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

Primary Purpose

Asthma Atopic

Status

Terminated

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Felis Catus

About this trial

This is an interventional basic science trial for Asthma Atopic focused on measuring Felis Catus (cat)

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Katie Mills

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Inhaled Allergen Challenge

Arm Description

Felis Catus sensitive, mild asthmatics will undergo inhaled allergen challenge.

Outcomes

Primary Outcome Measures

Maximum Change in the Percentage of Forced Expiratory Volume in 1 Second (FEV1)

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

Levels of IL-1β in Induced Sputum

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).

Change in the Percentage of Sputum Eosinophils

Induced sputum obtained pre-challenge and again at 24 hours post-challenge will be assessed for cells. (% eosinophils post-challenge - %eosinophils pre-challenge)

Mucins in Sputum

Sputum mucins will be measured at baseline, and again at 24 hours following inhaled allergen challenge

Number of Participants Who Experience a Late Phase Response (Fall in FEV1≥15%) to Inhaled Allergen

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.

Change in Airway Hyperresponsiveness Measured by Difference in Methacholine Dose Required to Produce a ≥20% Fall in FEV1 (PC20)

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).

Change in Exhaled Nitric Oxide (eNO) Levels in Ppb

eNO levels will be measured pre-challenge, and 24 hours post-challenge. (eNO value post-challenge - eNO value pre-challenge)

Heart Rate Variability (HRV)

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

Nasal fluid collected for analysis of cytokines IL-8, IL-6, IL-1alpha, IL-1 beta. [(Cytokine concentration immediately post-challenge) - (cytokine concentration pre-challenge)].

Change in Concentration of Inflammatory Cytokines in Nasal Epithelial Lining Fluid

Nasal strip to collect cytokines IL-8, IL-6, IL-1alpha, IL-1 beta. [(Cytokine concentration 7h post-challenge) - (cytokine concentration pre-challenge)].

Change in Concentration of Inflammatory Cytokines in Nasal Epithelial Lining Fluid

Nasal strip to collect cytokine IL-8, IL-6, IL-1alpha, IL-1 beta. [(Cytokine concentration 24h post-challenge) - (cytokine concentration pre-challenge)].

Full Information

NCT ID

NCT03780387

First Posted

December 17, 2018

Last Updated

September 22, 2022

Sponsor

University of North Carolina, Chapel Hill

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT03780387

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Terminated

Why Stopped

Terminated due to COVID-19 pandemic.

Study Start Date

April 16, 2019 (Actual)

Primary Completion Date

November 11, 2019 (Actual)

Study Completion Date

November 11, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of North Carolina, Chapel Hill

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Asthma Atopic

Keywords

Felis Catus (cat)

7. Study Design

Primary Purpose

Basic Science

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

1 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Inhaled Allergen Challenge

Arm Type

Experimental

Arm Description

Felis Catus sensitive, mild asthmatics will undergo inhaled allergen challenge.

Intervention Type

Biological

Intervention Name(s)

Felis Catus

Other Intervention Name(s)

Cat hair, Cat

Intervention Description

Inhalation of Felis Catus allergen in subjects allergic to Felis Catus

Primary Outcome Measure Information:

Title

Maximum Change in the Percentage of Forced Expiratory Volume in 1 Second (FEV1)

Description

Time Frame

Pre-challenge to 10 hours post-challenge

Secondary Outcome Measure Information:

Title

Levels of IL-1β in Induced Sputum

Description

Time Frame

Baseline and 24 hours post- inhalation challenge

Title

Change in the Percentage of Sputum Eosinophils

Description

Induced sputum obtained pre-challenge and again at 24 hours post-challenge will be assessed for cells. (% eosinophils post-challenge - %eosinophils pre-challenge)

Time Frame

Pre-challenge and 24 hours post-challenge

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

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

Title

Change in Airway Hyperresponsiveness Measured by Difference in Methacholine Dose Required to Produce a ≥20% Fall in FEV1 (PC20)

Description

Time Frame

Baseline to 24 hours post-challenge

Title

Change in Exhaled Nitric Oxide (eNO) Levels in Ppb

Description

eNO levels will be measured pre-challenge, and 24 hours post-challenge. (eNO value post-challenge - eNO value pre-challenge)

Time Frame

Pre-challenge to 24 hours post-challenge

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

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. [(Cytokine concentration immediately post-challenge) - (cytokine concentration pre-challenge)].

Time Frame

Pre challenge and immediately post challenge

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. [(Cytokine concentration 7h post-challenge) - (cytokine concentration pre-challenge)].

Time Frame

Pre challenge and 7 hours post challenge

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. [(Cytokine concentration 24h post-challenge) - (cytokine concentration pre-challenge)].

Time Frame

Pre challenge and 24 hours post challenge

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michelle Hernandez, MD

Organizational Affiliation

University of North Carolina, Chapel Hill

Official's Role

Principal Investigator

Facility Information:

Facility Name

Katie Mills

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, ﬁgures, and appendices).

IPD Sharing Time Frame

Beginning 9 months and ending 36 months following article publication

IPD Sharing Access Criteria

Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata Requests for access to individual participant data should be sent to bring44@email.unc.edu or carole.robinette@med.unc.edu. Access will be granted after a data access agreement has been signed with the University of North Carolina (UNC)

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

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