Clinical trial NCT02739438: The Study of ELEctronic Cigarette Toxicity in a Human Model in Vivo Model of Inflammation and Vascular Dysfunction
Official title: The Study of ELEctronic Cigarette Toxicity in a Human Model in Vivo Model of Inflammation and Vascular Dysfunction (SELECT)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Acute Lung Injury
Keywords: Pulmonary inflammation
Endothelial dysfunction
Electronic Cigarettes
Lead sponsor: Queen's University, Belfast
Sponsor class: OTHER
First posted: 2016-04-15
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Healthy subjects, including electronic cigarette users, cigarette smokers and controls will be recruited.

Brief summary: To carry out a prospective cohort study of healthy volunteers, assessing differences between baseline pulmonary inflammation, response to LPS inhalation and endothelial function, as measured by flow mediated dilation between, electronic cigarette uses, cigarette smokers and non smokers.

Detailed description: Background. Since their introduction, electronic cigarette (EC) use has increased substantially. Perhaps most concerning is the increased use amongst adolescents. Many e-cigarette users believe that electronic cigarettes are safer than conventional cigarettes \[1\]. However, the toxicities of electronic cigarettes, including those in the lung, are relatively poorly studied. Notably, early studies suggest that electronic cigarettes are not harmless. The fine and ultra-fine particles could deposit in the lungs and lead to harm. Animal studies of electronic cigarettes have been associated with a number of pulmonary toxicities, including increased inflammation and oxidative stress in the lung \[2\] as well as impaired pulmonary immunity \[3, 4\]. EC vapour reduces indoor air quality by increasing the concentrations of particulate matter, particle number concentrations, polycyclic aromatic hydrocarbons (PAH) which are known carcinogens \[5\]. Early studies on cardiovascular function also suggests harm from the constituents of EC vapour such as the direct effects of nicotine, carbonyls as well as fine and ultrafine particles \[6\].

There is limited understanding of the adverse effects of EC vapour of the pulmonary or cardiovascular physiology and additional studies, particularly in humans, are needed to better characterize the acute toxicities of electronic cigarettes

Hypothesis Our hypothesis is, when compared to cigarette or e-cigarette naïve healthy volunteers;

1. E-cigarette users will have a higher baseline pulmonary inflammation
2. E-cigarette users will have an exaggerated immune response after LPS inhalation
3. E-cigarettes users will have endothelial dysfunction as measured by FMD of the brachial artery

Trial design Prospective cohort study of healthy subjects exposed to inhaled LPS.

Population Healthy subjects, including electronic cigarette users, cigarette smokers and controls will be recruited by advertising.

Intervention Bronchoscopy and blood sampling to assess baseline pulmonary and systemic inflammation and injury and in response to inhaled LPS 50 mcg. Flow mediated dilation (FMD) of brachial artery to study endothelial dysfunction.

After informed consent, their baseline FMD of brachial artery will be measured as well as lung function. FMD of brachial artery will be measured within 5 mins of use of e-cigarette to reflect the acute effects of e-cigarette on systemic endothelial dysfunction. Bronchoscopy with BAL, blood and urine sampling will be performed. This will enable us to measure the baseline inflammation and markers of cellular injury without inhaled LPS. At 24 hours the subject will return and lung function will be measured and blood sampling will be performed.

Six weeks later, the above procedure will be repeated but with LPS stimulation. The subject will once again attend the hospital and lung function will be measured, blood and urine sampling will be performed. Subjects will inhale LPS (from Escherichia coli O26:B6, 50 μg; Sigma-Aldrich, St. Louis, MO) using a dosimeter. Bronchoscopy with BAL will be undertaken 6 hours following LPS inhalation. Prior to bronchoscopy, lung function will be measured in order to ensure that they may safely undergo LPS inhalation. At 24 hours subjects will return and lung function will be measured and blood sampling will be performed. The time points for BAL and plasma sampling are chosen to obtain insight into both cytokine/chemokine release and neutrophil recruitment after pulmonary delivery of LPS.

Statistical considerations The primary exposure variable will be e-cigarette exposure; the primary outcome variable will be plasma and BAL biomarkers of injury and inflammation. Given that early studies of electronic cigarettes suggest that they may be associated with inflammation, we have used BAL absolute neutrophil count, a key marker of inflammation, to inform our sample size. Based on data from controls in our prior study, a cohort of 10 e-cigarette users and 10 controls should be able to detect a minimal difference of 7.09 x 105 cells in the BAL after LPS inhalation between groups with 80% power using Wilcoxon Rank Sum testing. Of note, this is similar to the difference we observed between smokers and non-smokers after LPS in our prior study \[7\]. Additionally, we will compare biomarkers of inflammation and injury in electronic cigarette users to those from conventional cigarette smokers using Wilcoxon Rank Sum testing. All data will be analysed using STATA 13.1 (StataCorp LP, College Station, TX).

