In-vivo Effects of E-cigarette Aerosol on Innate Lung Host Defense (Cinimic)

• ClinicalTrials.gov Identifier: NCT03700892
• Recruitment Status: Terminated
• First Posted: October 9, 2018
• Results First Posted: June 10, 2021
• Last Update Posted: June 10, 2021
• Sponsor: University of North Carolina, Chapel Hill
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): University of North Carolina, Chapel Hill

Study Description

Brief Summary:

While e-cigs are commonly represented as safer alternatives to tobacco cigarettes, little is known regarding the health effects of their short- or long-term use. The responses and the e-cig components exerting these effects on the airways are largely unknown. This study will identify if specific e-cig flavors modify respiratory immune responses. This study will determine the effects of cinnamaldehyde (CA)-containing e-cigarettes on airway epithelial cell ciliary function (i.e., MCC) in humans. Additionally the study will determine the effects of CA-containing e-cigarettes on airway immune cells obtained through induced sputum (SI) after inhalation of CA-containing e-cig aerosols to determine CA-induced effects on a) immune cell function (e.g., phagocytosis, respiratory burst), b) immune cell surface phenotype, and c) mediator production in humans in vivo.

Condition or disease	Intervention/treatment	Phase
Smoking; Healthy	Other: Cinnamaldehyde e-liquid; Other: PG/VG e-liquid	Not Applicable

Detailed Description:

Investigators will evaluate the acute effect of CA-flavored e-cigs on MCC and IS immune cells in up to 32 healthy, young adults who are current e-cig users with a total of less than 10 pack-years cigarette smoking history. MCC will be measured by gamma scintigraphy at baseline and following controlled vaping of e-liquids with and without cinnamon flavoring. Two different e-liquids (one completely devoid and one containing at least 30 mM CA similar to "Hot Cinnamon Candies" which is commercially available) will be used for two separate randomized vaping sessions.

The randomization scheme for the two different e-liquids (e-liquids with and without CA) will be generated by using the Web site Randomization.com (http://www.randomization.com), assigned treatment Regimen A and B by an assigned study team member, and provided to the study team. This individual will also be responsible for loading the e-cigarette with the appropriate solution for that session prior to the vaping sessions.

Participants will undergo baseline testing during the screening visit, which will occur 2-3 weeks prior to the first controlled vaping session. Investigators will also recruit non-vaping control subjects (n=32), who will only undergo the baseline testing and thus serve as a non-exposed/non-vaping control group. will aim to recruit similar numbers of males and females in both cohorts. While investigators cannot guarantee age-matching and sex-matching in these cohorts, based on our previous studies, investigators do not expect to find significant age and sex differences in the two cohort. In addition, potential confounders, such as age, sex, and BMI will be included as covariates in our multivariate analysis.

Observations obtained from the non-vaping control group will provide necessary information on potential baseline differences in the two cohorts (i.e. current vapers versus non-vaping controls). These data from the non-vaping control group are important to provide a reference for any potential CA-induced changes in the vaping group. Hence, there are two stages of the study:

Stage 1. A cross sectional observational cohort comparison of baseline MCC and IS immune cells in a reference cohort of n=32 non-vaping control subjects and E-cig cohort of n=32 currently vaping subjects (confounding based on other variables such as BMI, sex, age is possible for this stage).

Stage 2. A randomized comparison of changes in MCC and IS immune cells after Regimen A (e-cig us without CA) and Regimen B (e-cig use with CA). The cohort of e-cig users will undergo a randomized 2-treatment, 2-period, 2-sequence crossover study of CA exposure.

For stage 1, baseline measurements of Tc99m-SC clearance will be used to measure each subject's normal baseline MCC and IS immune cell characteristics. For both stages, subjects will be asked to complete a vaping diary to record information on the device and e-liquids (name/vendor/e-liquids/puffs/device settings) used during their normal vaping sessions for the entire duration of the study. In addition, for stage 2, participants will be asked to maintain their current habits for the duration of the study, not to significantly increase or decrease their vaping patterns, including the nicotine concentrations of their e-liquids.

