Woodsmoke Particulate + Prednisone (Smokisone)

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

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.

Study Overview

• Status: Completed
• Conditions: Airway Inflammation
• Intervention / Treatment: Drug: 60 mg Prednisone; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Center for Environmental Medicine, Asthma and Lung Biology at UNC Chapel Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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 # 15-1775).
• Proof of vaccination to COVID-19.

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-19 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Prednisone, then Placebo; Participants will receive prednisone following WSP exposure. After a 4-week washout period, participants will receive placebo following WSP exposure.	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; Participants will receive placebo following WSP exposure. After a 4-week washout period, participants will receive prednisone following WSP exposure.	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to 4 Hours in Sputum Percent Neutrophils	Change in sputum percent neutrophils from baseline to 4 hours post WSP exposure	Baseline, 4 hours post WSP exposure
Change From Baseline to 24 Hours in Sputum Percent Neutrophils	Change in sputum percent neutrophils from baseline to 24 hours post WSP exposure	Baseline, 24 hours post WSP exposure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Number of Sputum Neutrophils	Neutrophil numbers/mg measured at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.	Baseline, 4 and 24 hours post WSP exposure
Change in Number of Sputum Eosinophils	Eosinophil numbers/mg measured at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.	Baseline, 4 and 24 hours post WSP exposure
Change in Percent Sputum Eosinophils	Percent eosinophil measured at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.	Baseline, 4 and 24 hours post WSP exposure
Change in IL-1b	Interleukin beta (IL-1b) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.	Baseline, 4 and 24 hours post WSP exposure
Change in IL-6	Interleukin-6 (IL-6) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.	Baseline, 4 and 24 hours post WSP exposure
Change in IL-8	Interleukin-8 (IL-8) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.	Baseline, 4 and 24 hours post WSP exposure
Change in TNFa	Tumor necrosis factor alpha (TNFa) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.	Baseline, 4 and 24 hours post WSP exposure

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mucociliary Clearance (MCC)	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.	4 hours post WSP exposure

