Screening Inhaled Allergen Challenge for Dermatophagoides Farinae

Early Phase 1

Terminated

Conditions: Asthma

Interventions: Biological: Der f

Registration Number: NCT03049111

Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary: This study is designed to identify Dermatophagoides farinae, or Der f, sensitive asthmatics who demonstrate a late phase asthmatic response after Der f inhalation. These subjects may be invited to participate in a planned future study investigating novel asthma treatments.

Detailed Description: Asthma is an increasingly common chronic illness among children and adults, and allergen exposure is among the most common common triggers for asthma exacerbations. Exacerbations of allergic asthma are characterized by an early phase response (EPR), mediated by release of preformed mediators like histamine from mast cells, and a late phase response (LPR) 3-7 hours later mediated by chemokines and cytokines that attract leukocytes such as neutrophils and eosinophils to the airways, increase mucus production, trigger airway smooth muscle contraction, and result in airway constriction and airway hyperreactivity (AHR). The LPR does not occur in the absence of an EPR. The LPR is thought to be predominantly responsible for the symptoms associated with acute exacerbations of allergic asthma and is often used as the measure of efficacy in trials of asthma therapeutics.

This group has taken a particular interest in targeting an inflammatory cytokine, Interleukin-1β, involved in both the early and late phase asthmatic responses to inhaled allergen in allergic asthmatics. In the lung, interleukin 1 beta (IL-1β) is produced by numerous cell types (including epithelial cells, macrophages, neutrophils, eosinophils, and mast cells), where it signals through its receptor to induce transcription of pro-inflammatory genes (17-19). IL-1β is increased in bronchoalveolar lavage fluid from persons with symptomatic asthma vs. those with asymptomatic asthma; likewise, immunohistochemistry of bronchial biopsies of allergic asthmatics reveal increased expression of IL-1β in both bronchial epithelial cells and macrophages. Previous studies in animal and in vitro models demonstrate that IL-1β can directly impact three aspects of an airway inflammatory response: 1). granulocyte (neutrophil/eosinophil) recruitment; 2). non-specific (23, 24) and allergen-specific airway reactivity; and 3). production and clearance of airway mucous. Supporting literature and preliminary studies in human subjects further promote the study of IL-1 blockade for mitigating features of acute allergen-induced asthma exacerbation.

The role of IL-1 in allergen challenge models has not been fully defined. In a study examining 12 asthmatics allergic to D. farinae at this research center, we found that 9/12 asthmatics had a greater than 10% reduction in forced expiratory volume in 1 second (FEV1) after inhaled dust mite challenge. These individuals were considered responders. It was notable that when comparing post-allergen levels of cytokines between responders and non-responders there was a much greater concentration of IL-1β in post-challenge sputum from responders vs. nonresponders, Furthermore, within the responders, post challenge IL-1β also significantly correlated with sputum eosinophil concentrations (r=0.83, P\<0.05) and neutrophil concentrations (r=0.89, P\<0.05) 24 hours after allergen challenge. These data suggest that IL-1β may play a role in both immediate airway hyperresponsiveness and the late phase recruitment of inflammatory cells (neutrophils and eosinophils) after inhaled allergen challenge.

In order to better understand the role of IL-1β in allergen-induced airway inflammation, induced sputum will be obtained to determine if higher baseline sputum IL-1β concentrations or larger increases in IL-1β following allergen challenge impact non-specific airway hyperresponsiveness (via methacholine challenge), sputum granulocyte recruitment (neutrophil and eosinophil counts and exhaled nitric oxide (eNO), a marker of airway eosinophilia), or changes in expression of inflammatory or allergy-related genes. To this last point, little is known about the mechanisms contributing to response patterns in allergic asthmatics undergoing allergen challenge. Changes in gene expression occurring during the window of time between the EPR and LPR, as these expression changes may dictate whether or not a LPR occurs or to what extent it occurs.

The goal of this screening protocol is to identify subjects who exhibit both an EPR and LPR and who will be eligible for enrollment in the yet to be developed Il-1β protocols. Subjects will undergo a baseline methacholine challenge to establish reactivity, then allergen exposure, followed 24 hours later by methacholine challenge.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Inhaled Allergen Challenge	Der f	Der f sensitive, mild asthmatic subjects will undergo inhaled allergen challenge

Primary Outcome Measures

Name	Time	Method
Number of Participants With Decline in FEV1 ≥ 10% From Pre-challenge During 3-10 Hours Post-allergen Challenge	Pre-challenge to 3-10 hours post-challenge	Participants will undergo an inhaled allergen challenge to identify those with a measurable late phase response (LPR) to inhaled house dust mite allergen. Pre-challenge FEV1 will be measured prior to administration of the allergen challenge. The presence of an LPR will be defined as a decline in FEV1 of ≥10% from pre-challenge values 3-10 hours post-challenge.

Secondary Outcome Measures

Name	Time	Method
Change in Concentration of IL-1β in Induced Sputum	Pre-challenge to 24 hours post-challenge	Participants provided induced sputum pre-allergen challenge and again at 24 hours post-allergen challenge. IL-1β concentrations in the sputum will be determined via ELISA.
Mucins in Sputum	Baseline and 24 hours post- inhalation challenge	Sputum mucins will be measured at baseline, and again at 24 hours following inhaled allergen challenge
Change in Exhaled Nitric Oxide (eNO) Levels	pre-challenge to 24 hours post-challenge	eNO levels will be measured pre-challenge, and 24 hours post-challenge.
Change in Percentage of Eosinophils in Induced Sputum	Pre-challenge to 24 hours post- challenge	Percentage %eosinophils post-challenge minus pre-challenge values
Change in Airway Hyperresponsiveness Measured by Difference in Methacholine Dose Required to Produce a ≥20% Fall in FEV1 (PC20)	Baseline and 24 hours post-challenge	Participants will undergo a methacholine challenge to assess airway hyper-responsiveness at baseline. Changes in methacholine reactivity from baseline to 24 hours post-allergen challenge will be determined.
Maximum Percentage Change in FEV1 From Pre-challenge Values at 3-10 Hours Post-challenge	Pre-challenge to 3-10 hours post-challenge	FEV1 will be measured prior to administration of the inhaled allergen challenge. The maximum change in FEV1 that occurs during the late phase (3-10 hours after challenge) will be determined. \[(lowest FEV1 value recorded post-challenge) - (pre-challenge FEV1 value)/ pre-challenge FEV1 value\] \*100