Eszopiclone for Obstructive Sleep Apnea

(TOP-CPAP Trial)

Overseen By Pamela DeYoung, RPSGT

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must be taking: Hypnotics

Must not be taking: Opioids, Benzodiazepines

Disqualifiers: Uncontrolled conditions, Pregnancy, Others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 2 weeks

50 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you do not regularly use opioids, benzodiazepines, or other hypnotics. If you are taking these medications, you may need to stop them to participate.

What data supports the effectiveness of the drug Eszopiclone for treating obstructive sleep apnea?

Research shows that while Eszopiclone, a drug used for insomnia, does not worsen obstructive sleep apnea (OSA) severity, it may not significantly improve it either. However, combining Eszopiclone with supplemental oxygen has shown marked improvement in OSA in some patients. ^{1 2 3 4 5}

Is Eszopiclone (Lunesta) generally safe for humans?

The safety profile of a drug like Eszopiclone can change after it is marketed, and safety issues not identified during clinical development may appear later. Regulatory agencies monitor product safety through various mechanisms, including reports of adverse experiences and safety studies, to ensure ongoing evaluation of risks. ^{6 7 8 9 10}

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

Eszopiclone is unique because it is a non-benzodiazepine hypnotic that selectively targets certain subunits of the GABA(A) receptor, which may help improve sleep maintenance and reduce awakenings. Unlike traditional treatments for obstructive sleep apnea, which often focus on mechanical interventions like CPAP machines, eszopiclone is a medication that may offer an alternative approach by enhancing sleep quality. ^{1 2 11 12 13}

What is the purpose of this trial?

More than 10% of the US population have obstructive sleep apnea (OSA). Standard of care is therapy with CPAP (continuous positive airway pressure) which virtually eliminates OSA. However, most patients use CPAP only for part of the night (4-5hours) and about 50% patients discontinue CPAP long-term. Alternative therapies are limited, thus many OSA patients remain at risk of OSA sequelae (e.g. sleepiness, memory issues, high blood pressure, etc.). Importantly, different patients get OSA for different reasons, and recent data show that some of the underlying causes of OSA ("endotypes") such as having a low arousal threshold (i.e. waking up easily) are associated with lower CPAP adherence. Using a randomized controlled trial design, this will be the first study using a targeted intervention to manipulate the underlying OSA causes (i.e., giving a safe hypnotic to patients with OSA to increase the arousal threshold) to test the hypothesis that endotype-targeted therapy increases CPAP-adherence in patients who have low but continued CPAP usage. Ultimately, this strategy may improve the care and outcomes of millions of undertreated OSA patients.

Research Team

Christopher N Schmickl, MD, PhD

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for adults aged 21-65 with a physician's diagnosis of obstructive sleep apnea (OSA), BMI under 32, and who use CPAP machines for 0.5-4 hours per night but want to continue trying CPAP. Excluded are those with significant side effects from CPAP, uncontrolled medical conditions, substance abuse, certain sleep disorders, or safety concerns.

Inclusion Criteria

Your body mass index is less than 32.

I am willing to keep using CPAP for my condition.

I have been diagnosed with sleep apnea based on a sleep study in the last 2 years.

Exclusion Criteria

I experience more than 3 issues with my CPAP machine.

Safety concern based on MD judgment

Any uncontrolled medical/psychiatric condition, or safety concern based on MD judgment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive CPAP+Eszopiclone or CPAP+Placebo for 2 weeks to test the effect on CPAP adherence

2 weeks

Daily self-administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of CPAP usage, sleepiness, and other outcomes

2 weeks

1 visit (in-person) at the end of treatment

Treatment Details

Interventions

• Eszopiclone

Trial Overview The TOP-CPAP study tests whether taking Eszopiclone—a hypnotic drug—can help people with OSA adhere better to their CPAP therapy by targeting the underlying cause of their condition. It's a randomized controlled trial comparing Eszopiclone against a placebo.

