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

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Terminated
• CT.gov ID: NCT01554488
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 2
• Actual Duration (Months): 36.9
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Asthma; Chronic Obstructive Pulmonary Disease; Obstructive Sleep Apnea	Drug: Inhaled Fluticasone Propionate	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Inhaled Fluticasone Effects on Upper Airway Patency in Obstructive Lung Disease
• Actual Study Start Date: Mar 12, 2013
• Actual Primary Completion Date: Feb 3, 2016
• Actual Study Completion Date: Apr 7, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Upper Airway Critical Closing Pressure (Pcrit) at Week 16 [16-week randomized controlled phase]

   Pressure at which the pharyngeal upper airway closes during stable non-REM sleep, measured as described in the referenced citation.

Secondary Outcome Measures

1. Tongue Strength at Anterior Location at Week 16 [16-week randomized phase]

   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.

2. Tongue Strength at Posterior Location at Week 16 [16-week randomized phase]

   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.

3. Tongue Fatigability at Anterior Location at Week 16 [16-week randomized treatment phase]

   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.

4. Tongue Fatigability of Posterior Location at Week 16 [16-week randomized treatment phase]

   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.

Other Outcome Measures

1. Tongue Volume at Week 16 [16-week randomized treatment phase]

   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.

2. Percentage Fat Content (Fat Fraction) of the Tongue at Week 16 [16-week randomized controlled phase]

   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.

3. Volume of Pharyngeal Upper Airway Surrounding Structures at Week 16 [16-week randomized controlled phase]

   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.

4. Percentage Fat Content (Fat Fraction) of Pharyngeal Upper Airway Surrounding Structures at Week 16 [16-week randomized controlled phase]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	William S. Middleton Memorial Veterans Hospital, Madison, WI	Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Mihaela Teodorescu, MD, William S. Middleton Memorial Veterans Hospital, Madison, WI

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01554488
• Other Study ID Numbers: CLIN-20-11S
• First Posted: Mar 15, 2012
• Last Update Posted: Feb 5, 2020
• Last Verified: Jan 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by VA Office of Research and Development: asthma; COPD; sleep apnea, obstructive
• Additional relevant MeSH terms: Lung Diseases; Sleep Apnea Syndromes; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Sleep Apnea, Obstructive; Fluticasone; Xhance

Study Results

Participant Flow

Recruitment Details	subjects enrolled 3/12/2013-11/6/2015
Pre-assignment Detail	28 subjects were eligible at V2 and entered the 2-week low dose fluticasone run-in phase, necessary to assess fluticasone adherence. Thereafter, three subjects withdrew consent and were not randomized. Thus, 25 subjects were randomized.

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1,760mcg/day)	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Period Title: Overall Study
STARTED	13	12
COMPLETED	12	9
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone	Total
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Total of all reporting groups
Overall Participants	13	12	25
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 92.3%	12 100%	24 96%
>=65 years	1 7.7%	0 0%	1 4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.9 (18)	37.3 (14)	42.2 (16.8)
Sex: Female, Male (Count of Participants)
Female	4 30.8%	7 58.3%	11 44%
Male	9 69.2%	5 41.7%	14 56%
Asthma (Count of Participants)
randomized	9 69.2%	11 91.7%	20 80%
completed the study	8 61.5%	8 66.7%	16 64%
Chronic Obstructive Pulmonary Disease (COPD) (Count of Participants)
randomized	4 30.8%	1 8.3%	5 20%
completed the study	4 30.8%	1 8.3%	5 20%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Measure Participants	12	9
Mean (Standard Deviation) [cmH2O]	-3.03 (3.66)	-1.68 (2.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Inhaled Fluticasone, Low Dose Inhaled Fluticasone
	Comments	All of the comparisons were based on mixed effects linear regression models with visit and group*visit as fixed effects and subject as a random effect. Confidence intervals for the treatment difference (group*visit interaction) were constructed using the Wald method.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.03
	Confidence Interval	(2-Sided) 95%; -5.03 to 2.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Tongue Strength at Anterior Location at Week 16
Description	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.
Time Frame	16-week randomized phase

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Measure Participants	12	9
Mean (Standard Deviation) [KiloPascals]	61 (14.4)	63.7 (18.5)

3. Secondary Outcome

Title	Tongue Strength at Posterior Location at Week 16
Description	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.
Time Frame	16-week randomized phase

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Measure Participants	12	9
Mean (Standard Deviation) [KiloPascals]	55.5 (11.7)	58.1 (16.7)

4. Secondary Outcome

Title	Tongue Fatigability at Anterior Location at Week 16
Description	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.
Time Frame	16-week randomized treatment phase

