Benefits of E-Cigarettes Among Heavy Smokers Undergoing a Lung Cancer Screening Program: Randomized Controlled Trial Protocol

Abstract

Background:
Smoking is a global public health problem. For this reason, experts have called smoking dependence a global epidemic. Over the past 5 years, sales of electronic cigarettes, or e-cigarettes, have been growing strongly in many countries. Yet there is only partial evidence that e-cigarettes are beneficial for smoking cessation. In particular, although it has been proven that nicotine replacement devices may help individuals stop smoking and tolerate withdrawal symptoms, e-cigarettes' power to increase the quitting success rate is still limited, ranging from 5% to 20% dependent on smokers' baseline conditions as shown by a recent Cochrane review. Consequently, it is urgent to know if e-cigarettes may have a higher success rate than other nicotine replacement methods and under what conditions. Furthermore, the effects of the therapeutic setting and the relationship between individual characteristics and the success rate have not been tested. This protocol is particularly innovative, because it aims to test the effectiveness of electronic devices in a screening program (the COSMOS II lung cancer prevention program at the European Institute of Oncology), where tobacco reduction is needed to lower individuals' lung cancer risks.

Objective:
This protocol was designed with the primary aim of investigating the role of tobacco-free cigarettes in helping smokers improve lung health and either quit smoking or reduce their tobacco consumption. In particular, we aim to investigate the impact of a 3-month e-cigarettes program to reduce smoking-related respiratory symptoms (eg, dry cough, shortness of breath, mouth irritation, and phlegm) through reduced consumption of tobacco cigarettes. Furthermore, we evaluate the behavioral and psychological (eg, well-being, mood, and quality of life) effects of the treatment.

Methods:
This is a prospective, randomized, placebo-controlled, double-blind, three-parallel group study. The study is organized as a nested randomized controlled study with 3 branches: a nicotine e-cigarettes group, a nicotine-free e-cigarettes group, and a control group. The study is nested in a screening program for early lung cancer detection in heavy smokers.

Results:
The study is open and is still recruiting.

Conclusions:
Stopping or reducing tobacco consumption should be a main goal of any health organization. However, traditional antismoking programs are expensive and not always effective. Therefore, favoring a partial or complete shift to e-cigarettes in heavy smokers (eg, persons at high risk for a number of diseases) could be considered a moral imperative. However, before following this path, sound and reliable data on large samples and in a variety of contexts are required.

Trial registration:
Clinicaltrials.gov NCT02422914; https://clinicaltrials.gov/ct2/show/NCT02422914 (Archived by WebCite at http://www.webcitation.org/6etwz1bPL).

