MAST: Study of the Mechanisms of Asthma

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00595153
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 127
• Location: 1
• Arms: 3
• Duration (Months): 50
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief Summary

The purpose of this study is to identify the causes of asthma that were not previously suspected, to better understand the effects of inhaled steroids on asthma and to identify new way to treat asthma. In order to take advantage of the most current scientific expertise, we (scientists at UCSF) plan to work together with Genentech Inc. We believe that working with Genentech will provide the best chance of developing new treatments for asthma.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Pulmicort	Phase 1

Detailed Description

Asthma is a common airway disease with persistent unmet needs on terms of treatment. Although many asthmatics enjoy good control of their disease by using regularly scheduled corticosteroid treatment, a significant minority do not achieve optimal control with steroids and suffer asthma exacerbations which can be severe and even fatal. Asthma pathophysiology is complex and involves multiple cell types and multiple signaling mechanisms. One approach to this complexity has been to study responses of isolated airway cells to experimental conditions which model asthmatic inflammation; another has been genetic manipulations of candidate mediators of asthma in inbred mice. These studies have yielded important insights about possible mechanisms of asthma in humans, but the relevance of these mechanisms to human disease has not always been proven, and it is possible that unsuspected mechanism have not yet been revealed by these approaches. In the studies proposed here we will take an experimental approach which takes advantage of the distinct clinical phenotype of human asthma, the ability to measure steroid response in asthma, the relative ease of collecting airway cells and tissues by bronchoscopy, and the availability of new technologies such as high density microarrays which have probes for all genes in the genome or proteomics which can identify all proteins present in a biologic sample. Using this approach, we will identify differential expression of genes and proteins in airway cells and tissues in asthma that can then be explored further in cell and animal model systems to determine their potential as drug targets in asthma. We further believe that our approach will identify previously unsuspected mechanisms of action of corticosteroids in airway cells and tissues in asthma. Presently, relatively little is known about why some asthmatics respond well and some poorly to steroids and closing this gap in knowledge will help identify candidate genes and proteins to target in order to address unmet therapeutic needs in asthmatics with steroid resistant asthma.

Study Design

• Study Type: Interventional
• Actual Enrollment: 127 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Determining Mechanisms of Asthma Through Detailed Analysis of Airway Secretions and Tissues
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: B Asthmatics not on inhaled corticosteroids who will be put on an inhaled steroid during the study	Drug: Pulmicort; inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks; Other Names: Budesonide
No Intervention: A Healthy, non-asthmatics who will not be put on any intervention
Active Comparator: C Asthmatics, who are already on inhaled corticosteroids who will be put on standardized dose of inhaled corticosteroids	Drug: Pulmicort; inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks; Other Names: Budesonide

Outcome Measures

Primary Outcome Measures

1. Gene Expression in Airway Secretions and Tissues [Healthy Control: Visit 2 (at 1 week); Steroid Naive Asthmatics: Visit 2 (at 1 week); Steroid Treated Asthmatics: Visit 5 (at 9 weeks)]

   The primary outcome measure for this study is the scaled mean value of three gene expression markers of IL-13 in the airway: PERIOSTIN, calcium-activated chloride channel regulator 1 (CLCA1), and plasminogen activator inhibitor-2 (SERPINB2). First, for each of the three interleukin-13 (IL-13) signature genes, the log (base-2) transformed relative expression value for each subject is measured using real-time polymerase chair reaction (PCR) and normalized with the geometric mean of 5 housekeeping genes. Next, these values are centered (by subtracting the mean for that gene) and scaled (by dividing by the standard deviation for that gene) so that each gene makes an equal, assay-independent contribution to the Th2 phenotype. Then, for each subject, the arithmetic mean of the three centered & scaled genes is calculated, producing the "three-gene-mean" metric.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Group C:

• Male and female subjects between the ages of 18 and 70 years

• History of asthma

• Continuous treatment with inhaled corticosteroids for at least the 6-week

• Hyperreactivity to methacholine (provocative concentration of methacholine causing a 20% drop in forced expiratory volume in 1 second (PC20 FEV1) Methacholine ≤ 16.0 mg/mL).

Exclusion Criteria:

• History of asthma

• No use of oral or inhaled corticosteroids for the treatment of asthma in the past 6 weeks

• Hyperreactivity to methacholine (PC20 FEV1 Methacholine ≤ 8.0 mg/mL).

• At least one of the following symptoms, beta agonist use, or FEV1 criteria:

• Asthma symptoms on at least two days per week; OR

• Beta agonist use on at least two days per week; OR

• Forced expiratory volume in 1 second (FEV1) < 85% predicted

• Subjects must be non-smokers (patients who have never smoked or patients who have not smoked for 1 year and have a total pack-year smoking history < 15 packs).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143

Sponsors and Collaborators

• University of California, San Francisco
• Genentech, Inc.

Investigators

• Principal Investigator: John V Fahy, M.D., M.Sc., University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Airway Clinical Research Center website

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00595153
• Other Study ID Numbers: UCSF CHR# H6788-30617
• First Posted: Jan 16, 2008
• Last Update Posted: Jan 20, 2014
• Last Verified: Dec 1, 2013

• Additional relevant MeSH terms: Asthma; Budesonide

Study Results

Participant Flow

Recruitment Details	The MAST study enrolled 103 adults with asthma and 24 healthy controls between 8/2007 to 6/2011. Participants were seen in a clinical research center.
Pre-assignment Detail	Steroid naïve asthmatics had bronchoscopy before and after an 8 week treatment with inhaled corticosteroids, and asthmatics already taking an inhaled corticosteroid had their treatment standardized for 8 weeks followed by a bronchoscopy. Healthy control subjects participated in a cross-sectional study for characterization and bronchoscopy.

