Combination Therapies for Central Sleep Apnea

(CSA Trial)

Overseen By M S Badr, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: VA Office of Research and Development

Must be taking: Opioid analgesics

Disqualifiers: Severe respiratory disease, BMI >40, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to treat central sleep apnea (CSA), a condition where breathing repeatedly stops and starts during sleep, often affecting people with heart failure or those using opioid pain relievers. Researchers aim to determine if combining positive airway pressure (PAP) therapy with drugs like acetazolamide (a diuretic), buspirone (an anxiolytic), or zolpidem (a sedative) improves breathing during sleep more effectively than PAP alone. The goal is to find more effective treatments to enhance the quality of life for those struggling with CSA. Veterans diagnosed with central sleep apnea may be a good fit for this study. As a Phase 4 trial, this research focuses on understanding how these FDA-approved treatments can benefit more patients.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if the principal investigator finds a certain drug unsuitable, you may not be allowed to participate.

What is the safety track record for these treatments?

Research shows that buspirone, acetazolamide, and zolpidem are generally safe, but their safety profiles differ.

Buspirone has a strong safety record. Studies have found that side effects are rare and mild. It is often used for anxiety, and people usually tolerate it well without serious problems.

Acetazolamide also has a good safety record, though long-term data is limited. Some people might feel anxious, panicky, or have trouble sleeping. However, studies have shown it effectively reduces episodes of sleep apnea.

Zolpidem, also known as Ambien, is generally safe for many people. However, those with sleep apnea should use it cautiously, as it can rarely cause serious issues like sleepwalking or other complex sleep behaviors.

Overall, these treatments appear safe for most people, but discussing any concerns or existing conditions with a doctor is important before considering participation in a trial. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for central sleep apnea because they offer new approaches compared to standard care, which typically involves positive airway pressure (PAP) devices alone. Acetazolamide is unique as it reduces chemoreceptor sensitivity and plant gain, potentially leading to better control of CO2 levels. Buspirone targets serotonin A1 receptors, which might lower the incidence of central apneas by modulating breathing patterns during sleep. Zolpidem, a sleep aid, is being tested for its ability to decrease respiratory-related arousals, which could reduce apnea events. These treatments explore different mechanisms and could provide more effective solutions for managing central sleep apnea.

What evidence suggests that this trial's treatments could be effective for central sleep apnea?

This trial will compare the effects of different treatments on central sleep apnea. Studies have shown that buspirone, one treatment in this trial, can reduce central sleep apnea by decreasing the body's sensitivity to changes in blood gases and increasing its carbon dioxide tolerance. In one study, buspirone lowered the apnea-hypopnea index (AHI), which measures sleep apnea severity, by 45%. Acetazolamide, another treatment option in this trial, decreased the AHI and improved oxygen levels during sleep by altering the body's response to oxygen and carbon dioxide. Research indicates that zolpidem, also tested in this trial, can reduce central apnea events and enhance overall sleep quality by decreasing nighttime awakenings. Each of these treatments has shown promise in reducing symptoms of central sleep apnea, which can be especially helpful for people with heart failure or those using opioid medications. ^{1 4 5 6 7}

Who Is on the Research Team?

M. Safwan Badr, MD

Principal Investigator

John D. Dingell VA Medical Center, Detroit, MI

Are You a Good Fit for This Trial?

This trial is for Veterans with central sleep apnea, where they stop breathing frequently during sleep. Participants must have a specific severity of the condition and not be pregnant, breastfeeding, or have severe insomnia or respiratory diseases. They should also not be extremely overweight or mentally unstable.

Inclusion Criteria

I am a veteran with central sleep apnea, with more than 15 breathing pauses per hour and more than 5 of those are central apneas.

Exclusion Criteria

If at any time the principal investigator (PI) identifies that a certain drug is not suitable, or are unable to use the device that is used to treat sleep apnea, will be not be allowed to participate in the study

I have severe trouble sleeping.

I am under 18 years old.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination therapies including PAP plus a pharmacological agent such as acetazolamide, zolpidem, or buspirone to test their effects on central sleep apnea

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, focusing on central apnea indices and CO2 reserve

4 weeks

Extension

Participants may continue to receive treatment to further assess long-term effects on central sleep apnea

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Acetazolamide
• Buspirone
• Zolpidem

Trial Overview

The study tests if combining positive airway pressure (PAP) therapy with one of three drugs—Acetazolamide, Buspirone, or Zolpidem—can better treat central sleep apnea in patients with heart failure or those using opioid analgesics.

