Identification of Allergic Asthmatics Reactive to Felis Catus (Cat Hair) Allergen Inhalation

Early Phase 1

Terminated

• Conditions: Asthma Atopic
• Interventions: Biological: Felis Catus

• Registration Number: NCT03780387
• Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary

This study is designed to identify Felis Catus, or cat hair, sensitive asthmatics who demonstrate a late phase asthmatic response after cat hair 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 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.

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.

Study Timeline

• Study First Submitted: 2018-12-17
• Study First Submitted QC: 2018-12-17
• Study First Posted: 2018-12-19
• Study Start: 2019-04-16
• Primary Completion: 2019-11-11
• Study Completion: 2019-11-11
• Status Verified: 2022-06
• Results First Submitted: 2022-06-16
• Results First Submitted QC: 2022-06-16
• Results First Posted: 2022-07-14
• Last Update Submitted: 2022-09-22
• Last Update Posted: 2022-10-18

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 1

Inclusion Criteria

• Age range 18-45 years, inclusive
• FEV1 of at least 80% of predicted and FEV1/FVC (Forced Vital Capacity) ratio of at least 0.7 (without use of bronchodilator medications for 8 hours or long acting beta agonists for 24 hours), consistent with lung function of persons with no more than mild episodic or mild persistent asthma.
• Physician diagnosis of asthma
• Allergic sensitization to felis catus (cat hair) as confirmed by positive immediate skin prick test response
• Negative pregnancy test for females who are not s/p hysterectomy or who have been amenorrheic for 12 months or more.
• Oxygen saturation of >94% and blood pressure within the following limits: (Systolic between 150-90 mmHg, Diastolic between 90-60 mmHg).

Read More

Exclusion Criteria

Clinical contraindications:

• Any chronic medical condition considered by the PI as a contraindication to participation in the study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic infections or immunodeficiency.
• Physician directed emergency treatment for an asthma exacerbation within the preceding 12 months.
• Exacerbation of asthma more than 2x/week which could be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma.
• Daily requirements for albuterol due to asthma symptoms (cough, wheeze, chest tightness) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma (not to include prophylactic use of albuterol prior to exercise).
• Viral upper respiratory tract infection within 4 weeks of challenge.
• Any acute infection requiring antibiotics within 6 weeks of exposure or fever of unknown origin within 6 weeks of challenge.
• Severe asthma
• Mental illness or history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements.
• Cigarette smoking >1 pack per month
• Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a clearly recognized viral induced asthma exacerbation) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma.
• Allergy/sensitivity to study drugs or their formulations
• Known hypersensitivity to methacholine or to other parasympathomimetic agents
• History of intubation for asthma
• Unwillingness to avoid coffee, tea, cola drinks, chocolate, or other foods containing caffeine after midnight on the days that methacholine challenge testing is to be performed.
• Unwillingness to use reliable contraception if sexually active (IUD, birth control pills/patch, condoms).
• Pregnancy or nursing a baby. Female volunteers will be asked to use effective birth control (stable regimen of hormonal contraceptive use for at least 3 months, intrauterine device placement, tubal ligation or endometrial ablation for at least 3 months through at least one week after study completion) and will provide a urine sample to test for pregnancy on study days. If the test is positive or the subject has reason to believe she may be pregnant, she will be dismissed from the study. Women who have been amenorrheic for 12 months may participate. Male volunteers will be asked to use condoms for the duration of the study through at least one week after study completion.

Usage of the following medications:

• Use of systemic steroid therapy within the preceding 12 months for an asthma exacerbation. All use of systemic steroids in the last year will be reviewed by a study physician.
• Subjects who are prescribed daily inhaled corticosteroids, cromolyn, or leukotriene inhibitors (Montelukast or Zafirlukast) will be required to discontinue these medications at least 2 weeks prior to their screening visit.
• Use of daily theophylline within the past month.
• Daily requirement for albuterol due to asthma symptoms (cough, wheeze, chest tightness) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma. (Not to include prophylactic use of albuterol prior to exercise).
• Use of any immunosuppressant therapy within the preceding 12 months will be reviewed by the study physician.
• Receipt of Live Attenuated Influenza Vaccine (LAIV), also known as FluMist®, or any other live viral vaccine within the prior 30 days, or any vaccine for at least 5 days
• Use of beta blocking medications
• Antihistamines in the 5 days prior to allergen challenge
• Routine use of NSAIDs, including aspirin.

Physical/laboratory indications:

• Abnormalities on lung auscultation
• Temperature >37.8°C
• Oxygen saturation of <94%
• Systolic BP>150 mmHg or <90 mmHg or diastolic BP>90 mmHg or <60 mmHg
• Inability or unwillingness of a participant to give written informed consent

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Inhaled Allergen Challenge	Felis Catus	Felis Catus sensitive, mild asthmatics will undergo inhaled allergen challenge.

Primary Outcome Measures

Name	Time	Method
Maximum Change in the Percentage of Forced Expiratory Volume in 1 Second (FEV1)	Pre-challenge to 10 hours post-challenge	Pre-challenge FEV1 is measured just prior to administration of the allergen challenge. FEV1 is measured at regular intervals for 10 hours after the challenge. \[(Lowest FEV1 value post-challenge - Pre-challenge FEV1 value)/(Pre-challenge FEV1 value)\]\*100

Secondary Outcome Measures

Name	Time	Method
Change in the Percentage of Sputum Eosinophils	Pre-challenge and 24 hours post-challenge	Induced sputum obtained pre-challenge and again at 24 hours post-challenge will be assessed for cells. (% eosinophils post-challenge - %eosinophils pre-challenge)
Number of Participants Who Experience a Late Phase Response (Fall in FEV1≥15%) to Inhaled Allergen	Pre-challenge to 10 hours post-challenge	FEV1 will be measured prior to administration of the inhaled allergen challenge. The maximum drop in FEV1 that occurs during the late phase (3-10 hours after challenge) will be determined.
Levels of IL-1β in Induced Sputum	Baseline and 24 hours post- inhalation challenge	Participants will undergo a hypertonic saline induced sputum procedure at baseline (within \~2 weeks of the allergen challenge), and again at 24 hours following inhaled allergen challenge. IL-1β concentrations in the sputum will be determined via ELISA. In addition to assessing changes in IL-1β levels, we will determine if IL-1β levels are predictive of key asthma outcomes following inhaled allergen challenge (see outcomes 3-7).
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 in Ppb	Pre-challenge to 24 hours post-challenge	eNO levels will be measured pre-challenge, and 24 hours post-challenge. (eNO value post-challenge - eNO value pre-challenge)
Change in Airway Hyperresponsiveness Measured by Difference in Methacholine Dose Required to Produce a ≥20% Fall in FEV1 (PC20)	Baseline to 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. Negative values indicate decrease and positive values indicate increase in doubling. (methacholine PC20 post-challenge - methacholine PC20 pre-challenge).
Heart Rate Variability (HRV)	Pre challenge and immediately post challenge	HRV with Spacelabs technology will be measured 24 hours pre and during inhalation challenge
Change in Concentration of Inflammatory Cytokines in Nasal Epithelial Lining Fluid	Pre challenge and 24 hours post challenge	Nasal strip to collect cytokine IL-8, IL-6, IL-1alpha, IL-1 beta. \[(Cytokine concentration 24h post-challenge) - (cytokine concentration pre-challenge)\].

Trial Locations

Locations (1)

Katie Mills; 🇺🇸 Chapel Hill, North Carolina, United States