For stage 2, for each e-cig vaping session (Training and MCC Test Days), subjects will be asked to follow a laboratory-based protocol involving 6, 5-minute paced vaping segments (1 puff/minute) over a 1 hour time period, vaping the e-liquid with and without CA provided by us. On each Test Day, participants will undergo the vaping protocol immediately prior to inhalation of the Tc99m-SC (10 min between end of vaping and inhalation of Tc99m-SC). An initial deposition scan of Tc99m-SC will then be obtained followed by dynamic imaging of the lung with subjects seated in front of the gamma camera to determine potential changes in MCC induced by acute exposure to CA-flavored e- cigarettes. Induced sputum samples will be collected at baseline, and after each MCC scan.

24 hours after completion of the MCC scans. The two randomized vaping sessions will be separated by 2-3 weeks. While there are no data providing specific information on the duration needed to washout the effects of CA on MCC, previous studies examining changes in MCC following inhalation of other aerosols have shown that this washout period is sufficient to prevent potential carryover between the two treatments.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Controls will not be randomized and will not receive the study intervention.
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: The e-liquids will be maintained by an individual not active in the study procedures or analysis.
• Primary Purpose: Basic Science
• Official Title: In-vivo Effects of E-cigarette Aerosol on Innate Lung Host Defense
• Actual Study Start Date: October 19, 2018
• Actual Primary Completion Date: March 3, 2020
• Actual Study Completion Date: March 3, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cinnamaldehyde, then PG/VG; Participants will inhale cinnamaldehyde e-liquid in 6, 5-minute paced vaping segments (1 puff/minute) over 1 hour. A 2-3 week washout period will follow. Then participants will inhale Propylene Glycol/Vegetable Glycerin (PG/VG) e-liquid in 6, 5-minute paced vaping segments (1 puff/minute) over 1 hour.	Other: Cinnamaldehyde e-liquid; Participants will inhale an e-liquid that contains cinnamaldehyde from Vapor Shark DNA 250™ e-cigarette device allowing manual control and vapor setting recordings (voltage, wattage, puff volume, and frequency).; Other Name: Cinnamon; Other: PG/VG e-liquid; Participants will inhale an e-liquid that contains PG/VG from the Vapor Shark DNA 250™ e-cigarette device allowing manual control and vapor setting recordings (voltage, wattage, puff volume, and frequency).; Other Name: Placebo
Experimental: PG/VG, then Cinnamaldehyde; Participants will inhale PG/VG e-liquid in 6, 5-minute paced vaping segments (1 puff/minute) over 1 hour. A 2-3 week washout period will follow. Then participants will inhale cinnamaldehyde e-liquid in 6, 5-minute vaping segments (1 puff/minute) over 1 hour.	Other: Cinnamaldehyde e-liquid; Participants will inhale an e-liquid that contains cinnamaldehyde from Vapor Shark DNA 250™ e-cigarette device allowing manual control and vapor setting recordings (voltage, wattage, puff volume, and frequency).; Other Name: Cinnamon; Other: PG/VG e-liquid; Participants will inhale an e-liquid that contains PG/VG from the Vapor Shark DNA 250™ e-cigarette device allowing manual control and vapor setting recordings (voltage, wattage, puff volume, and frequency).; Other Name: Placebo
No Intervention: Healthy Controls; Participants will only undergo the baseline testing and thus serve as a non-exposed/non-vaping control group.

Outcome Measures

Primary Outcome Measures :

1. CA-induced Changes in Whole Lung MCC [ Time Frame: Through study completion, an average of three months ]
   Absolute values of whole lung MCC at baseline compared to after CA vaping session. Absolute repeat values of Whole lung MCC = average % mucus cleared from the whole lung over a 90-minute period.

Secondary Outcome Measures :

1. CA-induced Changes in Regional Lung MCC [ Time Frame: Through study completion, an average of three months ]
   Absolute repeat values of Central and Peripheral lung MCC = average % mucus cleared from the Central and Peripheral lung over a 90-minute period. This will assess clearance rates from the central (C) and peripheral (P) regions as secondary endpoints that may reflect differential effects between a region with relatively more (C) vs. less (P) large bronchial airways.
2. Percent Polymorphonuclear Leukocytes (PMN) in Induced Sputum [ Time Frame: Through study completion, an average of three months ]
   Percent change of PMNs in vapers from baseline compared to post CA vaping session. Percent change in PMNs in vapers from baseline compared to post PG/VG vaping session are included as an additional comparison.
3. Absolute Values of Whole Lung MCC for Each Group [ Time Frame: Start of study, up to three months ]
   Baseline Differences in Whole lung MCC clearance rates in Non-smokers/Non-vapers as Compared to E-cigarette Users. Absolute group values of Whole Lung MCC =average % mucus cleared from the whole lung over a 90-minute period.