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Measure Participants	12	9
Mean (Standard Deviation) [seconds]	74.4 (53.3)	78 (25.5)

5. Secondary Outcome

Title	Tongue Fatigability of Posterior Location at Week 16
Description	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.
Time Frame	16-week randomized treatment phase

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Measure Participants	12	9
Mean (Standard Deviation) [seconds]	53 (18)	65.9 (23.7)

6. Other Pre-specified Outcome

Title	Tongue Volume at Week 16
Description	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.
Time Frame	16-week randomized treatment phase

Outcome Measure Data

Analysis Population Description

1 subject in High dose and 2 subjects in Low dose inhaled fluticasone groups had contraindications, eg, metal in their bodies (2) or claustrophobia (1) and could not undergo MRI testing, per the set exclusion criteria.

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Measure Participants	11	7
Mean (Standard Deviation) [mm^3]	73.2 (15.5)	75.9 (15)

7. Other Pre-specified Outcome

Title	Percentage Fat Content (Fat Fraction) of the Tongue at Week 16
Description	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.
Time Frame	16-week randomized controlled phase

Outcome Measure Data

Analysis Population Description

1 subject in High dose and 2 subjects in Low dose inhaled fluticasone groups had contraindications, eg, metal in their bodies (2) or claustrophobia (1) and could not undergo MRI testing, per the set exclusion criteria.

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Measure Participants	11	7
Mean (Standard Deviation) [percentage of total tongue volume]	27.8 (9.98)	24.6 (7.88)

8. Other Pre-specified Outcome

Title	Volume of Pharyngeal Upper Airway Surrounding Structures at Week 16
Description	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.
Time Frame	16-week randomized controlled phase

Outcome Measure Data

Analysis Population Description

1 subject in High dose and 2 subjects in Low dose inhaled fluticasone groups had contraindications, eg, metal in their bodies (2) or claustrophobia (1) and could not undergo MRI testing, per the set exclusion criteria.

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Measure Participants	11	7
Mean (Standard Deviation) [mm^3]	205 (67.9)	194 (73.7)

9. Other Pre-specified Outcome

Title	Percentage Fat Content (Fat Fraction) of Pharyngeal Upper Airway Surrounding Structures at Week 16
Description	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.
Time Frame	16-week randomized controlled phase

Outcome Measure Data

Analysis Population Description

1 subject in High dose and 2 subjects in Low dose inhaled fluticasone groups had contraindications, eg, metal in their bodies (2) or claustrophobia (1) and could not undergo MRI testing, per the set exclusion criteria.

Arm/Group Title	High Dose Inhaled Fluticasone	Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid	Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
Measure Participants	11	7
Mean (Standard Deviation) [percentage of total airway volume]	41.5 (24.6)	31.5 (17.4)

Adverse Events

Time Frame	from study initiation up to 16 weeks of randomized treatment. In addition, monitoring continued for an additional two months step-down inhaled fluticasone treatment under medical supervision by the study team.
Arm/Group Title	High Dose Inhaled Fluticasone		Low Dose Inhaled Fluticasone
Arm/Group Description	High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid		Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid
All Cause Mortality
	High Dose Inhaled Fluticasone		Low Dose Inhaled Fluticasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	High Dose Inhaled Fluticasone		Low Dose Inhaled Fluticasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		1/9 (11.1%)
Hepatobiliary disorders
needed gallbladder surgery for stones	1/12 (8.3%)	1	1/9 (11.1%)	1
Respiratory, thoracic and mediastinal disorders
asthma exacerbation	1/12 (8.3%)	1	1/9 (11.1%)	1
Other (Not Including Serious) Adverse Events
	High Dose Inhaled Fluticasone		Low Dose Inhaled Fluticasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/12 (50%)		5/9 (55.6%)
Gastrointestinal disorders
tongue lesion from broken tooth	0/12 (0%)	0	1/9 (11.1%)	1
broken tooth	0/12 (0%)	0	1/9 (11.1%)	1
Reproductive system and breast disorders
yeast infection	1/12 (8.3%)	1	0/9 (0%)	0
Respiratory, thoracic and mediastinal disorders
bronchitis	1/12 (8.3%)	1	1/9 (11.1%)	1
asthma exacerbation	0/12 (0%)	0	1/9 (11.1%)	1
hoarseness	3/12 (25%)	3	0/9 (0%)	0
URI	1/12 (8.3%)	1	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
rash	0/12 (0%)	0	1/9 (11.1%)	1
Vascular disorders
hypertension	1/12 (8.3%)	1	0/9 (0%)	0

Limitations/Caveats

Study was terminated early due to low accrual. The original scientific question remains unanswered. Based on the experience with this study, a multi-center study would be necessary to accrue sufficient participants to answer the question.

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.