Smokisone: Woodsmoke Particulate + Prednisone

Sponsor

University of North Carolina, Chapel Hill (Other)

Overall Status

Recruiting

CT.gov ID

NCT03861390

Collaborator

United States Department of Defense (U.S. Fed)

Enrollment

Location

Arms

46.4

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Deployment of military personnel has been associated with increased respiratory illness likely due, in part, to inhalation of unusual particulate matter (PM), such as from burn pits. Inflammation is a key initial response to inhaled particulates. The researchers have developed a protocol using inhaled wood smoke particles (WSP) as a way to study PM-induced airway inflammation. Exposure to wood smoke particles causes symptoms, even in healthy people, such as eye irritation, cough, shortness of breath, and increased mucous production. The purpose of this research study is to see if an oral steroid treatment can reduce the airway inflammation caused by the inhaled WSP. The exposure will be 500 µg/m³ of WSP for 2 hours, with intermittent exercise on a bicycle and rest. The wood is burned in a typical wood stove and piped into the chamber.

Condition or Disease	Intervention/Treatment	Phase
Airway Inflammation	Drug: 60 mg Prednisone Drug: Placebo	Phase 1/Phase 2

Detailed Description

Military deployment is associated with exposure to novel particulate matter (PM), such as from burn pits, aeroallergens, and increased cigarette consumption. War fighters exposed to these inhalational exposures exhibit immediate and chronic respiratory morbidity. For example, military service personnel surveyed in both the Republic of Korea (ROK) and Kabul, Afghanistan reported a general increase in respiratory morbidity, including asthma and chronic bronchitis, associated with their deployment. Air contaminants in the ROK were characterized by elevated levels of both PM 0.5-2.5 and PM 2.5-10. Similarly, exposures in Kabul were characterized by multiple airborne PM exposures, including those from burn pits. Burn pit PM includes metals, bioaerosols, organic by-products, and biomass combustion particles. These findings indicate that inhaled PM is a likely cause of respiratory morbidity in the field.

Inflammation is a key initial response to inhaled particulates. Wood smoke particles (WSP) serve as a model agent to study PM-induced bronchitis. WSP inhalation generates reactive oxidant (and nitrosative) species which cause local injury of airway epithelial cells and release of damage-associated molecular patterns (DAMPs) that activate toll-like receptors (TLR) and Interleukin (IL)-1-mediated innate immune responses by resident airway macrophages. Contamination of PM with bioaerosols, which contain lipopolysaccharide (LPS), also activates innate immune responses through toll-like receptor 4 (TLR4) activation of resident airway macrophages. These complementary processes result in recruitment of neutrophils (PMN), which mediate luminal airway inflammation with release of toxic mediators such as neutrophil elastase and myeloperoxidase that promote acute and chronic bronchitis.

Therefore, mitigation of PM-induced airway neutrophilic inflammation should be a key focus in order to reduce the respiratory morbidity of military personnel. The researchers have studied a number of pro-inflammatory inhaled agents, such as nebulized LPS, ozone (O3), and WSP, as models of acute neutrophilic bronchitis against which to test a number of therapeutic agents. To this effect, the researchers have reported that inhaled fluticasone inhibits O3-induced and LPS-induced neutrophilic inflammation, and that parenteral anakinra and oral gamma-tocopherol inhibit neutrophilic responses to inhaled LPS. In this study, the researchers will evaluate the efficacy of oral prednisone, a readily available anti-inflammatory medication commonly used in airway inflammatory diseases, in mitigating WSP-induced airway inflammation.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

14 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

The randomization schedule will be generated by using permuted block randomization with a block size of 4 (2 prednisone, 2 placebo for the first treatment period of the protocol).The randomization schedule will be generated by using permuted block randomization with a block size of 4 (2 prednisone, 2 placebo for the first treatment period of the protocol).

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Phase I/II Randomized, Double-blind, Placebo-controlled Cross-over Study of Prednisone on Airway Inflammatory Response to Inhaled Wood Smoke.

Actual Study Start Date :

Mar 22, 2019

Anticipated Primary Completion Date :

Feb 1, 2023

Anticipated Study Completion Date :

Feb 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Prednisone, then Placebo	Drug: 60 mg Prednisone Immediately following exit from the wood smoke chamber, subjects will receive 60 mg of prednisone per randomization schema Drug: Placebo Immediately following exit from the wood smoke chamber, subjects will receive a matching placebo to the 60 mg of prednisone per randomization schema
Placebo Comparator: Placebo, then Prednisone	Drug: 60 mg Prednisone Immediately following exit from the wood smoke chamber, subjects will receive 60 mg of prednisone per randomization schema Drug: Placebo Immediately following exit from the wood smoke chamber, subjects will receive a matching placebo to the 60 mg of prednisone per randomization schema

Arm

Intervention/Treatment

Active Comparator: Prednisone, then Placebo

Drug: 60 mg Prednisone

Immediately following exit from the wood smoke chamber, subjects will receive 60 mg of prednisone per randomization schema

Drug: Placebo

Immediately following exit from the wood smoke chamber, subjects will receive a matching placebo to the 60 mg of prednisone per randomization schema