Participant Groups

Group I: Eszopiclone Experimental Treatment 1 Intervention

Subjects will be asked to take their study drugs nightly at bedtime and use their CPAP during sleep as much as possible

Group II: Placebo Placebo Group 1 Intervention

Subjects will be asked to take their study drugs nightly at bedtime and use their CPAP during sleep as much as possible

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

American Academy of Sleep Medicine

Collaborator

Trials

29

Recruited

3,000+

Findings from Research

Eszopiclone did not significantly change the apnea and hypopnea index (AHI) in patients with mild to moderate obstructive sleep apnea syndrome (OSAS), indicating it does not worsen respiratory issues during sleep.

However, eszopiclone improved sleep maintenance and efficiency, leading to less wake time after sleep onset and during sleep, suggesting potential benefits for overall sleep quality in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study evaluating acute use of eszopiclone in patients with mild to moderate obstructive sleep apnea syndrome. Rosenberg, R., Roach, JM., Scharf, M., et al.[2014]

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]

In a study involving 20 patients with obstructive sleep apnea (OSA), a combination therapy of eszopiclone and oxygen significantly reduced the severity of OSA, as shown by a decrease in the apnea-hypopnea index from 51.9 to 29.5 events per hour (P < 0.001).

Responders to the combination therapy exhibited less severe OSA and better upper airway muscle effectiveness, indicating that targeting both non-anatomical traits (like loop gain and arousal threshold) can effectively resolve OSA in patients with less compromised airway anatomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Combination of Supplemental Oxygen and a Hypnotic Markedly Improves Obstructive Sleep Apnea in Patients with a Mild to Moderate Upper Airway Collapsibility. Edwards, BA., Sands, SA., Owens, RL., et al.[2019]

In a 6-month open-label extension study involving 360 adults with primary insomnia, eszopiclone significantly improved sleep quality, reduced sleep latency, and enhanced daytime functioning without evidence of tolerance.

Patients who switched from placebo to eszopiclone maintained and even further improved their sleep and daytime function over the 6-month period, with the treatment being well tolerated, aside from a mild side effect of unpleasant taste.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Roth, T., Walsh, JK., Krystal, A., et al.[2022]

A 1-month treatment with zopiclone did not worsen obstructive sleep apnoea (OSA) severity or increase next-day sleepiness and alertness in patients with low-moderate respiratory arousal thresholds, suggesting it may be safe for selected individuals.

The study, involving 30 patients and comparing zopiclone to a placebo, found no significant differences in the apnoea-hypopnoea index (AHI) or hypoxaemia levels, providing valuable long-term safety data on hypnotic use in OSA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of 1 month of zopiclone on obstructive sleep apnoea severity and symptoms: a randomised controlled trial. Carter, SG., Carberry, JC., Cho, G., et al.[2019]

The definition of an adverse drug event (ADE) should be tailored to the specific purpose of the evaluation, with stricter definitions needed for scientific studies and more flexible ones for clinical use.

Postmarketing safety data for drugs is limited at launch, but can be supplemented through systems like the FDA's Spontaneous Reporting System and targeted research projects, emphasizing the importance of robust epidemiological evidence for regulatory actions like drug recalls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug events: identification and attribution. Rogers, AS.[2022]

The Italian version of the Liverpool Adverse Events Profile (iLAEP) was validated as a reliable tool for monitoring adverse events of antiepileptic drugs (AEDs) in 204 patients, showing high internal consistency and a quick completion time of about 9 minutes.

The iLAEP effectively predicts treatment discontinuation, with a cutoff score of 36.5 indicating a significant risk of dropout, as patients scoring above this threshold had a 20.27-fold increased risk of stopping their AED treatment within 3 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liverpool Adverse Events Profile: Italian validation and predictive value for dropout from antiepileptic treatment in people with epilepsy. Romoli, M., Eusebi, P., Siliquini, S., et al.[2019]

In a study involving 2080 patients across outpatient clinics in Mexico, Peru, Brazil, and Colombia, adverse events (AEs) were found to have a prevalence of 5.2% and a cumulative incidence of 2.4%, indicating a significant occurrence of AEs in ambulatory care settings in Latin America.