Arm/Group Title	Healthy Control	Steroid Naive Asthmatics	Asthmatics on ICS Treatment
Arm/Group Description	Healthy, non-asthmatics who will not be put on any intervention	Asthmatics not on inhaled corticosteroids who will be put on an inhaled steroid during the study Pulmicort : inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks	Asthmatics, who are already on inhaled corticosteroids who will be put on standardized dose of inhaled corticosteroids Pulmicort : inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks
Period Title: Overall Study
STARTED	24	42	61
COMPLETED	20	26	36
NOT COMPLETED	4	16	25

Baseline Characteristics

Arm/Group Title	Healthy Control	Steroid Naive Asthmatics	Asthmatics on ICS Treatment	Total
Arm/Group Description	Healthy, non-asthmatics who will not be put on any intervention	Asthmatics not on inhaled corticosteroids who will be put on an inhaled steroid during the study Pulmicort : inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks	Asthmatics, who are already on inhaled corticosteroids who will be put on standardized dose of inhaled corticosteroids Pulmicort : inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks	Total of all reporting groups
Overall Participants	24	42	61	127
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	24 100%	42 100%	61 100%	127 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.5 (9.0)	32.0 (11.6)	39.0 (11.9)	35.9 (11.7)
Sex: Female, Male (Count of Participants)
Female	10 41.7%	27 64.3%	34 55.7%	71 55.9%
Male	14 58.3%	15 35.7%	27 44.3%	56 44.1%
Region of Enrollment (participants) [Number]
United States	24 100%	42 100%	61 100%	127 100%

Outcome Measures

1. Primary Outcome

Title	Gene Expression in Airway Secretions and Tissues
Description	The primary outcome measure for this study is the scaled mean value of three gene expression markers of IL-13 in the airway: PERIOSTIN, calcium-activated chloride channel regulator 1 (CLCA1), and plasminogen activator inhibitor-2 (SERPINB2). First, for each of the three interleukin-13 (IL-13) signature genes, the log (base-2) transformed relative expression value for each subject is measured using real-time polymerase chair reaction (PCR) and normalized with the geometric mean of 5 housekeeping genes. Next, these values are centered (by subtracting the mean for that gene) and scaled (by dividing by the standard deviation for that gene) so that each gene makes an equal, assay-independent contribution to the Th2 phenotype. Then, for each subject, the arithmetic mean of the three centered & scaled genes is calculated, producing the "three-gene-mean" metric.
Time Frame	Healthy Control: Visit 2 (at 1 week); Steroid Naive Asthmatics: Visit 2 (at 1 week); Steroid Treated Asthmatics: Visit 5 (at 9 weeks)

Outcome Measure Data

Analysis Population Description

Participants who met inclusion/exclusion requirements and completed all study activities were included in the analysis. Specifically, this included: 1. Having a bronchoscopy with complete PCR on RNA from epithelial brush samples.

Arm/Group Title	Healthy Control	Steroid Naive Asthmatics	Asthmatics on ICS Treatment
Arm/Group Description	Healthy, non-asthmatics who will not be put on any intervention	Asthmatics not on inhaled corticosteroids who will be put on an inhaled steroid during the study Pulmicort : inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks	Asthmatics, who are already on inhaled corticosteroids who will be put on standardized dose of inhaled corticosteroids Pulmicort : inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks
Measure Participants	19	24	21
Mean (Standard Deviation) [Relative gene expression level]	-0.66 (0.36)	0.54 (0.87)	-0.30 (0.60)

Adverse Events

Arm/Group Title	Healthy Control		Steroid Naive Asthmatics		Asthmatics on ICS Treatment
Arm/Group Description	Healthy, non-asthmatics who will not be put on any intervention		Asthmatics not on inhaled corticosteroids who will be put on an inhaled steroid during the study Pulmicort : inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks		Asthmatics, who are already on inhaled corticosteroids who will be put on standardized dose of inhaled corticosteroids Pulmicort : inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks
All Cause Mortality
	Healthy Control		Steroid Naive Asthmatics		Asthmatics on ICS Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Healthy Control		Steroid Naive Asthmatics		Asthmatics on ICS Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/42 (0%)		0/61 (0%)
Other (Not Including Serious) Adverse Events
	Healthy Control		Steroid Naive Asthmatics		Asthmatics on ICS Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/24 (25%)		5/42 (11.9%)		15/61 (24.6%)
Respiratory, thoracic and mediastinal disorders
Increased asthma symptoms following medication hold	0/0 (NaN)	0	0/42 (0%)	0	5/61 (8.2%)	60
Did not tolerate switch of asthma controller medication	0/0 (NaN)	0	0/42 (0%)	0	5/61 (8.2%)	60
Respiratory symptoms/decreased lung function following bronchoscopy	6/24 (25%)	28	5/42 (11.9%)	84	5/61 (8.2%)	60

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.