How Is the Trial Designed?

Group I: buspirone Active Control 1 Intervention

To determine the effect of augmenting serotonin A1 receptor activity on breathing during sleep. The investigators hypothesize that administration of PAP and buspirone, a serotonin A1 receptor agonist; will reduce the propensity to central apnea during sleep in Veterans with CSA compared to PAP plus placebo.

Group II: acetazolamide Active Control 1 Intervention

To determine the effect of dampening chemoreceptor sensitivity AND decreasing plant gain. The investigators hypothesize that combined therapy with PAP, acetazolamide and oxygen will be superior to PAP plus each intervention alone or placebo in reducing CAHI and the CO2 reserve during sleep in Veterans with CSA.

Group III: zolpidem Active Control 1 Intervention

To determine the effect of decreasing respiratory-related arousals on the propensity to develop central apnea. The investigators hypothesize that administration of PAP and zolpidem, will decrease respiratory-related arousals, CAHI and the CO2 reserve during sleep in Veterans with CSA compared to PAP plus placebo.

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

Zolpidem, a medication that targets GABA(A) receptors with alpha1 subunits, shows specific effects in squirrel monkeys trained to recognize its high doses, indicating its unique mechanism of action.

In contrast to non-selective GABA(A) agonists like diazepam and triazolam, zolpidem and zaleplon effectively substituted for each other, highlighting the importance of alpha1 receptor selectivity in the drug's effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transduction of the discriminative stimulus effects of zolpidem by GABA(A)/alpha1 receptors. Rowlett, JK., Lelas, S., Spealman, RD.[2019]

Zolpidem, a hypnotic drug, was shown to affect brain activity in young, healthy volunteers, with specific changes in event-related potentials (ERPs) that indicate its sedative effects, such as increased N2 and P3 latencies and decreased amplitudes.

Interestingly, zolpidem also caused an unexpected increase in P2 amplitude, suggesting it may enhance initial brain responses before diminishing overall cognitive resource allocation, which could be linked to its selective binding to benzodiazepine type 1 receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute neurophysiological effects of the hypnotic zolpidem in healthy volunteers. Lucchesi, LM., Braga, NI., Manzano, GM., et al.[2018]

Aztreonam for inhalation solution (Cayston) was approved by the US FDA in February 2010 specifically to help improve respiratory symptoms in cystic fibrosis patients.

This inhalable antibiotic targets Pseudomonas aeruginosa, a common and harmful bacteria in cystic fibrosis, indicating its efficacy in managing respiratory infections associated with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled aztreonam. O'Sullivan, BP., Yasothan, U., Kirkpatrick, P.[2021]

Zolpidem, a nonbenzodiazepine medication used for short-term treatment of sleep-onset insomnia, has a high affinity for the α1 subunit of the GABA-A receptor, which helps induce sleep.

Despite being initially viewed as safer than benzodiazepines, there are growing concerns about zolpidem's potential for misuse, as demonstrated by a case where a patient experienced serious abuse and withdrawal seizures, necessitating hospitalization for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Chronic Abuse of Zolpidem in Refractory Insomnia. Chiaro, G., Castelnovo, A., Bianco, G., et al.[2022]

Aztreoman (AZT) was effective in treating infections in obstetrics and gynecology, showing excellent clinical results against Klebsiella in a case of puerperal endometritis and good results against Bacteroides in another case.

However, the treatment was not effective against Enterococcus and Bacteroides in cases of pyometra, and side effects were noted in 2 patients, including elevated liver enzymes and serum markers in one case of eclampsia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical experience with aztreonam in the field of obstetrics and gynecology]. Yamada, E., Ueda, T., Mori, A., et al.[2016]

A review of 24 studies involving 3,909 participants found that Z-drugs (zaleplon, zolpidem, zopiclone) and benzodiazepines show few clear differences in effectiveness for treating insomnia, indicating that both classes of drugs can be similarly effective.

Zaleplon may lead to quicker sleep onset but results in shorter total sleep duration compared to zolpidem, highlighting the importance of understanding the pharmacological profiles of these medications when considering treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Dündar, Y., Dodd, S., Strobl, J., et al.[2018]

Zaleplon, a non-benzodiazepine hypnotic with an ultra-short half-life of about 1 hour, is effective for initiating sleep but less effective for maintaining it, offering a unique option for treating insomnia.

