CO3PD: Innate Immunity in Ozone-induced Airway Inflammation in COPD

Sponsor

University of California, San Francisco (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT04669743

Collaborator

(none)

Enrollment

Locations

Arm

101.8

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States. Patients with COPD are routinely exposed to indoor and outdoor air pollution, which appears to cause escalation of their respiratory symptoms, a process called exacerbation, with resulting need to seek medical attention. This research plan proposes to evaluate the impact of lung immune cells in susceptibility to develop exacerbation through an experimental model of inhalational exposure using ambient levels of a component of air pollution (ozone) in COPD patients and longitudinal sampling of their lung immune cells.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive Airway Disease COPD Exacerbation Pollution; Exposure Pollution Related Respiratory Disorder	Other: Ozone exposure	N/A

Detailed Description

A major cause of morbidity and mortality in COPD is exacerbation. The mechanisms underlying COPD exacerbation are poorly understood, but airway innate immune system has been implicated in its development. Air pollution contributes to development of COPD exacerbation, and exposure to ozone, a major component of air pollution, is associated with increased healthcare utilization among patients with COPD. Inhalation of ambient levels of ozone is known to affect airway innate immune system. This proposal sets out to characterize and investigate the role of innate immune system and in particular airway macrophages in ozone-induced COPD exacerbation through establishing an experimental model that employs controlled ozone exposure and longitudinal sampling via bronchoscopy. The research plan proposes to examine human immune cells trafficking in airways during the process of ozone-induced airway injury and inflammation in patients with COPD. The investigator's overall hypothesis is that inhalational challenge to a high ambient level of ozone in patients with COPD provides a safe human model of airway injury with resulting intraluminal shifts in the population and polarization of macrophages to study innate immunity processes relevant to ozone-induced COPD exacerbation.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

72 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Controlled inhalational challenge to ozoneControlled inhalational challenge to ozone

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Innate Immunity in Ozone-induced Airway Inflammation in COPD

Actual Study Start Date :

Apr 7, 2016

Anticipated Primary Completion Date :

Oct 1, 2024

Anticipated Study Completion Date :

Oct 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Study Population Subjects will be recruited and consented following screening. Subjects will be characterized into cohorts based on presence of COPD and smoking status. All subjects enrolled will be undergoing the same interventions: 1st Bronchoscopy (3 wks pre-exposure), Ozone Exposure, 2nd Bronchoscopy (1 day post-exposure), 3rd Bronchoscopy (5 days post-exposure). Ozone exposure will take place in an exposure chamber.	Other: Ozone exposure Exposures will take place at the UCSF Human Exposure Chamber Core Facility. Ozone will be added to the air in the chamber and concentration measured every 30 seconds. Subjects will exercise for two 15-minute intervals of each hour on a cycle ergometer, and will rest for two 15-minute intervals between exercise sessions. The rate of exercise will be individually adjusted to produce a targeted minute ventilation of 15-20 L/min/m2 body surface area. Subjects will be sent home post-exposure and will return to the laboratory on the following day and six days after the exposure for bronchoscopy.

Arm

Intervention/Treatment

Experimental: Study Population

Subjects will be recruited and consented following screening. Subjects will be characterized into cohorts based on presence of COPD and smoking status. All subjects enrolled will be undergoing the same interventions: 1st Bronchoscopy (3 wks pre-exposure), Ozone Exposure, 2nd Bronchoscopy (1 day post-exposure), 3rd Bronchoscopy (5 days post-exposure). Ozone exposure will take place in an exposure chamber.

Other: Ozone exposure

Exposures will take place at the UCSF Human Exposure Chamber Core Facility. Ozone will be added to the air in the chamber and concentration measured every 30 seconds. Subjects will exercise for two 15-minute intervals of each hour on a cycle ergometer, and will rest for two 15-minute intervals between exercise sessions. The rate of exercise will be individually adjusted to produce a targeted minute ventilation of 15-20 L/min/m2 body surface area. Subjects will be sent home post-exposure and will return to the laboratory on the following day and six days after the exposure for bronchoscopy.

