Clinical trial NCT00746954: Buspirone as a Potential Treatment for Recurrent Central Apnea
Official title: Buspirone as a Potential Treatment for Recurrent Central Apneas
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Central Apnea
Heart Failure
Keywords: buspirone
acetazolamide
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: University Hospitals Cleveland Medical Center
First posted: 2008-09-04
Enrollment: 8
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Apnea-hypopnea Index (Number of Central and Mixed Apneas/Hour of Sleep)
timeFrame: Overnight polysomnogram over 3 separate nights
Secondary outcomes:
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: VA Medical Center, Cleveland
state: Ohio
Study officials:
affiliation: VA Medical Center-Cleveland
name: Kingman P. Strohl, MD
role: PRINCIPAL_INVESTIGATOR
References: