Ventilation and Pulmonary Endothelium Toxicities of E-cigarettes: A Randomized Crossover Pilot Study

Pulmonary Disease, Chronic Obstructive Clinical Trial

— VaPE-Tox  

Official title:

Ventilation and Pulmonary Endothelium Toxicities (VaPE-Tox) of E-cigarettes: A Randomized Crossover Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02783768
• Other study ID #: AAAQ8089
• Status: Completed
• Phase: Early Phase 1
• Start date: March 1, 2017
• Est. completion date: July 24, 2018

Study information

• Verified date: September 2020
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Determination of the acute pulmonary toxicities of e-cigarettes in young adults is of major public health importance, as e-cigarette vapor contains established toxicants that as hypothesized cause acute damage to the airways and the pulmonary microvasculature that may promote the development of CLD, for which there remain few effective therapies.

The study therefore propose a pilot study using a randomized crossover design in ten healthy young adults to test the acute effects of a standardized e-cigarette exposure on two sensitive, safe, non-invasive imaging measures: (1) ventilation defects on hyperpolarized helium-enhanced magnetic resonance imaging, and (2) pulmonary microvascular blood flow on gadolinium-enhanced pulmonary magnetic resonance angiography.

Description:

Magnetic resonance imaging (MRI) and angiography (MRA) measures are promising approaches to detecting and characterizing the anticipated acute pulmonary toxicities of e-cigarettes. Hyperpolarized helium (3He)-enhanced MRI may be more sensitive than spirometry, a global lung function measure, for determination of airway toxicities. 3He-enhanced MRI has been used to demonstrate the extent of ventilation defects in healthy persons with normal spirometry; to measure ventilation changes in asthmatics pre- and post-challenge with bronchodilators and methacholine; and to predict pulmonary hospitalizations in persons with COPD. Meanwhile, until recently, non-invasive measures of pulmonary vascular toxicities were lacking. The investigators have developed an innovative measure of pulmonary microvascular blood flow on gadolinium (Gd)-enhanced MRA, which the investigators found to be markedly abnormal in early chronic obstructive pulmonary disease (COPD) and emphysema, and to be associated with increased endothelial microparticles, a marker of endothelial dysfunction. Nonetheless, neither of these sensitive, non-invasive, repeatable, and reproducible measures has ever been used to assess e-cigarette toxicities.

It is hypothesized that e-cigarette vapor inhalation will result in an acute increase in global and regional ventilation defects and an acute decrease in global and regional pulmonary microvascular perfusion.

This pilot work will provide the experience and data to support subsequent funding applications powered to definitively establish the acute toxicities of e-cigarette vapor of various compositions (e.g., with and without nicotine, with and without flavoring) in persons with and without chronic lung diseases (e.g., asthma) on pulmonary ventilation and microvascular perfusion. Furthermore, confirmation of the hypotheses in this sample would provide important preliminary evidence of e-cigarette pulmonary toxicities to inform interim regulatory decisions, as well as potentially generating vivid images of e-cigarette harms that may be meaningful to the general public and therefore suitable for use in public education campaigns.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: July 24, 2018
• Est. primary completion date: July 24, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 35 Years

Eligibility

Inclusion Criteria:

• current use of e-cigarettes (>1x/month but <4 days/week)

Exclusion Criteria:

• any chronic medical or major psychiatric problems including current asthma

• self-reported heavy snoring/sleep apnea

• pre-bronchodilator FEV1 or FVC <80% predicted or FEV1/FVC < lower limit of normal

• MRI exclusions (pregnancy, claustrophobia, metal in body, gadolinium allergy, eGFR <60 mL/min/1.73m2)

• MRI scan with contrast within the last 12 months or planned MRI with contrast in the next 6 months

• use of any of the following in the prior 30 days: any conventional cigarettes, marijuana >10 days, any illicit drugs, any medication or inhalers (excluding hormonal contraceptives)

• binge drinking (=5 alcoholic beverages over 2 hours) over the prior two weeks

• adverse symptomatic response to the study e-cigarette exposure (e.g., palpitations, shortness of breath, chest pain, headache, dizziness)

Related Conditions & MeSH terms

• E-cigarettes
• Pulmonary Disease, Chronic Obstructive

Intervention

Device:
• E-cigarette
The study e-cigarette exposure will be 10 puffs with 30-second inter-puff intervals, as directly observed by a trained research assistant, using a standardized e-cigarette. Cartomizers, batteries, and e-liquids will be obtained from commercial suppliers. The e-cigarette device will be loaded with 1 mL of flavorless e-liquid with a ratio of PG to vegetable glycerin of 70:30 and 1.8 mg/dL of nicotine.

Other:
• Sham
The "unexposed" condition will be breathing from the study e-cigarette (10 puffs with 30-second inter-puff intervals) with the battery off.

Drug:
• Hyperpolarized 3-Helium
Hyperpolarized 3-Helium will be used as an experimental contrast agent for the Ventilation MRIs performed twice per participant in both experimental arms. Approximately 250-600 mL of hyperpolarized 3He mixed with 300-750 mL nitrogen will be inhaled through a one-way valve in one inhalation starting approximately at residual volume.
• Gadolinium
Gadolinium contrast will be injected into the antecubital vein through an 18-20 gauge IV. The type of gadolinium will be 0.03 mmol/kg bodyweight of dotarem (gadoterate meglumine).

Locations

Country	Name	City	State
United States	Columbia University Irving Medical Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Columbia University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pulmonary Microvascular Blood Flow (PMBF), Measured on Gadolinium-enhanced MRI, Between E-cigarette Exposed and Unexposed Conditions	PMBF will be measured on gadolinium-enhanced MRI after e-cigarette and sham exposures. There were four days between the measurements of PMBF (e-cigarette) and PMBF (sham). PMBF is measured in mL(blood)/min/mL(lung volume). Lower PMBF has been observed in adults with COPD and emphysema.	After exposure (approximately 30 seconds)
Primary	Ventilation Defect Percentage (VDP), Measured on Hyperpolarized 3-helium Enhanced MRI	VDP will be measured on hyperpolarized 3Helium-enhanced MRI after e-cigarette and sham exposures. Due to limitations of prior qualitative/visual assessments of MRI, we developed and validated a new deep learning approach to the precise measurement of ventilation defects and report the percent non-fully ventilated lung using this method.	After exposure (approximately 30 seconds)
Secondary	Regional PMBF, Measured on Gadolinium-enhanced MRI	Regional PMBF (ie, in the right versus left, upper versus lower lobes) will be measured on gadolinium-enhanced MRI after e-cigarette and sham exposures.	After exposure (approximately 30 seconds)
Secondary	Regional VDP, Measured on Hyperpolarized 3-helium Enhanced MRI	Regional VDP in the lower lung was measured on hyperpolarized 3Helium-enhanced MRI after e-cigarette and sham exposures.	After exposure (approximately 30 seconds)
Secondary	Lung Function, Measured on Spirometry	Lung function will be measured on spirometry. Two participants had only one valid FEV1 measure, and one participant had no valid FEV1 measures. Hence, 3 participants (2 in "E-cigarette first" and 1 in "Sham first") were not analyzed. The analysis combines the groups in order to separate the effects of randomization group (order) and exposure.	After exposure (approximately 30 seconds)
Secondary	Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)	DLCO will be measured. There was a malfunction of the machine used to measure the DLCO. Hence, only one participant had paired DLCO values and 3 had unpaired measures.	After exposure (approximately 30 seconds)
Secondary	Cardiac Output, Measured on Cardiac MRI	Cardiac output will be measured on cardiac MRI. In the "E-cigarette first" arm, 2 participants did not have 2 valid measures of CO (one pair was missing, one was invalid). In the "Sham first" arm, 3 participants had one invalid measure of CO. The analysis combines the groups in order to separate the effects of randomization group (order) and exposure.	After exposure (approximately 30 seconds)