T Cell Effector and Regulatory Mechanisms in Asthma

NCT01612936 | Completed Phase 1 DMC

• 2 other identifiers: 2012P0007051U19AI095261
• Study Type: interventional
• Target: 168
• Locations: 1 country
• Sites: 1

Brief Summary

The specific hypothesis for this study is that there are fundamental differences in T effector and T regulatory cell responses in the lung to allergens in allergic asthma (AA) when compared to allergic nonasthmatics (ANA) that account for the difference in clinical responses. We will address this by comparing T cell responses in AA versus ANA subjects. These experiments will correlate T cell responses with measures of airway physiology using state-of-the art lung imaging and examine mechanisms controlling T cell activation in the airways of AA and the function of airway T regulatory cells during AA.

Conditions

Asthma; Allergies

Keywords

Asthma; Allergic; Inflammation; Constriction; Airway; Challenge; Chemokines

Outcome Measures

Primary Outcomes (1)

• Differences in airway physiology and airway constriction

  The primary endpoints are differences in airway physiology and airway constriction following segmental allergen challenge (SAC) in AA and ANA subjects using positron emission tomography (PET) in combination with high-resolution computed tomography (HRCT)

  24 hours

Secondary Outcomes (3)

• Differences in BAL inflammatory mediator release

  24 hours

• Differences in cellular analysis of BAL

  24 hours

• Differences in BAL inflammatory protein levels

  24 hours

Study Arms (1)

Allergic asthmatic, allergic nonasthmatic

EXPERIMENTAL

Adults who are allergic asthmatics or allergic non-asthmatics will receive segmental allergen challenge to the lung

Biological: Bronchoscopy, Segmental Allergen Challenge and Broncheoalveolar Lavage; Procedure: PET-CT imaging(13NN perfusion/ventilation, 18FDG inflammation, and CT imaging)

Interventions

Bronchoscopy, Segmental Allergen Challenge and Broncheoalveolar Lavage BIOLOGICAL

On the day of the first bronchoscopy,BAL will first be performed in the lingula without instillation of diluent or allergen.Then, a 2-ml aliquot of isotonic diluent is instilled into the right upper lobe. Then, the procedure will be repeated in the right middle lobe with instillation of 2-ml of standardized cat or mite allergen solution.A "test dose" concentration of allergen is administered first consisting of 2 ml of allergen at 1/10th(Cat,D.farinae) or 1/30th(D. pteronyssinus) the threshold concentration.If on visual inspection through the bronchoscope, there is no evidence of mucosal inflammation after two minutes, a second segmental allergen challenge will be done in the right middle lobe using 2-ml of full-dose allergen at the threshold concentration(Cat,D.farinae) or 1/3th the threshold concentration(D.pteronyssinus).This dose will be predetermined by quantitative skin prick testing.A second bronchoscopy is performed 24 hours after delivery of allergen extract and diluent.

Also known as: One of 3 Standardized allergen extracts will be used:, 1)Cat hair, 2)Dust Mite Dermatophagoides farinae, 3)Dust Mite Dermatophagoides pteronyssinus, Phenolized saline diluent will also be used in this study., All will be purchased from Greer Laboratories, Lenoir, NC.

Allergic asthmatic, allergic nonasthmatic

PET-CT imaging(13NN perfusion/ventilation, 18FDG inflammation, and CT imaging) PROCEDURE

Imaging is first performed the evening prior to the 1st bronchoscopy.An IV catheter is placed.An attenuation correction is performed to remove image distortion using a chest CT volumetric scan.Subjects are instructed to exhale to the same mean lung volume of the CT scan and hold their breath for 20sec.Simultaneous with apnea,13NNsaline is injected IV and a series of PET scans is acquired.Then subjects resume breathing, matching their previous respiratory rate and tidal volume.After 3 min,within an interval of 1 min,spirometry and 2 deep inhalations are performed,followed by 1 min of washout. For the second imaging visit, which will occur 24 hour later, the imaging sequence will be repeated as described above, but will also include 18FDG infusion.At least 30 minutes after the 13NN injection,10mCi of 18FDG is infused. Then, images are collected over a 75 minutes.Venous blood is sampled at 5 different time points over a 40-45 minute time window to determine plasma radioactive levels.