Placebo Comparator: Placebo, then Prednisone

Drug: 60 mg Prednisone

Immediately following exit from the wood smoke chamber, subjects will receive 60 mg of prednisone per randomization schema

Drug: Placebo

Immediately following exit from the wood smoke chamber, subjects will receive a matching placebo to the 60 mg of prednisone per randomization schema

Outcome Measures

Primary Outcome Measures

change in sputum % neutrophils with WSP exposure [(6 hours post WSP - pre WSP [Prednisone]) vs (6 hours post WSP - pre WSP [Placebo])]
comparing the change in sputum % neutrophils 6 hours post WSP exposure with Prednisone versus placebo

Secondary Outcome Measures

change in sputum % neutrophils with WSP at 24 hours [(24 hours post WSP - pre WSP [Prednisone]) vs (24 hours post WSP - pre WSP [Placebo])]
comparing the change in sputum % neutrophils 24 hours post WSP exposure with Prednisone versus placebo
change in neutrophils/mg with WSP at 6 and 24 hours [(6 hours post WSP - pre WSP [Prednisone]) vs (6 hours post WSP - pre WSP [Placebo]) and (24 hours post WSP - pre WSP [Prednisone]) vs (24 hours post WSP - pre WSP [Placebo])]
comparing the change in neutrophils/mg 6 and 24 hours post WSP exposure with Prednisone versus Placebo
Mucociliary Clearance (MCC) Associated With Inhaled Wood Smoke Exposure as Affected by Prednisone [4 hours post WSP with Prednisone vs 4 hours post WSP with Placebo]
4 hours post WSP exposure, the MCC is done. A whole lung region of interest (ROI) bordering the right lung is used to estimate (by computer analysis) whole lung retention of inhaled radiolabeled particles. Labeled particle counts are measured over a 2 hour period to determine the fraction of initial particle counts remaining. From this data, the investigators will determine the percentage of labeled particles cleared from the lung during the 2 hour observation period and compare Prednisone vs Placebo.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Age 18-45 years, inclusive, of both genders
Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy
No history of episodic wheezing, chest tightness, or shortness of breath consistent with asthma, or physician-diagnosed asthma.
Forced expiratory volume at one second (FEV1) of at least 80% of predicted and FEV1/ forced vital capacity (FVC) ≥0.70.
Oxygen saturation of ≥93%
Ability to provide an induced sputum sample.
Subject must demonstrate a ≥10% increase in sputum %PMNs 6 hours following inhaled WSP exposure, when compared to baseline sputum (to be completed in a separate protocol IRB# 15-1775).
Proof of vaccination to Covid

Exclusion Criteria:

Clinical contraindications:

Any chronic medical condition considered by the PI as a contraindication to the exposure study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic infections/immunodeficiency.
Viral upper respiratory tract infection within 4 weeks of challenge.
Any acute infection requiring antibiotics within 4 weeks of exposure or fever of unknown origin within 4 weeks of challenge.
Abnormal physical findings at the baseline visit, including but not limited to abnormalities on auscultation, temperature of 37.8° C, Systolic BP > 150mm Hg or < 85 mm Hg; or Diastolic BP > 90 mm Hg or < 50 mm Hg, or pulse oximetry saturation reading less than 93%.
Physician diagnosis of asthma
If there is a history of allergic rhinitis, subjects must be asymptomatic of allergic rhinitis at the time of study enrollment.
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.
Medications which may impact the results of the WSP exposure, interfere with any other medications potentially used in the study (to include steroids, beta antagonists, non-steroidal anti-inflammatory agents)
Cigarette smoking > 1 pack per month
Unwillingness to use reliable contraception if sexually active (IUD, birth control pills/patch, condoms).
Use of immunosuppressive or anticoagulant medications including routine use of NSAIDS. Oral contraceptives are acceptable, as are antidepressants and other medications may be permitted if, in the opinion of the investigator, the medication will not interfere with the study procedures or compromise safety and if the dosage has been stable for 1 month.
Orthopedic injuries or impediments that would preclude bicycle or treadmill exercise.
Inability to avoid NSAIDS, Multivitamins, Vitamin C or E or herbal supplements.
Allergy/sensitivity to study drugs or their formulations
Positive Covid test in the past 90 days
Pregnant/lactating women and children (< 18 years as this is age of majority in North Carolina) will also be excluded since the risks associated with WSP exposure to the fetus or child, respectively, are unknown and cannot be justified for this non-therapeutic protocol. Individuals over 45 years of age will not be included due to the increased possibility of co-morbidities and need for prohibited medications.
Inability or unwillingness of a participant to give written informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Center for Environmental Medicine, Asthma and Lung Biology at UNC Chapel Hill	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

University of North Carolina, Chapel Hill
United States Department of Defense

Investigators

Principal Investigator: Terry Noah, MD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

University of North Carolina, Chapel Hill

ClinicalTrials.gov Identifier:

NCT03861390

Other Study ID Numbers:

18-2196

First Posted:

Mar 4, 2019

Last Update Posted:

Aug 1, 2022

Last Verified:

Jul 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Additional relevant MeSH terms:

Inflammation

Prednisone

Study Results

No Results Posted as of Aug 1, 2022