Inhaled Fluticasone Effects on Upper Airway Patency in Obstructive Lung Disease (InFLOW)

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Obstructive Pulmonary Disease; Asthma; Obstructive Sleep Apnea
• Intervention / Treatment: Drug: Inhaled Fluticasone Propionate

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • William S. Middleton Memorial Veterans Hospital, Madison, WI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; High dose inhaled fluticasone (1760mcg/day)	Drug: Inhaled Fluticasone Propionate; Inhaled corticosteroid
Active Comparator: Arm 2; Low dose inhaled fluticasone (88mcg/day)	Drug: Inhaled Fluticasone Propionate; Inhaled corticosteroid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper Airway Critical Closing Pressure (Pcrit) at Week 16	Pressure at which the pharyngeal upper airway closes during stable non-REM sleep, measured as described in the referenced citation.	16-week randomized controlled phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tongue Strength at Anterior Location at Week 16	Wakefulness tongue function was measured using the Iowa Oral Performance Instrument (IOPI) at anterior and posterior tongue locations, as described in the referenced citation. In brief, this instrument has a small-sized, air-filled plastic balloon, called sensor or bulb, which was inserted between the tongue blade and the roof of the mouth. At each location, the tongue strength was determined as the maximum pressure generated against the IOPI bulb during a forced tongue contraction. Several standardized trials were conducted to ensure reproducibility.	16-week randomized phase
Tongue Strength at Posterior Location at Week 16	Wakefulness tongue function was measured using the Iowa Oral Performance Instrument (IOPI) at anterior and posterior tongue locations, as described in the referenced citation. In brief, this instrument has a small-sized, air-filled plastic balloon, called sensor or bulb, which was inserted between the tongue blade and the roof of the mouth. At each location, the tongue strength was determined as the maximum pressure generated against the IOPI bulb during a forced tongue contraction. Several standardized trials were conducted to ensure reproducibility.	16-week randomized phase
Tongue Fatigability at Anterior Location at Week 16	Wakefulness tongue function was measured using the Iowa Oral Performance Instrument (IOPI) at anterior and posterior tongue locations, as described in the referenced citation. In brief, this instrument has a small-sized, air-filled plastic balloon, called sensor or bulb, which was inserted between the tongue blade and the roof of the mouth. At each location, the tongue strength was determined as the maximum pressure generated against the IOPI bulb during a forced tongue contraction. Then, tongue fatigability was measured through a submaximal task, as the time (in seconds) able to maintain > 50% of the above measured strength, at each location. Several standardized trials were conducted for each measure and at each location, to ensure reproducibility.	16-week randomized treatment phase
Tongue Fatigability of Posterior Location at Week 16	Wakefulness tongue function was measured using the Iowa Oral Performance Instrument (IOPI) at anterior and posterior tongue locations, as described in the referenced citation. In brief, this instrument has a small-sized, air-filled plastic balloon, called sensor or bulb, which was inserted between the tongue blade and the roof of the mouth. At each location, the tongue strength was determined as the maximum pressure generated against the IOPI bulb during a forced tongue contraction. Then, tongue fatigability was measured through a submaximal task, as the time (in seconds) able to maintain > 50% of the above measured strength, at each location. Several standardized trials were conducted for each measure and at each location, to ensure reproducibility.	16-week randomized treatment phase

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tongue Volume at Week 16	Tongue volume was assessed on Magnetic Resonance (MR) imaging of the area extending from the level of the roof of the hard palate to the vocal cords, with the subject awake and lying on their back. We used a specialized technique called Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation Fast Spin-Echo (IDEAL-FSE), developed at University of Wisconsin by our collaborator and used for assessing the tongue (2). In brief, at first, the method provides well co-registered, separate water and fat images, which are free from the artifact that corrupts the usual MR images. Subsequently, these separate images are recombined in new high resolution images which provide: 1) comprehensive anatomical reference to delineate the tongue and measure its volume, and; 2) unambiguous separation of adipose tissue, to allow determination of fat volume and fraction in the tongue.	16-week randomized treatment phase
Percentage Fat Content (Fat Fraction) of the Tongue at Week 16	Tongue fat content was assessed on Magnetic Resonance (MR) imaging of the area extending from the level of the roof of the hard palate to the vocal cords, with the subject awake and lying on their back. We used a specialized technique called Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation Fast Spin-Echo (IDEAL-FSE), developed at University of Wisconsin by our collaborator and used for assessing the tongue (2). In brief, at first, the method provides well co-registered, separate water and fat images, which are free from the artifact that corrupts the usual MR images. Subsequently, these separate images are recombined in new high resolution images which provide: 1) comprehensive anatomical reference to delineate the tongue and measure its volume, and; 2) unambiguous separation of adipose tissue, to allow determination of fat volume and fraction in the tongue.	16-week randomized controlled phase
Volume of Pharyngeal Upper Airway Surrounding Structures at Week 16	The volume of pharyngeal upper airway surrounding structures was assessed on Magnetic Resonance (MR) imaging, as we published (1). We scanned the area extending from the level of the roof of the hard palate to the vocal cords, with the subject awake and lying on their back, We used a specialized technique called Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation Fast Spin-Echo (IDEAL-FSE). In brief, at first, the method provides well co-registered, separate water and fat images, which are free from the artifact that corrupts the usual MR images. Subsequently, these separate images are recombined in new high resolution images which provide: 1) comprehensive anatomical reference to delineate the tongue and measure its volume, and; 2) unambiguous separation of adipose tissue, to allow determination of fat volume and fraction in the upper airway structures.	16-week randomized controlled phase
Percentage Fat Content (Fat Fraction) of Pharyngeal Upper Airway Surrounding Structures at Week 16	Pharyngeal upper airway fat content was assessed on Magnetic Resonance (MR) imaging, as we published (1). We scanned the area extending from the level of the roof of the hard palate to the vocal cords, with the subject awake and lying on their back, We used a specialized technique called Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation Fast Spin-Echo (IDEAL-FSE). In brief, at first, the method provides well co-registered, separate water and fat images, which are free from the artifact that corrupts the usual MR images. Subsequently, these separate images are recombined in new high resolution images which provide: 1) comprehensive anatomical reference to delineate the tongue and measure its volume, and; 2) unambiguous separation of adipose tissue, to allow determination of fat volume and fraction in the upper airway structures.	16-week randomized controlled phase

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Mihaela Teodorescu, MD, William S. Middleton Memorial Veterans Hospital, Madison, WI

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2013
• Primary Completion (Actual): February 3, 2016
• Study Completion (Actual): April 7, 2016

Study Registration Dates

• First Submitted: February 29, 2012
• First Submitted That Met QC Criteria: March 12, 2012
• First Posted (Estimate): March 15, 2012

Study Record Updates

• Last Update Posted (Actual): February 5, 2020
• Last Update Submitted That Met QC Criteria: January 24, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: COPD; asthma; sleep apnea, obstructive
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Fluticasone; Xhance
• Other Study ID Numbers: CLIN-20-11S

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No