, sedating antidepressants such as trazodone, and the melatonin receptor agonist ramelteon.
Eszopiclone: an update on its use in insomnia. [2017]Eszopiclone is the single (S)-enantiomer of the cyclopyrrolone hypnotic zopiclone. It was marketed in the U.S. in December 2004. Its kinetics and possible mode of action, pivotal regulatory trials and its use in insomnia comorbid with other conditions are reviewed, together with trials in patients with obstructive sleep apnea syndromes. Safety and tolerability aspects are discussed, including its dysgeusic profile and effects on memory, cognitive and psychomotor function. U.S.-based pharmacoeconomic data are included together with the design features of key regulatory studies submitted for regulatory approval in Japan.
Which medications are safe and effective for improving sleep at high altitude? [2018]Given the well-established problems with sleep at high altitude, it is not uncommon for people planning trips to the mountains to seek advice from clinicians regarding pharmacologic options for improving sleep during their trip. This review article considers the various medications that have been studied for this purpose at high altitude with an emphasis on both their efficacy and safety. The available data support the use of either acetazolamide, temazepam, zolpidem or zaleplon in this environment. Other agents commonly used at sea-level such as eszopiclone and diphenhydramine have not been studied at high altitude but are likely safe to use given their mechanism of action and known side effects. Limited evidence suggests diazepam may cause hypoventilation at high altitude and its use in this environment should be discouraged. Insufficient data exist to determine which agent is most effective at altitude nor do we know whether combination therapy with acetazolamide and a hypnotic agent offers any benefits over monotherapy.
Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone--Sepracor. [2018]Eszopiclone [Lunesta, Estorra] is a short-acting hypnotic agent that is a stereoselective isomer of the agent zopiclone, which has been available in Europe since 1992. Eszopiclone is structurally unrelated to the benzodiazepines, and Sepracor (the originator of eszopiclone) has stated that the drug acts rapidly, with the duration of effect lasting up to 6 hours. This may result in improved sleep maintenance, with less nocturnal awakening.Originally, racemic zopiclone was developed and marketed by Rhone-Poulenc Rorer, which merged with Hoechst Marion Roussel to form Aventis. Sepracor anticipates that eszopiclone will have equivalent efficacy to the racemic version with potential for an improved side effect profile. In October 1999, Sepracor exclusively licensed Aventis Pharma's preclinical, clinical and postmarketing surveillance data package for zopiclone, its isomers and metabolites. The company intends to use this information in addition to data from Sepracor's own studies as part of the regulatory package to gain approval of eszopiclone in the US. In July 2004, Sepracor announced terms of an additional agreement with Aventis under which it would have the right to read and reference Aventis' regulatory filings related to zopiclone outside the US for the purpose of development and regulatory registration of eszopiclone outside the US. Additionally, Aventis would assign Sepracor the foreign counterparts to the US patent covering eszopiclone and its therapeutic use. In August 2004, Paul Royalty Fund II, an affiliate of Paul Capital Partners, purchased from Sanofi-Aventis the royalty rights on US sales of eszopiclone. In exchange for the rights, Sanofi-Aventis will receive fixed and milestone payments totalling up to US$115 million. In December 2004 the US FDA approved eszopiclone (Lunesta) for the treatment of insomnia. It is indicated for patients who experience difficulty falling asleep as well as for patients who have sleep maintenance difficulty, and is approved for long-term treatment. The recommended dosing to improve sleep onset and/or maintenance is 2mg or 3mg for adult patients (aged 18-64 years) and 2mg for older adult patients (aged > or =65 years). The 1mg dose is for sleep onset in older adult patients whose primary complaint is difficulty falling asleep. The launch of eszopiclone in the US is expected to take place in the first quarter of 2005. The approval follows an NDA submission in January 2003, an approvable letter in February 2004, and a resubmission of the NDA in June 2004. The NDA contained data from 24 clinical trials that included >2700 adult and elderly subjects, as well as data from >60 preclinical studies. Six phase III trials in adult and elderly patients with chronic or transient insomnias were also included in the data submission. Preliminary results from a completed phase IIIB/IV trial report that eszopiclone in combination with fluoxetine significantly improved sleep parameters among patients with insomnia and co-existing major depressive disorder. Furthermore the combination of eszopiclone and fluoxetine resulted in greater improvement in HAM-D17 scores in patients than the fluoxetine-placebo group. This trial and three other phase IIIB/IV were initiated in late 2003 to evaluate the efficacy of eszopiclone in the treatment of insomnia in patients with depression, rheumatoid arthritis, chronic insomnia, and in women who experience symptoms of perimenopause. Sepracor has been granted a US patent for eszopiclone [S-zopiclone, (+)-zopiclone, Lunesta, Estorra], a single isomer of zopiclone.US patents (Nos. 6,319,926 and 6,444,673) have been issued covering the use of eszopiclone for the treatment of insomnia, eszopiclone and pharmaceutical compositions comprising eszopiclone.
The effect of acetazolamide on sleep apnea at high altitude: a systematic review and meta-analysis. [2018]Acetazolamide has been investigated for treating sleep apnea in newcomers ascending to high altitude. This study aimed to assess the effect of acetazolamide on sleep apnea at high altitude, determine the optimal therapeutic dose, and compare its effectiveness in healthy trekkers and obstructive sleep apnea (OSA) patients.
Treatment-emergent central sleep apnoea managed by CPAP with adjunctive acetazolamide: A case report. [2022]Treatment-emergent central sleep apnoea (TECSA) refers to the emergence of central apnoea during treatment for obstructive sleep apnoea (OSA), most commonly continuous positive airway pressure (CPAP). It has been reported in 8% of OSA patients treated with CPAP and spontaneous resolution rate varies between 60% and 80%. Management options include watchful waiting with continuation of CPAP, bi-level positive pressure ventilation, adaptive servo-ventilation and CPAP with supplemental oxygen. Acetazolamide has been shown to be effective in other forms of central sleep apnoea; its use as adjunct to CPAP in TECSA is sparsely reported. We report a 74-year-old man with severe OSA who developed moderate central apnoea upon CPAP initiation. Subsequent addition of acetazolamide led to gratifying resolution of the TECSA. In TECSA patients with significant symptoms and high central apnoea index, treatment with acetazolamide as adjunct to CPAP may be considered, particularly in patients in whom CPAP adherence is imperative.
Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. [2017]Many patients with obstructive sleep apnea syndrome (OSA) are unable or unwilling to use continuous positive airway pressure (CPAP) therapy when traveling to the mountains for work or recreation even though they risk pronounced hypoxemia and exacerbation of sleep apnea. Because the treatment of OSA at altitude has not been established, we tested the hypothesis that acetazolamide improves hypoxemia, sleep, and breathing disturbances in otherwise untreated patients with OSA at altitude.