Full text

Original Paper
Benefits of E-Cigarettes Among Heavy Smokers Undergoing a
Lung Cancer Screening Program: Randomized Controlled Trial
Protocol
Claudio Lucchiari1, MS Psych, PhD (HK); Marianna Masiero2, PhD; Giulia Veronesi3, MD; Patrick Maisonneuve4,
MEng; Stefania Spina5, MPsych (Clin); Costantino Jemos6, PharmD; Emanuela Omodeo Salè6, PharmD; Gabriella
Pravettoni5,7, MS Psych, PhD (Psych)
1Università Degli Studi di Milano, Department of Philosophy, Milano, Italy
2Università Degli Studi di Milano, Health Sciences, Università Degli Studi di Milano, Milano, Italy
3European Institute of Oncology, Thoracic Devision, MIlan, Italy
4European Institute of Oncology, Division of Epidemiology and Biostatistics, MIlan, Italy
5European Institute of Oncology, Applied Research Unit for Cognitive and Psychological Science, MIlan, Italy
6European Institute of Oncology, Division of Pharmacy, Milan, Italy
7Università Degli Studi di Milano, Department of Oncology and Hemato-oncology, Milan, Italy
Corresponding Author:
Claudio Lucchiari, MS Psych, PhD (HK)
Università Degli Studi di Milano
Department of Philosophy
Via Festa del Perdono 7
Milano, 20122
Italy
Phone: 39 0250312240
Fax: 39 0250312241
Email: claudio.lucchiari@unimi.it
Abstract
Background: Smoking is a global public health problem. For this reason, experts have called smoking dependence a global
epidemic. Over the past 5 years, sales of electronic cigarettes, or e-cigarettes, have been growing strongly in many countries. Yet
there is only partial evidence that e-cigarettes are beneficial for smoking cessation. In particular, although it has been proven that
nicotine replacement devices may help individuals stop smoking and tolerate withdrawal symptoms, e-cigarettes’power to increase
the quitting success rate is still limited, ranging from 5% to 20% dependent on smokers’baseline conditions as shown by a recent
Cochrane review. Consequently, it is urgent to know if e-cigarettes may have a higher success rate than other nicotine replacement
methods and under what conditions. Furthermore, the effects of the therapeutic setting and the relationship between individual
characteristics and the success rate have not been tested. This protocol is particularly innovative, because it aims to test the
effectiveness of electronic devices in a screening program (the COSMOS II lung cancer prevention program at the European
Institute of Oncology), where tobacco reduction is needed to lower individuals’lung cancer risks.
Objective: This protocol was designed with the primary aim of investigating the role of tobacco-free cigarettes in helping
smokers improve lung health and either quit smoking or reduce their tobacco consumption. In particular, we aim to investigate
the impact of a 3-month e-cigarettes program to reduce smoking-related respiratory symptoms (eg, dry cough, shortness of breath,
mouth irritation, and phlegm) through reduced consumption of tobacco cigarettes. Furthermore, we evaluate the behavioral and
psychological (eg, well-being, mood, and quality of life) effects of the treatment.
Methods: This is a prospective, randomized, placebo-controlled, double-blind, three-parallel group study. The study is organized
as a nested randomized controlled study with 3 branches: a nicotine e-cigarettes group, a nicotine-free e-cigarettes group, and a
control group. The study is nested in a screening program for early lung cancer detection in heavy smokers.
Results: The study is open and is still recruiting.
Conclusions: Stopping or reducing tobacco consumption should be a main goal of any health organization. However, traditional
antismoking programs are expensive and not always effective. Therefore, favoring a partial or complete shift to e-cigarettes in
JMIR Res Protoc 2016 | vol. 5 | iss. 1 | e21 | p.1http://www.researchprotocols.org/2016/1/e21/ (page number not for citation purposes)
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heavy smokers (eg, persons at high risk for a number of diseases) could be considered a moral imperative. However, before
following this path, sound and reliable data on large samples and in a variety of contexts are required.
Trial Registration: Clinicaltrials.gov NCT02422914; https://clinicaltrials.gov/ct2/show/NCT02422914 (Archived by WebCite
at http://www.webcitation.org/6etwz1bPL)
(JMIR Res Protoc 2016;5(1):e21) doi:10.2196/resprot.4805
KEYWORDS
tobacco cessation; electronic cigarettes; lung cancer screening; smoking related diseases.
Introduction
The World Health Organization estimates that cigarette smoking
will claim the lives of 500 million people who are alive today
and as many as 1 billion people during the 21st century.
Although clinical therapies for smoking cessation have proven
effective, the long-term abstinence rate remains low.
Electronic cigarettes, which are also known as tobacco-free
cigarettes or e-cigarettes, are battery-operated devices that
vaporize a liquid solution of propylene glycol and/or vegetable
glycerin in which nicotine and/or flavors are dissolved. A recent
review of the field showed that e-cigarettes may be considered
safe, with few adverse effects and limited toxicity [1].
The value of these tools is that they reduce the risk of
smoking-related diseases. However, while the use of e-cigarettes
in heavy smokers will reduce the risk of tobacco-related cancers,
their role in antismoking programs has not yet been approved.
The World Health Organization and the US Food and Drug
Administration have promoted the launch of research on this
field of study, but study results are not convergent.
In a prospective study, e-cigarettes were shown to substantially
decrease the consumption of tobacco cigarettes without causing
significant side effects [2]. In the study, reductions in the number
of cigarettes smoked per day and breath carbon monoxide (CO)
levels were observed at each visit in all study groups, with no
consistent differences among them. Furthermore, rapid
improvement in breathing symptoms was observed.
However, most participants continued smoking or started
