Woodsmoke Particulate + Prednisone

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: February 2022

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.

Interventions

  • 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

Arms, Groups and Cohorts

  • Active Comparator: Prednisone, then Placebo
  • Placebo Comparator: Placebo, then Prednisone

Clinical Trial Outcome Measures

Primary Measures

  • change in sputum % neutrophils with WSP exposure
    • Time Frame: (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 Measures

  • change in sputum % neutrophils with WSP at 24 hours
    • Time Frame: (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
    • Time Frame: (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
    • Time Frame: 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.

Participating in This Clinical Trial

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). 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 – 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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 45 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of North Carolina, Chapel Hill
  • Collaborator
    • United States Department of Defense
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Michelle Hernandez, MD, Principal Investigator, University of North Carolina, Chapel Hill
  • Overall Contact(s)
    • Martha Almond, 9199660759, martha_almond@med.unc.edu

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