Woodsmoke Particulate + Prednisone

Airway Inflammation Clinical Trial

— Smokisone  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03861390
• Other study ID #: 18-2196
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 22, 2019
• Est. completion date: September 2024

Study information

• Verified date: August 2023
• Source: University of North Carolina, Chapel Hill
• Contact: Carole Robinette, MS
• Phone: 919-966-5683
• Email: carole_robinette[@]med.unc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 14
• Est. completion date: September 2024
• Est. primary completion date: September 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Airway Inflammation
• Inflammation

Intervention

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

Locations

Country	Name	City	State
United States	Center for Environmental Medicine, Asthma and Lung Biology at UNC Chapel Hill	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	United States Department of Defense

Country where clinical trial is conducted

United States, 

References & Publications (23)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Jones B, and Kenward, M.G. . Design and analysis of cross-over trials. Third ed: CRC Press; 2015

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Primary	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
Primary	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	Change in Number of Sputum Neutrophils	Neutrophil numbers/mg measured at 4 and 24 hours post WSP exposure	up to 24 hours
Secondary	Change in Number of Sputum Eosinophils	Eosinophil numbers/mg measured at 4 and 24 hours post WSP exposure	up to 24 hours
Secondary	Change in Percent Sputum Eosinophils	Percent eosinophil measured at 4 and 24 hours post WSP exposure	up to 24 hours
Secondary	Change in IL-1b	IL-1b via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure	up to 24 hours
Secondary	Change in IL-6	IL-6 via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure	up to 24 hours
Secondary	Change in IL-8	IL-8 via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure	up to 24 hours
Secondary	Change in TNFa	TNFa via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure	up to 24 hours