Healthy, Smoking
Conditions
Keywords
e-cig, E-cigarette, Electronic cigarette, Vaping
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.
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.
Interventions
OTHERCinnamaldehyde 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).
OTHERPG/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).
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
The e-liquids will be maintained by an individual not active in the study procedures or analysis.
Intervention model description
Controls will not be randomized and will not receive the study intervention.
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CA-induced Changes in Whole Lung MCC | 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
| Measure | Time frame | Description |
|---|---|---|
| CA-induced Changes in Regional Lung MCC | 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. |
| Percent Polymorphonuclear Leukocytes (PMN) in Induced Sputum | 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. |
| Absolute Values of Whole Lung MCC for Each Group | 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
| Measure | Time frame | Description |
|---|---|---|
| CA-Induced Changes in Epithelial Lining Fluid 24 Hours After Vaping Session | Through study completion, an average of three months | Percent change as compared to post-vaping session sample |
| Changes in Epithelial Lining Fluid | Through study completion, an average of three months | Percent change as compared to baseline |
| Tidal Volume Subjects Own E-cigarette Device | Through study completion, an average of three months | Tidal Volume in milliliters |
| Respiratory Rate With Subjects Own E-cigarette Device | Through study completion, an average of three months | Respiratory Rate in breaths per minute |
| Minute Ventilation With Subjects Own E-cigarette Device | Through study completion, an average of three months | Minute Ventilation in L/min |
| Inspiratory Flow With Subjects Own E-cigarette Device | Through study completion, an average of three months | Inspiratory flow in L/min |
| CA-Induced Changes in Immune Cell Function | Through study completion, an average of three months | Percent change from baseline in phagocytosis |
| Tidal Volume With Investigator E-cigarette Device | Through study completion, an average of three months | Tidal Volume in milliliters |
| Respiratory Rate With Investigator E-cigarette Device | Through study completion, an average of three months | Respiratory Rate in breaths per minute |
| Minute Ventilation With Investigator E-cigarette Device | Through study completion, an average of three months | Minute Ventilation in L/min |
| Inspiratory Flow With Investigator E-cigarette Device | Through study completion, an average of three months | Inspiratory flow in L/min |
| Expiratory Flow With Investigator E-cigarette Device | Through study completion, an average of three months | Expiratory flow in L/min |
| Expiratory Flow With Subjects Own E-cigarette Device | Through study completion, an average of three months | Expiratory flow in L/min |
| Peripheral Blood Mononuclear Cell Analysis | Through study completion, an average of three months | Percent change in cell counts as compared to baseline |
| Blood Serum Analysis of Inflammatory Mediators | Through study completion, an average of three months | Percent change of mediator expression as compared to baseline |
| CA-Induced Changes in Epithelial Lining Fluid | Through study completion, an average of three months | Pre-vaping session versus post-vaping session expressed as a percent change |
Countries
United States
Participant flow
Pre-assignment details
After qualifying, all participants move to the baseline day in which an mucociliary clearance (MCC) scan and sputum are collected for baseline measurements. The vaping participants continue on to the crossover design for CA and PG/VG sessions followed by MCC scans and sputum collections for post exposure measurements.
Participants by arm
| Arm | Count |
|---|---|
| All Treated Participants All participants inhaled cinnamaldehyde e-liquid or Propylene Glycol/Vegetable Glycerin (PG/VG) e-liquid in either Period 1 or Period 2 as per randomization schedule.
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).
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). | 15 |
| Healthy Controls Participants will only undergo the baseline testing and thus serve as a non-exposed/non-vaping control group. | 4 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Second Intervention (Single 1-Day Visit) | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Treated Participants | Healthy Controls | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 4 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 4 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 4 Participants | 15 Participants |
| Region of Enrollment United States | 15 Participants | 4 Participants | 19 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 12 Participants | 1 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 0 / 4 | 0 / 5 | 0 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 5 | 0 / 4 |
Outcome results
Primary
CA-induced Changes in Whole Lung MCC
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.
Time frame: Through study completion, an average of three months
Population: The healthy control participants only undergo the baseline testing and thus serve as a non-exposed/non-vaping control group. This Primary outcome does not apply to the healthy control group as they did not receive the intervention and only baseline data was collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cinnamaldehyde | CA-induced Changes in Whole Lung MCC | 41 percent clearance | Standard Deviation 5 |
| PG/VG | CA-induced Changes in Whole Lung MCC | 27 percent clearance | Standard Deviation 17 |
Secondary
Absolute Values of Whole Lung MCC for Each Group
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.
