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

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03780387
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 1
• Location: 1
• Arm: 1
• Actual Duration (Months): 6.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Asthma Atopic	Biological: Felis Catus	Early Phase 1

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 Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Identification of Allergic Asthmatics Reactive to Felis Catus (Cat Hair) Allergen Inhalation
• Actual Study Start Date: Apr 16, 2019
• Actual Primary Completion Date: Nov 11, 2019
• Actual Study Completion Date: Nov 11, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Inhaled Allergen Challenge Felis Catus sensitive, mild asthmatics will undergo inhaled allergen challenge.	Biological: Felis Catus; Inhalation of Felis Catus allergen in subjects allergic to Felis Catus; Other Names: Cat hair Cat

Outcome Measures

Primary Outcome Measures

1. Maximum Percent Change in 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.

Secondary Outcome Measures

1. 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).

2. Change in 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.

3. 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

4. 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.

5. 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 .

6. 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.

7. Heart Rate Variability (HRV) [Pre challenge and immediately post challenge]

   HRV with Spacelabs technology will be measured 24 hours pre and during inhalation challenge

8. Change in Concentration of Inflammatory Cytokines in Nasal Epithelial Lining Fluid [Pre challenge and immediately post challenge]

   Nasal fluid collected for analysis of cytokines IL-8, IL-6, IL-1alpha, IL-1 beta

9. Change in Concentration of Inflammatory Cytokines in Nasal Epithelial Lining Fluid [Pre challenge and 7 hours post challenge]

   Nasal strip to collect cytokines IL-8, IL-6, IL-1alpha, IL-1 beta

10. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Katie Mills	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Michelle Hernandez, MD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 13, 2019

More Information

Publications

None provided.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT03780387
• Other Study ID Numbers: 18-2006; 1R01HL135235-01A1
• First Posted: Dec 19, 2018
• Last Update Posted: Jul 14, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of North Carolina, Chapel Hill: Felis Catus (cat)
• Additional relevant MeSH terms: Respiratory Aspiration; Asthma

Study Results

Participant Flow

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of Felis Catus allergen in participants with documented allergic sensitization to cat hair
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Felis Catus sensitive, mild asthmatics will undergo inhaled allergen challenge. Felis Catus: Inhalation of Felis Catus allergen in subjects allergic to Felis Catus
Overall Participants	1
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	1 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Percent Change in Forced Expiratory Volume in 1 Second (FEV1)
Description	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.
Time Frame	Pre-challenge to 10 hours post-challenge

Outcome Measure Data

Analysis Population Description

A single participant completed the cat allergen inhalation challenge

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	1
Mean (Standard Deviation) [percent change in FEV1]	-21 (0)

2. Secondary Outcome

Title	Levels of IL-1β in Induced Sputum
Description	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).
Time Frame	Baseline and 24 hours post- inhalation challenge

Outcome Measure Data

Analysis Population Description

Samples are typically batch processed and it was cost-prohibitive to run one participant's sample.

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	0

3. Secondary Outcome

Title	Change in Sputum %Eosinophils
Description	Induced sputum obtained pre-challenge and again at 24 hours post-challenge will be assessed for cells.
Time Frame	Pre-challenge and 24 hours post-challenge

Outcome Measure Data

Analysis Population Description

a single participant underwent inhaled cat allergen challenge

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	1
Mean (Standard Deviation) [percentage point change in %eosinophils]	-0.16 (0)

4. Secondary Outcome

Title	Mucins in Sputum
Description	Sputum mucins will be measured at baseline, and again at 24 hours following inhaled allergen challenge
Time Frame	Baseline and 24 hours post- inhalation challenge

Outcome Measure Data

Analysis Population Description

Samples are typically batch processed and it was cost-prohibitive to run one participant's sample.

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	0

5. Secondary Outcome

Title	Number of Participants Who Experience a Late Phase Response (Fall in FEV1≥15%) to Inhaled Allergen
Description	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.
Time Frame	Pre-challenge to 10 hours post-challenge

Outcome Measure Data

Analysis Population Description

A single participant underwent inhaled challenge with cat hair allergen

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	1
Count of Participants [Participants]	1 100%

6. Secondary Outcome

Title	Change in Airway Hyperresponsiveness Measured by Difference in Methacholine Dose Required to Produce a ≥20% Fall in FEV1 (PC20)
Description	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 .
Time Frame	Baseline to 24 hours post-challenge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	1
Mean (Standard Deviation) [mg/mL]	2.5 (0)

7. Secondary Outcome

Title	Change in Exhaled Nitric Oxide (eNO) Levels in Ppb
Description	eNO levels will be measured pre-challenge, and 24 hours post-challenge.
Time Frame	Pre-challenge to 24 hours post-challenge

Outcome Measure Data

Analysis Population Description

A single participant underwent inhalation challenge with cat hair allergen

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	1
Mean (Standard Deviation) [parts per billion]	-4 (0)

8. Secondary Outcome

Title	Heart Rate Variability (HRV)
Description	HRV with Spacelabs technology will be measured 24 hours pre and during inhalation challenge
Time Frame	Pre challenge and immediately post challenge

Outcome Measure Data

Analysis Population Description

Monitoring equipment were unavailable after being lost during transit and these data were not collected.

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	0

9. Secondary Outcome

Title	Change in Concentration of Inflammatory Cytokines in Nasal Epithelial Lining Fluid
Description	Nasal fluid collected for analysis of cytokines IL-8, IL-6, IL-1alpha, IL-1 beta
Time Frame	Pre challenge and immediately post challenge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	1
IL-8	-14790.89 (0)
IL-6	-11.54 (0)
IL-1alpha	22.12 (0)
IL-1 beta	-23.71 (0)

10. Secondary Outcome

Title	Change in Concentration of Inflammatory Cytokines in Nasal Epithelial Lining Fluid
Description	Nasal strip to collect cytokines IL-8, IL-6, IL-1alpha, IL-1 beta
Time Frame	Pre challenge and 7 hours post challenge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	1
IL-8	-16076.98 (0)
IL-6	-21.78 (0)
IL-1a	24.52 (0)
IL-1b	4.74 (0)

11. Secondary Outcome

Title	Change in Concentration of Inflammatory Cytokines in Nasal Epithelial Lining Fluid
Description	Nasal strip to collect cytokine IL-8, IL-6, IL-1alpha, IL-1 beta
Time Frame	Pre challenge and 24 hours post challenge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Inhalation of cat hair allergen in participants with documented allergic sensitization to cat hair
Measure Participants	1
IL-8	-10763.58 (0)
IL-6	7.09 (0)
IL-1a	70.14 (0)
IL-1b	-21.21 (0)

Adverse Events

Time Frame	Adverse event data were collected from the time written informed consent was obtained until 10 days after the inhaled allergen challenge.
Arm/Group Title	Inhaled Allergen Challenge
Arm/Group Description	Felis Catus sensitive, mild asthmatics will undergo inhaled allergen challenge. Felis Catus: Inhalation of Felis Catus allergen in subjects allergic to Felis Catus
All Cause Mortality
	Inhaled Allergen Challenge
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Inhaled Allergen Challenge
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Inhaled Allergen Challenge
	Affected / at Risk (%)	# Events
Total	0/1 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.