Microglia Activation in Asthma (MAIA)

The primary purpose of this study is to provide preliminary data to determine if an acute increase in airway inflammation, provoked by an inhaled allergen challenge, is associated with an increase in microglial activation and may inform whether individuals with asthma, in the long-term, are at increased risk for neurodegeneration, cognitive decline, and forms of dementia. Though in the long-term airway inflammation may be associated with neurodegenerative processes, these changes reflect the accumulation over a lifetime of allergen exposures and disease-related changes. This relationship between peripheral inflammation and microglial activation is analogous to the impact of sleep loss. No single night of poor sleep will lead to long-term change in brain structure, function, or cognitive function, but the accumulation of frequent and repeated sleep loss over a lifetime has been shown to have a major impact. These data will be used for a larger scale study to determine if asthma is a risk factor for neurodegeneration, and will inform brain health issues in asthma more broadly.

Study Overview

• Status: Recruiting
• Conditions: Asthma
• Intervention / Treatment: Biological: Whole lung antigen challenge (WLAC); Radiation: [18F]FEPPA

Detailed Description

First schedule version:

Screening Visit 0: Consent/Eligibility, Pregnancy Test, Vital Signs, Medical History, Concomitant Meds, Allergy Skin Test, Spirometry, Physical Exam, Blood Draw, MRI Simulation, Fraction of exhaled nitric oxide (FeNO)

Screening Visit 0a: Pregnancy Test, Vital Signs, Adverse Events, Concomitant Meds, Spirometry, WLAC, Fraction of exhaled nitric oxide (FeNO)

Visit 1: Pregnancy Test, Vital Signs, Adverse Events, Concomitant Meds, Spirometry, Blood Draw, Sputum Induction, Fraction of exhaled nitric oxide (FeNO), Cognitive Tests, PET/MRI Scan, Questionnaires

Visit 2: Vital Signs, Adverse Events, Concomitant Meds, Spirometry, Physical Exam, WLAC, Blood Draw, Fraction of exhaled nitric oxide (FeNO)

Visit 3: Pregnancy Test, Vital Signs, Adverse Events, Concomitant Meds, Spirometry, Blood Draw, Sputum Induction, Fraction of exhaled nitric oxide (FeNO), Cognitive Tests, PET/MRI Scan, Questionnaires

Visit 4: Adverse Events, Spirometry, Fraction of exhaled nitric oxide (FeNO)

Second schedule version:

Screening Visit 0: Consent/Eligibility, Pregnancy Test, Vital Signs, Medical History, Concomitant Meds, Allergy Skin Test, Spirometry, Physical Exam, Blood Draw, MRI Simulation

Screening Visit 0a: Pregnancy Test, Vital Signs, Adverse Events, Concomitant Meds, Spirometry, WLAC

Visit 1: Pregnancy Test, Vital Signs, Adverse Events, Concomitant Meds, Spirometry, Blood Draw, Sputum Induction, Fraction of exhaled nitric oxide (FeNO), Cognitive Tests, PET/MRI Scan, Questionnaires

Visit 2: Vital Signs, Adverse Events, Concomitant Meds, Spirometry, Physical Exam, WLAC, Blood Draw, Fraction of exhaled nitric oxide (FeNO), Cognitive Tests, PET/MRI Scan, Questionnaires

Visit 3: Vital Signs, Adverse Events, Concomitant Meds, Spirometry, Blood Draw, Sputum Induction, Fraction of exhaled nitric oxide (FeNO)

Visit 4: Adverse Events, Spirometry, Fraction of exhaled nitric oxide (FeNO)

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Jane Sachs; Phone Number: 6088902980; Email: jfsachs@wisc.edu
• Study Contact Backup: Name: Corrina Frye; Phone Number: 6088903073; Email: cfrye@wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53703-2637
      • Recruiting
      • University of Wisconsin Madison
      • Contact: Jane Sachs, MBE, MPH; Phone Number: 680-890-2960; Email: jfsachs@wisc.edu
      • Principal Investigator: Melissa Rosenkranz, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults (age 18-50) with mild allergic asthma

Description

Inclusion Criteria:

• Male or female with no health concerns that might affect the outcome of the study
• Physician diagnosis of asthma for at least six months prior to screening (can be determined at the discretion of an asthma/allergy physician member of the study team)
• At least a 20% decrease in forced expiratory volume (FEV1) during the immediate response following inhaled allergen challenge
• FEV1 > 70% at baseline
• Positive immediate skin test for allergies to ragweed, cat dander, or house dust mite (historical data documented within the last 5 years is acceptable)
• Women of child-bearing potential (WCBP) must have a negative urine pregnancy test for human chorionic gonadotropin (hCG) at screening and within 48 hours of the inhaled allergen challenge(s) and the positron emission tomography (PET) scans. WCBP must agree to use a medically-acceptable form of birth control for the duration of the study (medically-acceptable birth control methods can include: abstinence, barrier methods, oral contraceptives, injection contraceptives or skin absorption contraceptives).
• Asthma medications consisting of only inhaled beta-agonists taken as needed or leukotriene inhibitors
• Ability to tolerate a simulated functional magnetic resonance imaging (fMRI) brain scanning session
• In the opinion of the investigator, capable and willing to grant written informed consent and cooperate with study procedures and requirements
• High-affinity TSPO-binding genotype. Mixed (high/low) binding-affinity genotype may be included at principal investigator's (PI) discretion.

