Clinical trial NCT01554488: Inhaled Fluticasone Effects on Upper Airway Patency in Obstructive Lung Disease
Official title: Inhaled Fluticasone Effects on Upper Airway Patency in Obstructive Lung Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Asthma
Chronic Obstructive Pulmonary Disease
Obstructive Sleep Apnea
Keywords: asthma
COPD
sleep apnea, obstructive
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2012-03-15
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The Chairman of the Veterans' Disability Benefits Commission reported at a recent US Senate hearing that asthma, chronic obstructive pulmonary disease (COPD), and sleep apnea are among the top 13 most frequent diagnoses leading to disability under the Department of Defense and the VA system statutes. Recent research finds that sleep apnea is more common among asthma and COPD individuals, and this may be caused by inhaled corticosteroid use. Many Veterans are currently using inhaled corticosteroids, and many more will be prescribed such medications, given their recent inclusion in international treatment guidelines. As such, this study addresses a critical need by researching the role of a potent inhaled corticosteroid in promoting sleep apnea, the determinants of this response, and the ways through which it occurs. Results from this study will form the foundation for future research aimed at expanding understanding of the effects of inhaled corticosteroids on the upper airway, as well as developing means to prevent or counteract them.

Detailed description: BACKGROUND: Growing data suggest that patients with obstructive lung disease (OLD) such as asthma and chronic obstructive pulmonary disease (COPD) have an increased predisposition for obstructive sleep apnea, but the mechanism(s) remain unknown. One characteristic these patients share is use of inhaled corticosteroid (ICS). The investigators recently found a dose-dependent relationship of ICS use with high OSA risk. Furthermore, in a 16-week observational inhaled fluticasone (FP) treatment study, the investigators observed increased upper airway (UAW) collapsibility during sleep, as measured by the critical closing pressure (Pcrit), paralleling the improvement in lower airways obstruction, with the largest Pcrit deterioration in the subject with most sleep-disordered breathing (SDB) at baseline. These findings suggest an effect of ICS on the "unified airway" of steroid responsive patients and of those with more collapsible upper airways at baseline. The investigators also found a dose-dependent relationship of ICS with obesity. Based on their known effects, ICSs could deleteriously affect UAW collapsibility through inducing dilators' myopathy and fat deposition around the UAW. FP is the most potent and commonly used ICS.

HYPOTHESIS/AIMS: The central hypothesis is that FP will increase UAW collapsibility (less negative Pcrit) and worsen SDB in steroid responsive patients with OLD and those with UAWs more susceptible to collapse at baseline, through alterations in tongue muscle function and fat accumulation in the UAW surrounding structures. To address this hypothesis, the investigators propose to test the effects of inhaled FP on: 1) UAW collapsibility during sleep and SDB severity, assessed by Pcrit, measured as we previously reported (1) and polysomnographic (PSG) measures. Exploratory aims will test the role of steroid responsiveness and baseline collapsibility as determinants of FP effects on Pcrit and SDB; 2) tongue strength and fatigability, and fat accumulation (fraction and volume, measured on MRI) in the surrounding UAW structures, measured as we previously reported (1,2).

DESIGN: The investigators propose a proof-of-concept and mechanistic, randomized-controlled, parallel groups study of high (220 mcg, 4 puffs twice a day) vs. low (44 mcg twice a day) dose inhaled FP, followed by an 8-week wash-out period, in 58 steroid-naive subjects with OLD. Following baseline Pcrit, PSG, MRI and tongue function, subjects will enter a 2-week low-dose FP run-in, with subsequent randomization to either high- vs. low-dose FP, for 16 weeks. At mid-period, Pcrit, tongue function and steroid responsiveness status (defined as 5% improvement from baseline in FEV1%) will be determined. At the end of treatment, Pcrit, PSG, MRI and tongue measurements will be taken. Then, subjects will enter an 8-week wash-out that ends with repeat Pcrit and tongue function assessments.