Study Monitoring Site monitoring will be directed by the sponsor according to the study risk assessment. Site visits will be performed on a regular basis as required by the sponsor to ensure that all regulatory requirements are met and to monitor the quality of the data collected. The CRF will be used for source data verification.

Eligibility criteria: Inclusion Criteria:

1. Healthy subjects less than 45 years of age and BMI \< 35

Exclusion Criteria:

1. Age \< 18 years
2. Pregnant or Breast-Feeding
3. Participation in a clinical trial of an investigational medicinal product within 30 days
4. Consent declined
5. History of asthma
6. Marijuana use or other inhaled products with or without nicotine in the last 3 months
7. Alcohol abuse, as defined by the Alcohol Use Disorders Identification Test (AUDIT)

Primary outcomes:
measure: bronchoalveolar lavage neutrophil count in response to LPS stimulation
timeFrame: BAL 6 hours after LPS inhalation
Secondary outcomes:
measure: Alveolar inflammatory response
timeFrame: 24 hours after LPS inhalation
measure: Plasma inflammatory response
timeFrame: 24 hours after LPS inhalation
measure: Indices of alveolar epithelial and endothelial and injury
timeFrame: 24 hours after LPS inhalation
measure: 4. FMD of brachial artery as a marker of the effects of e-cigarettes on endothelial function
timeFrame: 5 mins within use of an electronic cigarette
Other outcomes:
Locations:
city: Belfast
country: United Kingdom
facility: Queens University
state: N Ireland
Study officials:
affiliation: Queen's University, Belfast
name: Murali Shyamsundar, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rutten LJ, Blake KD, Agunwamba AA, Grana RA, Wilson PM, Ebbert JO, Okamoto J, Leischow SJ. Use of E-Cigarettes Among Current Smokers: Associations Among Reasons for Use, Quit Intentions, and Current Tobacco Use. Nicotine Tob Res. 2015 Oct;17(10):1228-34. doi: 10.1093/ntr/ntv003. Epub 2015 Jan 14.
citation: Lerner CA, Sundar IK, Yao H, Gerloff J, Ossip DJ, McIntosh S, Robinson R, Rahman I. Vapors produced by electronic cigarettes and e-juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung. PLoS One. 2015 Feb 6;10(2):e0116732. doi: 10.1371/journal.pone.0116732. eCollection 2015.
citation: Wu Q, Jiang D, Minor M, Chu HW. Electronic cigarette liquid increases inflammation and virus infection in primary human airway epithelial cells. PLoS One. 2014 Sep 22;9(9):e108342. doi: 10.1371/journal.pone.0108342. eCollection 2014.
citation: Sussan TE, Gajghate S, Thimmulappa RK, Ma J, Kim JH, Sudini K, Consolini N, Cormier SA, Lomnicki S, Hasan F, Pekosz A, Biswal S. Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model. PLoS One. 2015 Feb 4;10(2):e0116861. doi: 10.1371/journal.pone.0116861. eCollection 2015.
citation: Schober W, Szendrei K, Matzen W, Osiander-Fuchs H, Heitmann D, Schettgen T, Jorres RA, Fromme H. Use of electronic cigarettes (e-cigarettes) impairs indoor air quality and increases FeNO levels of e-cigarette consumers. Int J Hyg Environ Health. 2014 Jul;217(6):628-37. doi: 10.1016/j.ijheh.2013.11.003. Epub 2013 Dec 6.
citation: Morris PB, Ference BA, Jahangir E, Feldman DN, Ryan JJ, Bahrami H, El-Chami MF, Bhakta S, Winchester DE, Al-Mallah MH, Sanchez Shields M, Deedwania P, Mehta LS, Phan BA, Benowitz NL. Cardiovascular Effects of Exposure to Cigarette Smoke and Electronic Cigarettes: Clinical Perspectives From the Prevention of Cardiovascular Disease Section Leadership Council and Early Career Councils of the American College of Cardiology. J Am Coll Cardiol. 2015 Sep 22;66(12):1378-91. doi: 10.1016/j.jacc.2015.07.037.