Exclusion Criteria:

• Current smoker (defined as more than 0.5 pack per week for the past 6 months and any smoking within two weeks of study procedures) or has a smoking history exceeding 5 pack years within the last 10 years
• Currently receiving immunotherapy
• Not able to withhold medication(s) as outlined by the study
• Use of psychotropic medication that might affect function of neurocircuitry implicated in the investigator's hypotheses at the discretion of the PI or Co-Investigator (Co-I)
• Needle phobia or claustrophobia
• Major health problems such as autoimmune disease, heart disease, uncontrolled hypertension or lung diseases other than asthma. The listed health problems are definitively exclusionary, but decisions regarding major health problems not listed will be based upon the judgment of the investigator.
• Pre-existing chronic infectious disease
• Use of inhaled corticosteroids or oral corticosteroids within 1 month of screening
• Use of an investigational drug within 30 days of entering the study. This criteria will be reviewed on a case by case basis by the principal investigators or co-investigator to determine appropriate washout period. Appropriate wash out period may be greater than 30 days depending on the half-life of the investigational drug. Participants may be eligible for study participation after completing the washout period designated by the PI or Co-I (physician only).
• Any MRI incompatibility as determined by WIMRs most current MRI screening form
• Does not fit in the MRI scanner
• History of a diagnosed Bipolar Disorder, Schizophrenia, or Schizoaffective Disorder
• History of serious head trauma or seizure disorder (can be included at the discretion of the PI or Co-I)
• Unable, in the judgement of the investigator, to comply with directions and/or tolerate the procedures required for participation in this study
• Pregnant or breast-feeding or has a planned pregnancy during the course of the study
• History of positive COVID-19 test (nasal swab or antibody test)
• Have corrected vision and are not able to wear contacts or see sufficiently well to read without glasses or contacts, as glasses will not fit in the PET/MR head coil
• Any other medical condition or disease that would impact subject safety or data integrity in the opinion of the PIs

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of Neuroinflammation measured by TSPO observed via PET scan	The investigators propose that, in subjects with asthma, provocation of airway inflammation activates microglia, indicative of a neuroinflammatory signal. The hypothesis is that microglial activation will occur following an inhaled allergen challenge, relative to pre-challenge. Activation of microglia will be measured using positron emission tomography (PET) with the radiotracer [18F]FEPPA, a tracer selective for translocator protein (TSPO) binding, which is elevated in activated microglia.	up to 9 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intensity of Airway Response measured by Fraction of exhaled nitric oxide (FeNO) Level	The investigators propose that a more intense airway inflammatory response, created by the inhaled allergen challenge, will be associated with a greater increase in microglial activation. The hypothesis is that the increase in markers of airway inflammation, such as FeNO will be positively associated with the increase in microglial activation. Exhaled nitric oxide level will be determined using the Niox VERO instrumentation to measure FeNO. The test requires the participant to exhale into the mouthpiece of the FeNO measuring instrument for approximately 10 seconds.	up to 11 days
Intensity of Airway Response measured by Sputum Eosinophil Count	The investigators propose that a more intense airway inflammatory response, created by the inhaled allergen challenge, will be associated with a greater increase in microglial activation. The hypothesis is that the increase in markers of airway inflammation, such as sputum eosinophil count will be positively associated with the increase in microglial activation. Sputum induction is a relatively simple, repeatable, and non-invasive method to collect airway secretions and are a highly relevant biological sample to assess airway inflammation.	up to 10 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functionality Measured by Statistical Significance of Co-variation between Cognitive Tasks or Self-Report Instruments and Microglial Activation	The investigators propose that a greater increase in microglial activation will be associated with reduced performance on tasks that assess cognitive function and greater psychological symptoms. The hypothesis is that a greater post-allergen challenge increase in microglial activation will be associated with a decrement in performance, relative to baseline, on measures of memory, attention, or executive function and elevated reports of depressive and anxious symptoms. The instruments may include the State-Trait Anxiety Inventory, Beck Depression Inventory, Beck Anxiety Inventory, Penn State Worry Questionnaire, Perceived Stress Scale, Stress and Adversity Inventory, Childhood Trauma and Adversity, and Peak Flow Diary (a diary of asthma symptoms recorded daily).	up to 10 days

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Melissa Rosenkranz, Center for Healthy Minds

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2019
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: March 10, 2020
• First Submitted That Met QC Criteria: March 12, 2020
• First Posted (Actual): March 13, 2020

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: 2019-1309; A483000 (Other Identifier: UW Madison); L&S CTR FOR HEALTHY MINDS (Other Identifier: UW Madison); 1R01HL123284-01A1 (U.S. NIH Grant/Contract); Protocol Version 4/21/2021 (Other Identifier: UW Madison)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no specific sharing plan at this time except most likely will collaborate with researchers within and outside UW-Madison who would have access to data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No