Outcome Measures

Primary Outcome Measures

Changes in prevalence and functional status of alveolar macrophage sub-populations in airway lumen [4 weeks]
Number of alveolar macrophages (AM) measured by flow cytometry (both absolute numbers and relative percentage of cells)
Changes in prevalence and functional status of monocyte-derived macrophage sub-populations in airway lumen [4 weeks]
Number of monocyte-derived macrophages (MDM) measured by flow cytometry (both absolute numbers and relative percentage of cells)
Changes in prevalence and functional status of interstitial macrophage sub-populations in airway lumen [4 weeks]
Number of interstitial macrophages (IM) measured by flow cytometry (both absolute numbers and relative percentage of cells)

Secondary Outcome Measures

Symptomatic responses [4 weeks]
Evidence for presence of mild exacerbation as measured by changes at or above the level of minimally clinically important difference (MCID) in each of the questionnaire's symptom score, 1-6, for the number of flare-ups in the past 3 years, with 6 being the worst outcome.
Physiologic responses [4 weeks]
Quantitative changes across ozone exposure in spirometric indices of airflow obstruction
Cardiovascular response using measurement of Heart Rate [4 weeks]
Cardiovascular outcome of heart rate will be measured for safety assessment before, during, and after ozone exposure. The maximum limit of their heart rate is 80% of their heart rate maximum.
Cardiovascular response using measurement of Blood Pressure [4 weeks]
Cardiovascular outcome of blood pressure (both systolic and diastolic) will be measured for safety assessment before, during, and after ozone exposure.
Cardiovascular response using measurement of ECG changes [4 weeks]
Cardiovascular outcomes of electrocardiogram (ECG) changes will be measured for safety assessment before and after ozone exposure. ECG changes, including ST-segment elevation and rhythm abnormalities, will be compared to the baseline ECG.

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Group 1:

No diagnosis of COPD or asthma.
No spirometric evidence of airflow obstruction as determined by FEV1/FVC ratio = or

0.7.

Less than 1 pack year history of tobacco smoking and no tobacco use within the past 12 months.

Group 2:

No diagnosis of COPD or asthma.
No spirometric evidence of airflow obstruction as determined by FEV1/FVC ratio = or

0.7.

Current smoker with history of at least 20 pack-years smoking.

Group 3:

Diagnosis of COPD as determined by GOLD criteria (FEV1/FVC ratio <0.7).
COPD severity of GOLD stage II or III (FEV1 >40% predicted).
Smoking Status: Former smokers with history of at least 20 pack-years smoking.

Group 4:

Diagnosis of COPD as determined by GOLD criteria (FEV1/FVC ratio <0.7).
COPD severity of GOLD stage II or III (FEV1 >40% predicted).
Smoking Status: Current smokers with history of at least 20 pack-years smoking.

During subject screening visit, Albuterol is used to determine whether the subjects have COPD based on the Global Initiative on Obstructive Lung Diseases (GOLD) criteria. Regardless of whether the subject has reversibility to Albuterol or not, if they have an abnormal ratio after inhalation of Albuterol, they would meet the GOLD criteria for COPD and will be included in the study.

Exclusion Criteria:

History of IV drug use or inhalation of recreational drugs other than marijuana:

A- within the past 20 years. B- more than 100 usage. C- longer than 1 year.

COPD severity of GOLD stage IV.
Inability to walk briskly or run on treadmill or pedal on ergometer to perform the study-required moderate exercise level (achieve minute ventilation of 15 to 20 L/min/m2 body surface area).
Pregnant/breast feeding.
Serious and active heart conditions - defined by stable or unstable angina, recent myocardial infarction (within the last 2 years), active congestive heart failure, ischemic cardiomyopathy.
Malnourishment - determined by BMI less than 19. If subject has BMI greater or equal to 19, but has a history of malnourishment, study staff will measure albumin level of subject's blood after initial blood draw. Albumin level must be greater than 2.5 mg per deciliter, or subject will be excluded.
Liver cirrhosis.
History of chronic active Hepatitis B or C
On visits where moderate sedation is preformed, subject are required to have an escort home. Inability to secure a ride home will result in the subject being ineligible for the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Zuckerberg San Francisco General Hospital and Trauma Center	San Francisco	California	United States	94110
2	San Francisco VA Medical Center	San Francisco	California	United States	94121
3	University of California, San Francisco	San Francisco	California	United States	94122