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Terry Noah, MD, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Hernandez ML, Mills K, Almond M, Todoric K, Aleman MM, Zhang H, Zhou H, Peden DB. IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers. J Allergy Clin Immunol. 2015 Feb;135(2):379-85. doi: 10.1016/j.jaci.2014.07.039. Epub 2014 Sep 5.
• National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138. doi: 10.1016/j.jaci.2007.09.043. Erratum In: J Allergy Clin Immunol. 2008 Jun;121(6):1330.
• Pugh MJ, Jaramillo CA, Leung KW, Faverio P, Fleming N, Mortensen E, Amuan ME, Wang CP, Eapen B, Restrepo M, Morris MJ. Increasing Prevalence of Chronic Lung Disease in Veterans of the Wars in Iraq and Afghanistan. Mil Med. 2016 May;181(5):476-81. doi: 10.7205/MILMED-D-15-00035.
• Korzeniewski K, Nitsch-Osuch A, Konior M, Lass A. Respiratory tract infections in the military environment. Respir Physiol Neurobiol. 2015 Apr;209:76-80. doi: 10.1016/j.resp.2014.09.016. Epub 2014 Sep 30.
• Baird CP. Review of the Institute of Medicine report: long-term health consequences of exposure to burn pits in Iraq and Afghanistan. US Army Med Dep J. 2012 Jul-Sep:43-7. No abstract available.
• Gomez JC, Yamada M, Martin JR, Dang H, Brickey WJ, Bergmeier W, Dinauer MC, Doerschuk CM. Mechanisms of interferon-gamma production by neutrophils and its function during Streptococcus pneumoniae pneumonia. Am J Respir Cell Mol Biol. 2015 Mar;52(3):349-64. doi: 10.1165/rcmb.2013-0316OC.
• Barth SK, Dursa EK, Bossarte R, Schneiderman A. Lifetime Prevalence of Respiratory Diseases and Exposures Among Veterans of Operation Enduring Freedom and Operation Iraqi Freedom Veterans: Results From the National Health Study for a New Generation of U.S. Veterans. J Occup Environ Med. 2016 Dec;58(12):1175-1180. doi: 10.1097/JOM.0000000000000885.
• Szema AM. Occupational Lung Diseases among Soldiers Deployed to Iraq and Afghanistan. Occup Med Health Aff. 2013;1:10.4172/2329-6879.1000117. doi: 10.4172/2329-6879.1000117.
• Morris MJ, Lucero PF, Zanders TB, Zacher LL. Diagnosis and management of chronic lung disease in deployed military personnel. Ther Adv Respir Dis. 2013 Aug;7(4):235-45. doi: 10.1177/1753465813481022. Epub 2013 Mar 7.
• Auerbach A, Hernandez ML. The effect of environmental oxidative stress on airway inflammation. Curr Opin Allergy Clin Immunol. 2012 Apr;12(2):133-9. doi: 10.1097/ACI.0b013e32835113d6.
• Alexis NE, Brickey WJ, Lay JC, Wang Y, Roubey RA, Ting JP, Peden DB. Development of an inhaled endotoxin challenge protocol for characterizing evoked cell surface phenotype and genomic responses of airway cells in allergic individuals. Ann Allergy Asthma Immunol. 2008 Mar;100(3):206-15. doi: 10.1016/S1081-1206(10)60444-9.
• Hernandez ML, Harris B, Lay JC, Bromberg PA, Diaz-Sanchez D, Devlin RB, Kleeberger SR, Alexis NE, Peden DB. Comparative airway inflammatory response of normal volunteers to ozone and lipopolysaccharide challenge. Inhal Toxicol. 2010 Jul;22(8):648-56. doi: 10.3109/08958371003610966.
• Hernandez M, Brickey WJ, Alexis NE, Fry RC, Rager JE, Zhou B, Ting JP, Zhou H, Peden DB. Airway cells from atopic asthmatic patients exposed to ozone display an enhanced innate immune gene profile. J Allergy Clin Immunol. 2012 Jan;129(1):259-61.e1-2. doi: 10.1016/j.jaci.2011.11.007.
• Alexis NE, Peden DB. Blunting airway eosinophilic inflammation results in a decreased airway neutrophil response to inhaled LPS in patients with atopic asthma: a role for CD14. J Allergy Clin Immunol. 2001 Oct;108(4):577-80. doi: 10.1067/mai.2001.118511.
• Hernandez ML, Wagner JG, Kala A, Mills K, Wells HB, Alexis NE, Lay JC, Jiang Q, Zhang H, Zhou H, Peden DB. Vitamin E, gamma-tocopherol, reduces airway neutrophil recruitment after inhaled endotoxin challenge in rats and in healthy volunteers. Free Radic Biol Med. 2013 Jul;60:56-62. doi: 10.1016/j.freeradbiomed.2013.02.001. Epub 2013 Feb 9.
• Burbank AJ, Duran CG, Pan Y, Burns P, Jones S, Jiang Q, Yang C, Jenkins S, Wells H, Alexis N, Kesimer M, Bennett WD, Zhou H, Peden DB, Hernandez ML. Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin-induced sputum neutrophilia in volunteers with asthma. J Allergy Clin Immunol. 2018 Apr;141(4):1231-1238.e1. doi: 10.1016/j.jaci.2017.06.029. Epub 2017 Jul 20.
• Ghio AJ, Soukup JM, Case M, Dailey LA, Richards J, Berntsen J, Devlin RB, Stone S, Rappold A. Exposure to wood smoke particles produces inflammation in healthy volunteers. Occup Environ Med. 2012 Mar;69(3):170-5. doi: 10.1136/oem.2011.065276. Epub 2011 Jun 30.
• Esther CR Jr, Lazaar AL, Bordonali E, Qaqish B, Boucher RC. Elevated airway purines in COPD. Chest. 2011 Oct;140(4):954-960. doi: 10.1378/chest.10-2471. Epub 2011 Mar 31.
• Alexis NE, Zhou H, Lay JC, Harris B, Hernandez ML, Lu TS, Bromberg PA, Diaz-Sanchez D, Devlin RB, Kleeberger SR, Peden DB. The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in human subjects. J Allergy Clin Immunol. 2009 Dec;124(6):1222-1228.e5. doi: 10.1016/j.jaci.2009.07.036.
• Stern A, Skalsky K, Avni T, Carrara E, Leibovici L, Paul M. Corticosteroids for pneumonia. Cochrane Database Syst Rev. 2017 Dec 13;12(12):CD007720. doi: 10.1002/14651858.CD007720.pub3.
• Walters JA, Tan DJ, White CJ, Wood-Baker R. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2018 Mar 19;3(3):CD006897. doi: 10.1002/14651858.CD006897.pub4.
• Venekamp RP, Thompson MJ, Hayward G, Heneghan CJ, Del Mar CB, Perera R, Glasziou PP, Rovers MM. Systemic corticosteroids for acute sinusitis. Cochrane Database Syst Rev. 2014 Mar 25;(3):CD008115. doi: 10.1002/14651858.CD008115.pub3.
• Jones B, and Kenward, M.G. . Design and analysis of cross-over trials. Third ed: CRC Press; 2015

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2019
• Primary Completion (Actual): May 12, 2023
• Study Completion (Actual): May 12, 2023

Study Registration Dates

• First Submitted: March 1, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 4, 2019

Study Record Updates

• Last Update Posted (Actual): June 25, 2024
• Last Update Submitted That Met QC Criteria: May 29, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisone
• Other Study ID Numbers: 18-2196

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No