Also known as: 13N-N2 saline, 18F-FDG, 0.019 mSv/MBq

Allergic asthmatic, allergic nonasthmatic

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Subjects with Allergic Asthma (AA subjects):
• All subjects will have a baseline FEV1 no less than 75 % of the predicted value after bronchodilator administration.
• All subjects will have both a clinical history of allergic symptoms to cat or dust mite allergen and a positive allergen prick test (3 mm diameter greater than diluent control)
• Life-long absence of cigarette smoking (lifetime total of \< 5 pack-years and none in 5 years).
• Willing and able to give informed consent.
• Expressed the desire to participate in an interview with the principal investigator.
• Age between 18 and 50 years.
• A methacholine PC20 \< 16 mg/ml.
• Asthma of severity defined as: requiring no more than step 3 therapy (NHLBI Guidelines, 2007 EPR-3, http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf), well-controlled and having a validated asthma control test (ACT) score of \> 19 for one month prior to the screening visit, and able to tolerate a 2 week stoppage of inhaled corticosteroids prior to Visit 2.
• Allergic Nonasthmatic Subjects (ANA subjects):
• ANA subjects will have a history of at least one of the following: (a) allergic rhinitis (with one or more of the following symptoms: nasal congestion, sneezing, runny nose, postnasal drainage), (b) allergic conjunctivitis (ocular itching, tearing and/or swelling) or (c) contact allergy associated with cat dander or dust mite and a positive allergy test to the same allergen.
• All subjects will have a baseline FEV1 and FVC determined at the characterization visit that is no less than 90 % of the predicted value before bronchodilator administration.
• All subjects will have a positive allergy skin prick test to cat dander or dust mite allergen.
• All subjects will be in good general health.
• Life-long absence of cigarette smoking (lifetime total of \< 5 pack-years and none in 5 years).

You may not qualify if:

• Subjects with Allergic Asthma (AA subjects):
• Women of childbearing potential who are pregnant (based on urine beta-HCG or STAT quantitative serum hCG testing), are sexually active and not using contraception, are seeking to become pregnant, or who are nursing.
• The presence of spontaneous asthmatic episode or clinical evidence of upper respiratory tract infection within the previous 6 weeks.
• Participation in a research study involving a drug or biologic during the 30 days prior to the study.
• Intolerance to albuterol, atropine, lidocaine, fentanyl, or midazolam.
• Antihistamines within 7 days of the screening visit.
• Presence of diabetes mellitus, congestive heart failure, ventricular arrhythmias, history of a cerebrovascular accident, renal failure, history of anaphylaxis, or cirrhosis.
• Use of systemic steroids, increased use of inhaled steroids, beta blockers and MAO inhibitors or a visit for an asthma exacerbation within 1 month of the screening visit.
• Antibiotic use for respiratory disease within 1 month of the characterization visit or a respiratory tract infection within 6 weeks of the bronchoscopy visits.
• A history of asthma-related respiratory failure requiring intubation.
• Quantitative skin-prick test positive reaction down to an allergen concentration of 0.056 BAU or AU/ml.
• Subjects with a high possibility of poor compliance with the study.
• Have a history of cigarette smoking within the past 5 years or \> 5 pack years total.
• Having second-hand cigarette smoke exposure or indoor furry pets except in the case of dog, if the subject is not allergic to the dog and the subject has a negative skin test to dog.
• Other lung diseases, such as sarcoidosis, bronchiectasis or active lung infection.

Sponsors & Collaborators

• Andrew D. Luster, M.D.,Ph.D.: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

MeSH Terms

Conditions

Asthma; Hypersensitivity; Inflammation; Constriction, Pathologic

Interventions

Bronchoscopy; Ventilation; Fluorodeoxyglucose F18

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Immune System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Pathological Conditions, Anatomical

Intervention Hierarchy (Ancestors)

Diagnostic Techniques, Respiratory System; Diagnostic Techniques and Procedures; Diagnosis; Endoscopy; Diagnostic Techniques, Surgical; Minimally Invasive Surgical Procedures; Surgical Procedures, Operative; Pulmonary Surgical Procedures; Thoracic Surgical Procedures; Environment, Controlled; Environment; Environment and Public Health; Deoxyglucose; Deoxy Sugars; Carbohydrates

Study Officials

• Andrew D Luster, M.D., Ph.D.

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chief, Division of Rheumatology, Allergy, and Immunology

Study Record Dates

• First Submitted: June 4, 2012
• First Posted: June 6, 2012
• Study Start: September 1, 2012
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: September 15, 2017

Record last verified: 2017-09

Locations

US (1)