Lung Macrophage Populations and Functions in Chronic Obstructive Pulmonary Disease (COPD)-Susceptible Smokers (Pre-COPD Pilot)

• ClinicalTrials.gov Identifier: NCT04722835
• Recruitment Status: Recruiting
• First Posted: January 25, 2021
• Last Update Posted: May 7, 2021
• Sponsor: University of California, San Francisco
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): University of California, San Francisco

Study Description

Brief Summary:

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease that affects only a fraction of those who smoke tobacco. The origin of this variability in susceptibility to develop COPD is unclear, but understanding its underlying biology has important implications for our ability to design suitable preventative and therapeutic strategies for its management. This Department of Defense (DOD) discovery research proposes to develop methodologies and generate preliminary data needed to lay the foundation for a large study that would investigate the underlying biological susceptibility of those who smoke tobacco to develop COPD.

Condition or disease	Intervention/treatment
Copd; Smoking; Tobacco Use	Procedure: Bronchoscopy with Bronchoalveolar Lavage (BAL)

Detailed Description:

This is a pilot observational study of 20 subjects ≥40 years of age with smoking history of at least 20 pack-years (former or current) who have preserved spirometry, as defined by normal Forced Expiratory Volume (FEV1) / Forced Vital Capacity (FVC). Of the 20 subjects, 10 with and 10 without air trapping as determined by high and abnormal versus low and normal Residual Volume (RV) / Total Lung Capacity (TLC) measured by plethysmography. The cohort will undergo extensive clinical characterization including full Pulmonary Function Testing (PFT) and medical, symptom, activity, and quality of life questionnaires assessment including modified Medical Council Research (mMRC), COPD Assessment Test (CAT), Short Form-12 (SF12), and St. George's Respiratory (SGRQ) questionnaires. Subjects will undergo bronchoscopy with bronchoalveolar lavage (BAL) to obtain luminal macrophages and BAL fluid (BALF). Live BAL cells, BALF, and BAL cell RNA will be collected and stored in our biorepository for proposed studies. Molecular, functional, and transcriptomics analyses of luminal (alveolar) macrophages obtained by BAL (Aim 2) and protease activity measurement in serum and BALF will be performed (Aim 2) and will be examined against the clinical phenotype of the subjects, in particular air trapping-phenotype, to see if an underlying biological signature for susceptibility to develop COPD could be identified.

To perform a more comprehensive molecular and functional phenotype examination of lung macrophages, additional methodologies will be developed including a second mass cytometry (CyTOF) panel for single-cell proteomics and CyTOF-based phagocytosis and efferocytosis assays to allow for performance of truly single-cell functional phenotyping of myeloid cells from BAL and lung tissue (Aim 1).

Study Design

• Study Type: Observational
• Estimated Enrollment: 40 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Lung Macrophage Populations and Functions in Chronic Obstructive Pulmonary Disease (COPD)-Susceptible Smokers
• Actual Study Start Date: March 1, 2021
• Estimated Primary Completion Date: December 31, 2022
• Estimated Study Completion Date: December 31, 2022

