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Low subject accrual
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1 | Experimental | High dose inhaled fluticasone (1760mcg/day) |
|
| Arm 2 | Active Comparator | Low dose inhaled fluticasone (88mcg/day) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Inhaled Fluticasone Propionate | Drug | Inhaled corticosteroid |
|
| 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 |
| 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. |
| 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mihaela Teodorescu, MD | William S. Middleton Memorial Veterans Hospital, Madison, WI | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| William S. Middleton Memorial Veterans Hospital, Madison, WI | Madison | Wisconsin | 53705 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24533002 | Background | 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. | |
| 18666214 |
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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.
subjects enrolled 3/12/2013-11/6/2015
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| ID | Title | Description |
|---|---|---|
| FG000 | High Dose Inhaled Fluticasone | High dose inhaled fluticasone (1,760mcg/day) |
| FG001 | Low Dose Inhaled Fluticasone | Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | High Dose Inhaled Fluticasone | High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid |
| BG001 | Low Dose Inhaled Fluticasone | Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | cmH2O | 16-week randomized controlled phase |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | High Dose Inhaled Fluticasone | High dose inhaled fluticasone (1760mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| needed gallbladder surgery for stones | Hepatobiliary disorders | Systematic Assessment | subject with chronic obstructive pulmonary disease (COPD) developed acute cholecystitis due to stones, had endoscopic retrograde cholangio-pancreatography, and ultimately needed cholecystectomy. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| tongue lesion from broken tooth | Gastrointestinal disorders | Systematic Assessment |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mihaela Teodorescu, MD-Principle Investigator | William S. Middleton Memorial VA Hospital | (608)2561901 | 11080 | mt3@medicine.wisc.edu |
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| ID | Term |
|---|---|
| D001249 | Asthma |
| D029424 | Pulmonary Disease, Chronic Obstructive |
| D020181 | Sleep Apnea, Obstructive |
| ID | Term |
|---|---|
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
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| 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 |
| 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 |
| Background |
| 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Asthma | The subject population also included those with COPD for which the numbers are reported in the next section. | Count of Participants | Participants |
|
| Chronic Obstructive Pulmonary Disease (COPD) | subject population included those with asthma, reported in the previous section | Count of Participants | Participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | KiloPascals | 16-week randomized phase |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | KiloPascals | 16-week randomized phase |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | seconds | 16-week randomized treatment phase |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | seconds | 16-week randomized treatment phase |
|
|
|
| Other Pre-specified | 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. | 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. | Posted | Mean | Standard Deviation | mm^3 | 16-week randomized treatment phase |
|
|
|
| Other Pre-specified | 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. | 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. | Posted | Mean | Standard Deviation | percentage of total tongue volume | 16-week randomized controlled phase |
|
|
|
| Other Pre-specified | 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. | 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. | Posted | Mean | Standard Deviation | mm^3 | 16-week randomized controlled phase |
|
|
|
| Other Pre-specified | 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. | 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. | Posted | Mean | Standard Deviation | percentage of total airway volume | 16-week randomized controlled phase |
|
|
|
| 1 |
| 12 |
| 6 |
| 12 |
| EG001 | Low Dose Inhaled Fluticasone | Low dose inhaled fluticasone (88mcg/day) Inhaled Fluticasone Propionate: Inhaled corticosteroid | 1 | 9 | 5 | 9 |
|
| asthma exacerbation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | subject with asthma, in the low fluticasone dose group, developed an exacerbation requiring prednisone bursts |
|
| broken tooth | Gastrointestinal disorders | Systematic Assessment |
|
| bronchitis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| asthma exacerbation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| hoarseness | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| URI | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| yeast infection | Reproductive system and breast disorders | Systematic Assessment |
|
| rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| hypertension | Vascular disorders | Systematic Assessment |
|
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| D012130 |
| Respiratory Hypersensitivity |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012891 | Sleep Apnea Syndromes |
| D001049 | Apnea |
| D012120 | Respiration Disorders |
| D020919 | Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |