Combination Therapies for Central Sleep Apnea

(CSA Trial)

Recruiting in Palo Alto (17 mi)

Overseen by M. Safwan Badr, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: VA Office of Research and Development

Must be taking: Opioid analgesics

Disqualifiers: Severe respiratory disease, BMI >40, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests a combination of a machine that keeps airways open and medications to improve breathing in patients with central sleep apnea who have heart failure or use opioid painkillers. The goal is to make breathing more stable and less sensitive to disruptions during sleep. A specific type of machine has been studied as a treatment for central sleep apnea in heart failure patients, showing mixed results in improving outcomes.

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 data supports the effectiveness of the drug Zolpidem for treating central sleep apnea?

The research shows that Zolpidem, a drug used for managing insomnia, is effective in improving sleep quality, which might indirectly benefit patients with central sleep apnea by helping them achieve better sleep. ^{1 2 3 4 5}

Is zolpidem generally safe for human use?

Zolpidem, a medication used to help with sleep, has been associated with potential risks such as abuse, dependence, and withdrawal. It may also cause adverse effects like parasomnias (unusual behaviors during sleep) and psychiatric symptoms. However, it is considered to have fewer muscle relaxant effects compared to some other sleep medications. ^{6 7 8 9 10}

How does the drug zolpidem differ from other treatments for central sleep apnea?

Zolpidem is unique because it is a hypnotic drug that specifically targets the GABA(A) receptors with alpha1 subunits, which is different from other sleep medications that may not have this selectivity. This specificity might offer a different mechanism of action compared to other treatments for sleep-related conditions. ^{6 11 12 13 14}

Research Team

M. Safwan Badr, MD

Principal Investigator

John D. Dingell VA Medical Center, Detroit, MI

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Acetazolamide (Carbonic Anhydrase Inhibitor)
• Buspirone (Anxiolytic)
• Zolpidem (Drug)

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.

Participant Groups

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+

Dr. Grant Huang

VA Office of Research and Development

Acting Chief Research and Development Officer

PhD in Medical Psychology and Master of Public Health from the Uniformed Services University of Health Sciences

Dr. Erica M. Scavella

VA Office of Research and Development

Chief Medical Officer since 2022

MD from University of Massachusetts School of Medicine

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Inhaled aztreonam. [2021]

2. Japan pubmed.ncbi.nlm.nih.gov

[Clinical experience with aztreonam in the field of obstetrics and gynecology]. [2016]

3. Japan pubmed.ncbi.nlm.nih.gov

[Clinical efficacy of aztreonam in refractory infections in children]. [2016]

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

Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. [2018]

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

Phenotypic synergy testing of ceftazidime-avibactam with aztreonam in a university hospital having high number of metallobetalactamase producing bacteria. [2021]

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

Transduction of the discriminative stimulus effects of zolpidem by GABA(A)/alpha1 receptors. [2019]

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

Benefit-risk assessment of zaleplon in the treatment of insomnia. [2018]

8. England 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. [2020]

9. Australia pubmed.ncbi.nlm.nih.gov

Differences in detected safety signals between benzodiazepines and non-benzodiazepine hypnotics: pharmacovigilance study using a spontaneous reporting system. [2021]

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

Zolpidem and Zolpidem Carboxylic Acid Results from Medication Monitoring. [2019]

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

Severe Chronic Abuse of Zolpidem in Refractory Insomnia. [2022]

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

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

13. England pubmed.ncbi.nlm.nih.gov

Acute neurophysiological effects of the hypnotic zolpidem in healthy volunteers. [2018]

14. Netherlands pubmed.ncbi.nlm.nih.gov

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