Time frame: Start of study, up to three months
Population: Includes all participants who completed the baseline MCC scan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cinnamaldehyde | Absolute Values of Whole Lung MCC for Each Group | 17 percent clearance | Standard Deviation 8 |
| PG/VG | Absolute Values of Whole Lung MCC for Each Group | 14 percent clearance | Standard Deviation 6 |
Secondary
CA-induced Changes in Regional Lung MCC
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.
Time frame: Through study completion, an average of three months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cinnamaldehyde | CA-induced Changes in Regional Lung MCC | Central Lung | 43 percent clearance | Standard Deviation 12 |
| Cinnamaldehyde | CA-induced Changes in Regional Lung MCC | Peripheral Lung | 33 percent clearance | Standard Deviation 3 |
| PG/VG | CA-induced Changes in Regional Lung MCC | Central Lung | 25 percent clearance | Standard Deviation 32 |
| PG/VG | CA-induced Changes in Regional Lung MCC | Peripheral Lung | 24 percent clearance | Standard Deviation 6 |
Secondary
Percent Polymorphonuclear Leukocytes (PMN) in Induced Sputum
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.
Time frame: Through study completion, an average of three months
Population: The healthy control participants only undergo the baseline testing and thus serve as a non-exposed/non-vaping control group. This outcome does not apply to the healthy control group as they did not receive the intervention and only baseline data was collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cinnamaldehyde | Percent Polymorphonuclear Leukocytes (PMN) in Induced Sputum | 3.6 percent PMN | Standard Error 7.2 |
| PG/VG | Percent Polymorphonuclear Leukocytes (PMN) in Induced Sputum | 89.4 percent PMN | Standard Error 5.8 |
Other Pre-specified
Blood Serum Analysis of Inflammatory Mediators
Percent change of mediator expression as compared to baseline
Time frame: Through study completion, an average of three months
Other Pre-specified
CA-Induced Changes in Epithelial Lining Fluid
Pre-vaping session versus post-vaping session expressed as a percent change
Time frame: Through study completion, an average of three months
Other Pre-specified
CA-Induced Changes in Epithelial Lining Fluid 24 Hours After Vaping Session
Percent change as compared to post-vaping session sample
Time frame: Through study completion, an average of three months
Other Pre-specified
CA-Induced Changes in Immune Cell Function
Percent change from baseline in phagocytosis
Time frame: Through study completion, an average of three months
Other Pre-specified
Changes in Epithelial Lining Fluid
Percent change as compared to baseline
Time frame: Through study completion, an average of three months
Other Pre-specified
Expiratory Flow With Investigator E-cigarette Device
Expiratory flow in L/min
Time frame: Through study completion, an average of three months
Other Pre-specified
Expiratory Flow With Subjects Own E-cigarette Device
Expiratory flow in L/min
Time frame: Through study completion, an average of three months
Other Pre-specified
Inspiratory Flow With Investigator E-cigarette Device
Inspiratory flow in L/min
Time frame: Through study completion, an average of three months
Other Pre-specified
Inspiratory Flow With Subjects Own E-cigarette Device
Inspiratory flow in L/min
Time frame: Through study completion, an average of three months
Other Pre-specified
Minute Ventilation With Investigator E-cigarette Device
Minute Ventilation in L/min
Time frame: Through study completion, an average of three months
Other Pre-specified
Minute Ventilation With Subjects Own E-cigarette Device
Minute Ventilation in L/min
Time frame: Through study completion, an average of three months
Other Pre-specified
Peripheral Blood Mononuclear Cell Analysis
Percent change in cell counts as compared to baseline
Time frame: Through study completion, an average of three months
Other Pre-specified
Respiratory Rate With Investigator E-cigarette Device
Respiratory Rate in breaths per minute
Time frame: Through study completion, an average of three months
Other Pre-specified
Respiratory Rate With Subjects Own E-cigarette Device
Respiratory Rate in breaths per minute
Time frame: Through study completion, an average of three months
Other Pre-specified
Tidal Volume Subjects Own E-cigarette Device
Tidal Volume in milliliters
Time frame: Through study completion, an average of three months
Other Pre-specified
Tidal Volume With Investigator E-cigarette Device
Tidal Volume in milliliters
Time frame: Through study completion, an average of three months