Groups and Cohorts

Group/Cohort	Intervention/treatment
Normal RV/TLC Group: Plethysmographic RV/TLC equal or less than lower limit of normal.	Procedure: Bronchoscopy with Bronchoalveolar Lavage (BAL); Bronchoscopy w/ (BAL): The bronchoscope will be introduced through mouth and directed into the right middle lobe bronchus for bronchial lavage. The BAL will be performed with two 60-mL aliquots (total of 120 ml) of saline in each of medial and lateral segments of Right Middle Lobe (RML) (total 240 ml lavage).; Albuterol Administration: The subjects will inhale 2 puffs of respiratory medication albuterol, then repeat the breathing test.; Peak Flow Measurement: Subjects will breathe in fully then out forcefully into the handheld device.; Pulmonary Function Test w/ Spirometry: will be used for determination of COPD and its severity. The PFT measures breathing capacity and lung function with different types of breathing maneuvers including flow-volume curve, single breath CO diffusing capacity, and total lung capacity.; Blood draw; Medical Health and Symptom Questionnaires; Physical Exam by study doctor to determine suitability and safety for participation.; Other Names: Albuterol Administration; Peak Flow Measurement; Pulmonary Function Test (with Spirometry); Blood draw; Medical Health and Symptom Questionnaires; Physical Exam
Abnormal RV/TLC Group: Plethysmographic RV/TLC higher than lower limit of normal.	Procedure: Bronchoscopy with Bronchoalveolar Lavage (BAL); Bronchoscopy w/ (BAL): The bronchoscope will be introduced through mouth and directed into the right middle lobe bronchus for bronchial lavage. The BAL will be performed with two 60-mL aliquots (total of 120 ml) of saline in each of medial and lateral segments of Right Middle Lobe (RML) (total 240 ml lavage).; Albuterol Administration: The subjects will inhale 2 puffs of respiratory medication albuterol, then repeat the breathing test.; Peak Flow Measurement: Subjects will breathe in fully then out forcefully into the handheld device.; Pulmonary Function Test w/ Spirometry: will be used for determination of COPD and its severity. The PFT measures breathing capacity and lung function with different types of breathing maneuvers including flow-volume curve, single breath CO diffusing capacity, and total lung capacity.; Blood draw; Medical Health and Symptom Questionnaires; Physical Exam by study doctor to determine suitability and safety for participation.; Other Names: Albuterol Administration; Peak Flow Measurement; Pulmonary Function Test (with Spirometry); Blood draw; Medical Health and Symptom Questionnaires; Physical Exam

Outcome Measures

Primary Outcome Measures :

1. Prevalence of macrophage sub-populations in airway lumen. [ Time Frame: 4 weeks ]
   Number of macrophages measured by flow cytometry.
2. Functional status of macrophage sub-populations in airway lumen. [ Time Frame: 4 weeks ]
   Relative percentage of macrophages measured by flow cytometry.

Secondary Outcome Measures :

1. Symptomatic responses [ Time Frame: 1 day ]
   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.

Biospecimen Retention:   Samples With DNA

10 tablespoons of blood as well as Bronchoalveolar Lavage (BAL) samples will be collected.

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

The investigators will recruit both healthy, non-smoking subjects as well as subjects with at least 20 pack-years of smoking and air trapping.

Criteria

Inclusion Criteria:

• Ages between 40 to 75 years old.
• History of at least 20 pack-years of smoking.
• No diagnosis of COPD or asthma.
• No spirometric evidence of airflow obstruction as determined by FEV1/FVC ratio ≥0.7.
• FEV1 and FVC >lower limit of normal.
• Less than 1 pack-year history of tobacco smoking and no tobacco use within the past 12 months.
• Subjects will be divided into two groups by their RV/TLC:

Normal RV/TLC Group:

• Plethysmographic RV/TLC equal or less than lower limit of normal.

Abnormal RV/TLC Group:

• Plethysmographic RV/TLC higher than lower limit of normal.

Exclusion Criteria:

• Any history of IV drug use or inhalation of recreational drugs other than marijuana: A- within the past 20 years. B- more than 100 times IV drug usage. C- longer than 1 year usage.
• Marijuana use >400 joints in lifetime or any within past 6 months.
• Inability to walk briskly, run on treadmill, or pedal on ergometer to perform the study-required exercise level.
• 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.
• Liver cirrhosis.
• History of chronic active Hepatitis B or C.

Contacts and Locations

Contacts

Contact: Yorusaliem Abrham; 415-221-4810 ext 24269; yorusaliem.abrham@ucsf.edu

Contact: Helen Lozier, B.A.; (415) 609-6738; helen.lozier@ucsf.edu

Locations

United States, California

Zuckerberg San Francisco General Hospital and Trauma Center; Active, not recruiting

San Francisco, California, United States, 94110

San Francisco VA Medical Center; Recruiting

San Francisco, California, United States, 94121

Contact: Yorusaliem Abrham 415-221-4810 ext 24269 yorusaliem.abrham@ucsf.edu

Principal Investigator: Mehrdad Arjomandi, M.D.

University of California, San Francisco; Active, not recruiting

San Francisco, California, United States, 94122

Sponsors and Collaborators

University of California, San Francisco

United States Department of Defense

Investigators

• Principal Investigator: Mehrdad Arjomandi, MD; University of California, San Francisco

More Information

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT04722835
• Other Study ID Numbers: 19-29768
• First Posted: January 25, 2021
• Last Update Posted: May 7, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Lung Diseases; Respiratory Tract Diseases; Albuterol; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Tocolytic Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action