Compared to traditional benzodiazepines, zaleplon has a better safety profile, with fewer adverse effects such as cognitive impairment, tolerance, and withdrawal symptoms, making it a suitable choice for certain patients with insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefit-risk assessment of zaleplon in the treatment of insomnia. Barbera, J., Shapiro, C.[2018]

A total of 33,240 adverse drug reactions related to misuse, abuse, dependence, and withdrawal from Z-drugs (zaleplon, zolpidem, zopiclone) were identified, indicating significant safety concerns with these medications.

Zolpidem was found to have a higher frequency of misuse and withdrawal issues compared to zopiclone, while zopiclone was more associated with overdose events, highlighting the need for caution in prescribing these drugs, especially to patients with a history of psychiatric issues or substance abuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions. Schifano, F., Chiappini, S., Corkery, JM., et al.[2020]

Switching from benzodiazepine-based hypnotics (BZ drugs) to non-benzodiazepine-based hypnotics (Z-drugs) can lead to specific adverse events (AEs) such as parasomnias and psychiatric symptoms, which were identified through analysis of the Japanese Adverse Drug Event Report database.

While BZ drugs are associated with higher risks of falls and fractures, Z-drugs exhibit stronger safety signals for certain AEs, highlighting the importance of understanding these differences for safer hypnotic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences in detected safety signals between benzodiazepines and non-benzodiazepine hypnotics: pharmacovigilance study using a spontaneous reporting system. Toyoshima, M., Noguchi, Y., Otsubo, M., et al.[2021]

Zolpidem, commonly used for insomnia, is found in urine of chronic pain patients less than 23% of the time, while its major metabolite, ZCA, is detected in up to 64.8% of samples, suggesting ZCA is a more reliable marker for monitoring zolpidem use.

Despite FDA recommendations for lower dosing in females, the majority of patients (83% male and 73% female) are prescribed the same higher doses of zolpidem, with females showing significantly higher levels of ZCA, indicating a need for careful dosing considerations based on gender.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zolpidem and Zolpidem Carboxylic Acid Results from Medication Monitoring. Feng, S., Cummings, OT., McIntire, G.[2019]

ZolpiMist™, an oral spray formulation of zolpidem, is approved for short-term treatment of insomnia, specifically for difficulty in sleep initiation, with recommended doses of 10 mg for adults and 5 mg for elderly patients.

Clinical studies have shown that ZolpiMist is bioequivalent to traditional zolpidem tablets, confirming its safety and efficacy, and it is currently being explored for use during middle-of-the-night awakenings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZolpiMist™: a new formulation of zolpidem tartrate for the short-term treatment of insomnia in the US. Neubauer, DN.[2021]

Pharmacists recognize the importance of building strong relationships with patients when reviewing z-drugs, which are typically prescribed for short-term insomnia management, but they sometimes feel pressured to continue prescribing these medications beyond their intended use.

Key factors influencing pharmacists' decision-making include patient needs, time constraints, and their own confidence in deprescribing, leading them to advocate for non-drug treatments for long-term insomnia management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors affecting clinical pharmacist decision-making when reviewing and prescribing z-drugs in primary care: a qualitative interview study. Kallis, TJ., Allinson, M.[2023]

Aztreonam (AZT) was effective in treating 10 hospitalized pediatric cases of refractory infections, achieving clinical cure in 8 out of 10 patients without any adverse reactions or drug toxicity.

The antibiotic demonstrated significant activity against aerobic Gram-negative bacteria, successfully eradicating 4 out of 7 isolated bacteria from patients with infections such as pneumonia and urinary tract infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy of aztreonam in refractory infections in children]. Ogura, H., Hamada, F., Fujieda, M., et al.[2016]

Ceftazidime-avibactam combined with aztreonam showed high synergy against resistant bacteria, particularly in Klebsiella pneumoniae (86% synergy) and Pseudomonas aeruginosa (70%), based on tests conducted on 153 bacterial isolates.

Rapid synergy testing in the lab allowed for better treatment decisions, highlighting the importance of this method in managing infections caused by metallobetalactamase-producing bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotypic synergy testing of ceftazidime-avibactam with aztreonam in a university hospital having high number of metallobetalactamase producing bacteria. Sahu, C., Pal, S., Patel, SS., et al.[2021]

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Acetazolamide improves sleep apnea at high altitude by decreasing AHI and percentage of periodic breathing time and increasing nocturnal oxygenation.

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