Asthma
Conditions
Keywords
Role of Pin-1 enzyme in Asthma
Brief summary
Pin1 is activated in asthmatic airways, increasing cytokine mRNA stability and eosinophil survival. This study is designed to test whether the Pin1 enzyme regulates TLR/IL-1R signal pathways in multiple cells in asthma.
Detailed description
The investigators will test their hypothesis that Pin1 regulates TLR/IL-1R signaling pathways in asthma by examining Pin1 and related pathway activation in BAL-derived eosinophils after house dust mite allergen challenge. The investigators will perform segmental allergen challenge. BAL and lung biopsy of the allergen-challenged segments will be performed 48 hr later and activation of Pin1 and related pathways will be examined.
Interventions
BIOLOGICALinstallation of D. pteronyssinus allergens
We will perform bronchoscopy and segmental allergen challenges. Subjects will undergo bronchoscopy with segmental installation of 5 ml of D. pteronyssinus (DerP). BAL and lung biopsy of the allergen-challenged segments will be performed 48 hr later
Sponsors
Brigham and Women's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Subjects 18-55 years of age, diagnosed with asthma for at least 1 year; * And FEV1 \> 70% predicted on only short acting beta agonists e.g albuterol * And methacholine PC20 \< 8 mg/ml * Positive skin prick test to Dermatophagoides pteronyssinus(DerP) * No prior history of intubation for asthma * No use of inhaled corticosteroids for 1 month prior to entry
Exclusion criteria
* Current smoking or smoking history of greater than 10 pack-years * Any other clinically important comorbidity determined by the principal investigator to affect subject safety, including uncontrolled diabetes, uncontrolled coronary artery disease, acute or chronic renal failure, and uncontrolled hypertension that would increase the risk of significant adverse events during bronchoscopy, * Worsening of asthma symptoms requiring treatment with steroids within 4 weeks of screening * Respiratory infection within four weeks * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant or who are currently pregnant or lactating. Unless they: * Are women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner * Are women whose partners have been sterilized by vasectomy or other means * Use one acceptable birth control method. Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent. * Pre-existing lung disease other than asthma * History of coagulation disorders or abnormal PT/PTT testing at screening * History of immunodeficiency diseases, including HIV * A disability that may prevent the patient from completing all study requirements * Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer * History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. * Diagnosis of Hepatitis B or C. * History of alcohol abuse (as determined by the principal investigator) within 6 months of screening. * History of illicit drug abuse (as determined by the principal investigator) within 6 months of screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Percentage of Total White Blood Cell That Were Eosinophils at 48 Hours | from baseline to 48 hours | Measure Pin1 activity in BAL-derived eosinophils after House Dust Mite (HDM) allergen challenge: Eosinophils post-challenge change from pre-challenge is reported: absolute change = \[eosinophils post (%) - eosinophils pre (%)\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the Percentage of Total White Blood Cell That Were Lymphocytes at 48 Hours | from baseline to 48 hours | Percent change in percentage of total white blood cell that were lymphocytes is measured from pre-challenge to post-challenge as: \[100% \* ((Post-Pre)/Pre)\] |
| Percent Change From Baseline in the Percentage of Total White Blood Cell That Were Macrophages at 48 Hours | from baseline to 48 hours | Percent change in percentage of total white blood cell that were macrophages is measured from pre-challenge to post-challenge as: \[100% \* ((Post-Pre)/Pre)\] |
| Change From Baseline in the Percentage of Total White Blood Cell That Were Neutrophils at 48 Hours | from baseline to 48 hours | Neutrophils have some zero values pre-challenge, so absolute change is reported instead of percent change: post-pre from baseline to 48 hours |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| D. Pteronyssinus Allergens Single arm study exploring the role of Pin-1 enzyme in development of Asthma. Bronchoscopy before and 48 hours after installation of D. pteronyssinus allergens into the lung segments
installation of D. pteronyssinus allergens: We will perform bronchoscopy and segmental allergen challenges. Subjects will undergo bronchoscopy with segmental installation of 5 ml of D. pteronyssinus (DerP). BAL and lung biopsy of the allergen-challenged segments will be performed 48 hr later | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | deemed ineligible after 1st visit | 6 |
Baseline characteristics
| Characteristic | D. Pteronyssinus Allergens |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 24.9 years STANDARD_DEVIATION 3.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 14 |
| serious Total, serious adverse events | 0 / 14 |
Outcome results
Primary
Change From Baseline in the Percentage of Total White Blood Cell That Were Eosinophils at 48 Hours
Measure Pin1 activity in BAL-derived eosinophils after House Dust Mite (HDM) allergen challenge: Eosinophils post-challenge change from pre-challenge is reported: absolute change = \[eosinophils post (%) - eosinophils pre (%)\]
Time frame: from baseline to 48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| D. Pteronyssinus Allergens | Change From Baseline in the Percentage of Total White Blood Cell That Were Eosinophils at 48 Hours | 82.11 percent of white blood cells |
Secondary
Change From Baseline in the Percentage of Total White Blood Cell That Were Neutrophils at 48 Hours
Neutrophils have some zero values pre-challenge, so absolute change is reported instead of percent change: post-pre from baseline to 48 hours
Time frame: from baseline to 48 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| D. Pteronyssinus Allergens | Change From Baseline in the Percentage of Total White Blood Cell That Were Neutrophils at 48 Hours | 3 percent of white blood cells |
Secondary
Percent Change From Baseline in the Percentage of Total White Blood Cell That Were Lymphocytes at 48 Hours
Percent change in percentage of total white blood cell that were lymphocytes is measured from pre-challenge to post-challenge as: \[100% \* ((Post-Pre)/Pre)\]
Time frame: from baseline to 48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| D. Pteronyssinus Allergens | Percent Change From Baseline in the Percentage of Total White Blood Cell That Were Lymphocytes at 48 Hours | -64.3 percent change |
Secondary
Percent Change From Baseline in the Percentage of Total White Blood Cell That Were Macrophages at 48 Hours
Percent change in percentage of total white blood cell that were macrophages is measured from pre-challenge to post-challenge as: \[100% \* ((Post-Pre)/Pre)\]
Time frame: from baseline to 48 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| D. Pteronyssinus Allergens | Percent Change From Baseline in the Percentage of Total White Blood Cell That Were Macrophages at 48 Hours | -82.4 percent change |