Buspirone as a Potential Treatment for Recurrent Central Apnea (CSA treatment)

• Sponsor: VA Office of Research and Development
• Collaborator: University Hospitals Cleveland Medical Center
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

Brief Summary:

The purpose of this study is to determine whether buspirone compared to acetazolamide and to placebo will reduce the number and/or severity of breathing pauses during sleep that occur in some patients with Heart Failure.

Condition or disease	Intervention/treatment	Phase
Central Apnea; Heart Failure	Drug: Acetazolamide; Drug: Buspirone	Phase 3

Detailed Description:

The hypothesis is that buspirone is a safe, effective drug to reduce the occurrence of recurrent central apnea and irregular breathing found in the setting of heart failure. A secondary hypothesis is that its effect will be similar to that or acetazolamide. Study Design: A one-dose double-blind crossover study of buspirone vs. placebo vs. acetazolamide will be performed to determine if active drug alters the number and/or severity of recurrent central apneas and hypopneas (AHI) in patients with heart failure. AHI is the primary outcome variable. In the initial phase of this study, we will recruit 18-20 patients to obtain ~15 complete studies, using the assumption of a ~20% drop-out, to reach a pre-set significance level of a 30% reduction in AHI in the drug groups with a power of 0.90 and a p=0.05 by post-hoc testing. Power estimates were calculated using the means and SDs derived from the population reported the study of acetazolamide by Javaheri et al (2006). A 30% reduction in AHI would be meaningful. A 15% dropout rate was present in the study by Javaheri et al (2006), but as our study is a three-way comparison, we chose a slightly higher rate. The reasons stated in these articles for a drop out included: viral illness, GI upset (on placebo or on theophyllin), tired of the sleep studies, and desire to terminate without cause. Statistical Analyses. Analysis of variance for repeated measures using Sidak's correction will be used to compare placebo, buspirone, and acetazolamide studies. For variables that are not normally distributed, Dunn's nonparametric test for multiple comparisons will be used. p > 0.05 will be considered significant. Mean values and SDs will be reported. This single dose, one night study is called Buspirone as a Potential Treatment for Recurrent Sleep Apnea I.

The randomization will be in a block design, and the analysis will take into account the blocked design. We will recruit 30 patients to obtain ~27 complete studies, using the assumption of a ~25% drop-out, to reach a pre-set significance level of a 50% reduction in AHI in the drug groups with a power of 0.90 and a p=0.05 by post-hoc testing (see Table C below). Power estimates were calculated using the means and SDs derived from the population reported the study of a one week trial of acetazolamide by Javaheri, values similar to those in the drug trial for theophyllin. Our reasoning is that a 50% reduction in AHI would be most meaningful. Our drop-out rate in the one-night study is estimated at ~25%.

Exclusion criteria of use of selective serotonin reuptake inhibitors (SSRIs) or antidepressants, while necessary because one of the drugs was buspirone, were too stringent for completion of this study in the VA setting. Of ~1000 patient charts screens, 8 were eventually entered into the trial, so that power criteria were not met. Records are being utilized to probe for hidden features in the PSG for use in future drug trials.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: Buspirone as a Potential Treatment for Recurrent Central Apneas
• Study Start Date: September 2008
• Actual Primary Completion Date: September 2011
• Actual Study Completion Date: December 2011

Arms and Interventions

Arm	Intervention/treatment
Arm 1 BUS to PLA to ACET; Each patient will act as their own control, with comparisons over three nights, each night given buspirone (BUS 20mg), actetazolamide (ACET 250mg), or placebo (PLA) n=3	Drug: Acetazolamide; Cabonic Anhydrase inhibitor; Drug: Buspirone; Agonist of a 5-HT1a receptor with some D2 agonist properties.
ARM 2 ACET to BUS to PLA; Each patient will act as their own control, with comparisons over three nights, each night given buspirone (BUS 20mg), actetazolamide (ACET 250mg), or placebo (PLA) n=3	Drug: Acetazolamide; Cabonic Anhydrase inhibitor; Drug: Buspirone; Agonist of a 5-HT1a receptor with some D2 agonist properties.
ARM 3 PLA to ACET to BUS; Each patient will act as their own control, with comparisons over three nights, each night given buspirone (BUS 20mg), actetazolamide (ACET 250mg), or placebo (PLA) n=2	Drug: Acetazolamide; Cabonic Anhydrase inhibitor; Drug: Buspirone; Agonist of a 5-HT1a receptor with some D2 agonist properties.

Outcome Measures

Primary Outcome Measures :

1. Apnea-hypopnea Index (Number of Central and Mixed Apneas/Hour of Sleep) [ Time Frame: Overnight polysomnogram over 3 separate nights ]

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Ability to provide informed consent,
• Ambulatory and in stable condition for the past 4 months,
• A diagnosis of heart failure with left ventricular systolic dysfunction as evidenced by an ejection fraction <35%,
• NYHA class II or III clinical status, and
• Diagnosis of dilated cardiomyopathy or ischemic cardiomyopathy.

Exclusion Criteria:

• Unstable angina, unstable heart failure, acute pulmonary edema, congenital heart disease
• History of unstable and/or advanced hepatic disease
• History of renal failure, CrCL < 30
• Current use of an SSRI, or use within one month of testing
• Intrinsic pulmonary diseases: ILD and/or COPD (FEV1/FVC < 65%)
• Kyphoscoliosis or neuromuscular disease
• Suboptimally treated hypothyroidism
• Use of narcotics or benzodiazepines
• Use of theophylline or pseudoephedrine

• Use the following medications:

  • MAO inhibitors
  • diazepam
  • haloperidol
  • nefazodone
  • trazodone
  • erythromycin
  • grapefruit juice
  • itraconazole
  • rifampin
  • ketoconazole
  • ritonavir,
  • cimetidine
• Known allergy to buspirone or acetazolamide

Contacts and Locations

Locations

United States, Ohio

VA Medical Center, Cleveland

Cleveland, Ohio, United States, 44106

Sponsors and Collaborators

VA Office of Research and Development

University Hospitals Cleveland Medical Center

Investigators

• Principal Investigator: Kingman P. Strohl, MD; VA Medical Center, Cleveland

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT00746954 History of Changes
• Other Study ID Numbers: RESP-006-07F
• First Posted: September 4, 2008
• Results First Posted: March 14, 2016
• Last Update Posted: March 14, 2016
• Last Verified: February 2016

Keywords provided by VA Office of Research and Development:

buspirone; acetazolamide

Additional relevant MeSH terms:

Heart Failure; Apnea; Sleep Apnea, Central; Heart Diseases; Cardiovascular Diseases; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Sleep Apnea Syndromes; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Acetazolamide; Buspirone; Anticonvulsants; Carbonic Anhydrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Anti-Anxiety Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Serotonin Receptor Agonists; Serotonin Agents; Neurotransmitter Agents