Importantly, 44% of the AEs identified during the prevalence period and 52.4% during the incidence period were considered preventable, highlighting the potential for improving patient safety through targeted interventions, especially considering factors like socioeconomic status and types of errors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frequency of ambulatory care adverse events in Latin American countries: the AMBEAS/PAHO cohort study. Montserrat-Capella, D., Suárez, M., Ortiz, L., et al.[2016]

The safety profile of medications can change after they are approved for public use, as new safety issues may arise that were not identified during clinical trials.

Regulatory agencies, like the FDA, actively monitor medication safety through various methods, including analyzing adverse experience reports and using large electronic databases to detect potential safety signals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring product safety in the postmarketing environment. Sharrar, RG., Dieck, GS.[2021]

In a study of 309 epilepsy patients in Poland, 73.8% reported at least one adverse event (AE) while on antiepileptic drugs (AEDs), with cognitive disturbances, psychological issues, and sedation being the most common AEs.

Treatment modifications occurred in 22.3% of patients, primarily due to lack of efficacy (10.7%) and adverse events (5.2%), highlighting the need for careful monitoring of AED effectiveness and side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pattern of adverse events of antiepileptic drugs: results of the aESCAPE study in Poland. Chmielewska, B., Lis, K., Rejdak, K., et al.[2022]

Eszopiclone is an effective treatment for chronic primary insomnia, significantly improving sleep onset, reducing awakenings, and increasing total sleep time in both non-elderly and elderly subjects, based on randomized controlled studies lasting up to 6 months.

Unlike traditional benzodiazepines, eszopiclone does not significantly affect slow wave sleep or REM sleep, and it does not lead to tolerance over a 12-month period, making it a safer long-term option for sleep management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eszopiclone: its use in the treatment of insomnia. Monti, JM., Pandi-Perumal, SR.[2021]

Eszopiclone, a non-benzodiazepine hypnotic, has been associated with acute liver injury in a patient with chronic hepatitis B, marking the first reported case of such an adverse effect linked to this medication.

The patient's liver enzyme levels returned to normal within a week after discontinuing eszopiclone, highlighting the importance of monitoring liver function in patients with pre-existing liver conditions when prescribing this drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report of acute liver injury caused by the eszopiclone in a patient with chronic liver disease. Wu, T., Yu, G., Li, Z., et al.[2023]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

A pilot study evaluating acute use of eszopiclone in patients with mild to moderate obstructive sleep apnea syndrome. [2014]

2. Spain pubmed.ncbi.nlm.nih.gov

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

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

The Combination of Supplemental Oxygen and a Hypnotic Markedly Improves Obstructive Sleep Apnea in Patients with a Mild to Moderate Upper Airway Collapsibility. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Effect of 1 month of zopiclone on obstructive sleep apnoea severity and symptoms: a randomised controlled trial. [2019]

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

Adverse drug events: identification and attribution. [2022]

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

Liverpool Adverse Events Profile: Italian validation and predictive value for dropout from antiepileptic treatment in people with epilepsy. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Frequency of ambulatory care adverse events in Latin American countries: the AMBEAS/PAHO cohort study. [2016]

9. England pubmed.ncbi.nlm.nih.gov

Monitoring product safety in the postmarketing environment. [2021]

10. Poland pubmed.ncbi.nlm.nih.gov

Pattern of adverse events of antiepileptic drugs: results of the aESCAPE study in Poland. [2022]

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

Eszopiclone: its use in the treatment of insomnia. [2021]

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

Case report of acute liver injury caused by the eszopiclone in a patient with chronic liver disease. [2023]

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

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