Other Outcome Measures:

1. CA-Induced Changes in Immune Cell Function [ Time Frame: Through study completion, an average of three months ]
   Percent change from baseline in phagocytosis
2. Peripheral Blood Mononuclear Cell Analysis [ Time Frame: Through study completion, an average of three months ]
   Percent change in cell counts as compared to baseline
3. Blood Serum Analysis of Inflammatory Mediators [ Time Frame: Through study completion, an average of three months ]
   Percent change of mediator expression as compared to baseline
4. CA-Induced Changes in Epithelial Lining Fluid [ Time Frame: Through study completion, an average of three months ]
   Pre-vaping session versus post-vaping session expressed as a percent change
5. CA-Induced Changes in Epithelial Lining Fluid 24 Hours After Vaping Session [ Time Frame: Through study completion, an average of three months ]
   Percent change as compared to post-vaping session sample
6. Changes in Epithelial Lining Fluid [ Time Frame: Through study completion, an average of three months ]
   Percent change as compared to baseline
7. Tidal Volume Subjects Own E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
   Tidal Volume in milliliters
8. Respiratory Rate With Subjects Own E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
   Respiratory Rate in breaths per minute
9. Minute Ventilation With Subjects Own E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
   Minute Ventilation in L/min
10. Inspiratory Flow With Subjects Own E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
    Inspiratory flow in L/min
11. Expiratory Flow With Subjects Own E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
    Expiratory flow in L/min
12. Tidal Volume With Investigator E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
    Tidal Volume in milliliters
13. Respiratory Rate With Investigator E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
    Respiratory Rate in breaths per minute
14. Minute Ventilation With Investigator E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
    Minute Ventilation in L/min
15. Inspiratory Flow With Investigator E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
    Inspiratory flow in L/min
16. Expiratory Flow With Investigator E-cigarette Device [ Time Frame: Through study completion, an average of three months ]
    Expiratory flow in L/min

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• An equal number of participants who currently use a vaping device and those who do not use a vaping device
• Age 18-40
• Must have a Forced Vital Capacity (FVC) and Forced Expiratory Volume in 1 second (FEV₁) of at least 80% of predicted. Participants who fall out of the normal range will be offered a copy of the test to share with their personal physician.

Exclusion Criteria:

• Any pre-existing lung disease (asthma, cystic fibrosis, etc.)
• Any significant chronic illness, such as, but not limited to, heart disease, uncontrolled hypertension, diabetes, auto-immune disease
• Any use of tobacco products (other than e-cig) in the past 3 months, or a greater than 10 pack year history of smoking cigarettes
• Pregnant or nursing women
• Participants with a history of radiation exposure in the past year which exceeds annual safe limits.

Contacts and Locations

Locations

United States, North Carolina

UNC Center for Environmental Medicine, Asthma and Lung Biology

Chapel Hill, North Carolina, United States, 27599-7310

Sponsors and Collaborators

University of North Carolina, Chapel Hill

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Ilona Jaspers, PhD; University of North Carolina

  Study Documents (Full-Text)

Documents provided by University of North Carolina, Chapel Hill:

Study Protocol and Statistical Analysis Plan  [PDF] November 15, 2018

More Information

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT03700892
• Other Study ID Numbers: 17-2275; R01HL139369 ( U.S. NIH Grant/Contract )
• First Posted: October 9, 2018
• Results First Posted: June 10, 2021
• Last Update Posted: June 10, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• Supporting Materials: Study Protocol
• Time Frame: Beginning 9 months and ending 36 months following article publication

Access Criteria

Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.

Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata

Requests for access to individual participant data should be sent to bring44@email.unc.edu or carole.robinette@med.unc.edu. Access will be granted after a data access agreement has been signed with UNC.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of North Carolina, Chapel Hill:

e-cig; E-cigarette; Electronic cigarette; Vaping

Additional relevant MeSH terms:

Cinnamaldehyde; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Antimutagenic Agents; Protective Agents; Physiological Effects of Drugs