Asthma
Conditions
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.
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.
Interventions
DRUGPulmicort
inhaled powder of inhaled corticosteroid, 1 puff (180mcg) twice a day for 8-10 weeks
Sponsors
Genentech, Inc.
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Control Healthy, non-asthmatics who will not be put on any intervention | 24 |
| Steroid Naive Asthmatics 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 | 42 |
| Asthmatics on ICS Treatment 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 | 61 |
| Total | 127 |
Baseline characteristics
| Characteristic | Steroid Naive Asthmatics | Asthmatics on ICS Treatment | Healthy Control | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 61 Participants | 24 Participants | 127 Participants |
| Age, Continuous | 32.0 years STANDARD_DEVIATION 11.6 | 39.0 years STANDARD_DEVIATION 11.9 | 34.5 years STANDARD_DEVIATION 9 | 35.9 years STANDARD_DEVIATION 11.7 |
| Region of Enrollment United States | 42 participants | 61 participants | 24 participants | 127 participants |
| Sex: Female, Male Female | 27 Participants | 34 Participants | 10 Participants | 71 Participants |
| Sex: Female, Male Male | 15 Participants | 27 Participants | 14 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 24 | 5 / 42 | 15 / 61 |
| serious Total, serious adverse events | 0 / 24 | 0 / 42 | 0 / 61 |
Outcome results
Primary
Gene Expression in Airway Secretions and Tissues
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)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | Gene Expression in Airway Secretions and Tissues | -0.66 Relative gene expression level | Standard Deviation 0.36 |
| Steroid Naive Asthmatics | Gene Expression in Airway Secretions and Tissues | 0.54 Relative gene expression level | Standard Deviation 0.87 |
| Asthmatics on ICS Treatment | Gene Expression in Airway Secretions and Tissues | -0.30 Relative gene expression level | Standard Deviation 0.6 |