SIGNIFICANCE: Millions of people, including many Veterans, are treated with ICS for OLD, and among those with COPD, these numbers are likely to escalate. However, do these medications alter UAW collapsibility and predispose to OSA in some individuals, as the investigators' preliminary observations suggest? This research is innovative because it will directly evaluate the effects of ICS on the UAW structure and function during sleep and wakefulness. At the study completion, it is the investigators expectation that they will have elucidated the effects and governing mechanisms of ICS on UAW patency and SDB severity. Data generated will form the foundation for future research aimed at expanding the investigators' understanding of ICS's effects on UAW and means to mitigate/prevent them. The clinical implication of these findings will be experimental-based verification of deleterious effects of ICS on UAW and risk for OSA, which will ultimately be of enormous financial benefit to the VA and OLD management programs.

Eligibility criteria: Inclusion Criteria:

* American Veterans
* age 18 and above
* diagnosis of asthma and COPD per guidelines
* for asthma, persistent symptoms per guidelines
* for asthma, a pre-bronchodilator FEV1 55-90% and DLCO 80% predicted
* for asthma, physiologic confirmation by bronchodilator or methacholine challenge
* for COPD, a post-bronchodilator ratio of FEV1/FVC 70% and FEV1 50%
* overall smoking history of \<10 pack-years for asthma and 10 pack-years for COPD.

Exclusion Criteria:

* any use of inhaled corticosteroid for \>2 weeks at a time during the last 6 months, or any use in the last 6 weeks;
* as needed use of nasal steroids in the prior 6 months
* select medications
* recent exacerbation requiring oral or systemic steroids in the past 6 months
* diagnosed vocal cords dysfunction
* other lung diseases (lung cancer, sarcoidosis, tuberculosis, lung fibrosis) or known 1-antitrypsin deficiency
* significant or actively unstable medical or psychiatric illnesses
* diagnosed osteopenia or osteoporosis
* established diagnosis of neuromuscular disease
* BMI 45 kg/m2 and higher
* treated OSA
* pregnancy (confirmed on urine test) or desire to get pregnant in the upcoming 6 months.
* smoking in the past 6 months
* metallic or electronic implants
* claustrophobia

Primary outcomes:
measure: Upper Airway Critical Closing Pressure (Pcrit) at Week 16
timeFrame: 16-week randomized controlled phase
Secondary outcomes:
measure: Tongue Strength at Anterior Location at Week 16
timeFrame: 16-week randomized phase
measure: Tongue Strength at Posterior Location at Week 16
timeFrame: 16-week randomized phase
measure: Tongue Fatigability at Anterior Location at Week 16
timeFrame: 16-week randomized treatment phase
measure: Tongue Fatigability of Posterior Location at Week 16
timeFrame: 16-week randomized treatment phase
Other outcomes:
measure: Tongue Volume at Week 16
timeFrame: 16-week randomized treatment phase
measure: Percentage Fat Content (Fat Fraction) of the Tongue at Week 16
timeFrame: 16-week randomized controlled phase
measure: Volume of Pharyngeal Upper Airway Surrounding Structures at Week 16
timeFrame: 16-week randomized controlled phase
measure: Percentage Fat Content (Fat Fraction) of Pharyngeal Upper Airway Surrounding Structures at Week 16
timeFrame: 16-week randomized controlled phase
Locations:
city: Madison
country: United States
facility: William S. Middleton Memorial Veterans Hospital, Madison, WI
state: Wisconsin
Study officials:
affiliation: William S. Middleton Memorial Veterans Hospital, Madison, WI
name: Mihaela Teodorescu, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Teodorescu M, Xie A, Sorkness CA, Robbins J, Reeder S, Gong Y, Fedie JE, Sexton A, Miller B, Huard T, Hind J, Bioty N, Peterson E, Kunselman SJ, Chinchilli VM, Soler X, Ramsdell J, Loredo J, Israel E, Eckert DJ, Malhotra A. Effects of inhaled fluticasone on upper airway during sleep and wakefulness in asthma: a pilot study. J Clin Sleep Med. 2014 Feb 15;10(2):183-93. doi: 10.5664/jcsm.3450.
citation: Humbert IA, Reeder SB, Porcaro EJ, Kays SA, Brittain JH, Robbins J. Simultaneous estimation of tongue volume and fat fraction using IDEAL-FSE. J Magn Reson Imaging. 2008 Aug;28(2):504-8. doi: 10.1002/jmri.21431.