smoking again; after 1 year, fewer than 10% remained abstinent.
This is probably due to the research targeting smokers who did
not intend to quit. As suggested by Remo and colleagues [3],
we argue that much better results might be achieved in smokers
motivated to quit.
From a physiological point of view, e-cigarettes appear to
eliminate the craving for tobacco in the same way as nicotine
replacement therapy (NRT). In an overview of the Cochrane
Library [4] that considered studies globally—including more
than 50,000 smokers—NRT was described as being particularly
efficacious for the short term (3 months) but less so in the long
term (12 months). However, the use of NRT increases the
success rate of quitting attempts independent of the setting if
compared to attempts made by smokers on their own or
supported only by counseling. Furthermore, NRT is particularly
useful for smokers who are prepared to quit, but who have high
nicotine dependence. Eventually, NRT will be particularly
effective when smokers’ baseline conditions are predictors of
successful quitting. Comparing the conclusion of the Cochrane
review with the results of studies on e-cigarettes effects, it is
clear that in some cases the sample used was quite different
from the one used in most trials on NRT. We argue that it is
necessary to study e-cigarettes efficacy while also considering
population baseline characteristics as well as psycho-cognitive
parameters. Indeed, we can expect smokers who are not prepared
to quit or in psychosocial conditions associated with a low
success rate (ie, mood disturbance, living in a context with high
prevalence of tobacco cigarettes smokers, low-income status)
to report a worse outcome in studies using e-cigarettes as
tobacco cessation treatment [2,4].
Previous research has stressed that monitoring lifestyle
parameters (in particular, physical activity and sleep quality)
and acting on them could help maintain abstinence. In particular,
physical exercise may aid smokers in the first 3 months, while
longer effects are less clear [5]. It has been observed that regular
physical activity among smokers reduces nicotine withdrawal
symptoms and craving. Last, smoking during the night is an
indicator of nicotine dependence and predicts failure in smoking
cessation [6]. Sleep disturbances have several negative
psychological effects, including reduced quality of life and
psychological distress (ie, anxiety and depression). Low sleep
quality due to abstinence is a predictor of a poor smoking
treatment outcome [7].
Low-cost, noninvasive devices are now available to monitor
lifestyle parameters. These electronic bracelets are reliable and
easy to use. Counseling approaches based on similar tools have
been shown to improve outcomes [8].
This protocol may also address a number of psychological
parameters, in order to determine whether individual features
might hamper behavioral changes and related positive effects
on health. Indeed, heavy smokers have specific psycho-cognitive
traits [9]. In particular, they generally show higher levels of
impulsiveness than nonsmokers. At the same time, smokers
tend to have a high level of activity in the behavioral activation
system (BAS). It has been suggested that high BAS sensitivity
is involved in addictive behaviors like smoking. Individuals
with high BAS are more inclined to enact approaching behaviors
and experience positive effects when they receive positive
rewards.
This study offers an opportunity to test the effectiveness of
e-cigarettes in a clinically controlled setting, in order to reduce
tobacco consumption and improve health benefits. Furthermore,
the protocol is nested in a screening program for early detection
of lung cancer at the European Institute of Oncology (IEO)
called COSMOS II (Continuous Observation of SMOking
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Subjects) that will allow subject recruitment and continuous
monitoring. The COSMOS II project aims to improve early
diagnosis of lung cancer, which is currently considered to be
the most important life-saving tool. This is an Italian program,
coordinated by IEO and created to identify an optimal
personalized protocol for early diagnosis in people with a high
risk of lung cancer (ie, heavy smokers or former smokers over
the age of 55). The COSMOS II program will enroll 10,000
heavy smokers or former smokers throughout Italy. COSMOS
II derives from the previous successful COSMOS I screening
project [10,11].
The main hypothesis is based on previous research on the effect
of e-cigarette use in substitution of tobacco cigarettes. We
hypothesize that the reduction of cigarette tobacco consumption
leads to a significant decrease of cough, breath shortness, and
other respiratory symptoms at 6 months. This reduction will
improve the quality of life and well-being. Furthermore, we
expect this effect to be higher for smokers using nicotine
e-cigarettes and support than for a placebo group and
support-only group. This would be coherent with previous
research on NRT and e-cigarettes. Indeed, we argue that smokers
who are both motivated to start a quitting attempt and aware of
smoking-related risks yet continue consuming several tobacco
cigarettes a day need an integrated antismoking strategy that
combines physiological, behavioral, and psychological
interventions. The use of electronic cigarettes, providing both
physiological and behavioral replacement of tobacco cigarette
consumption, and low-intensity counseling, providing
psychological support, might then be an optimal strategy in
these cases.
Eventually, we expect particular psychological conditions to
be associated with better outcomes. In particular, we hypothesize
that participants with a low level of depression, an active
lifestyle, and a low BAS will find the use of e-cigarettes more
advantageous.
Methods
Objectives
The main objective was to evaluate the impact of a 3-month
e-cigarettes program to reduce smoking-related respiratory
symptoms (eg, dry cough, breath shortness, mouth irritation,
and phlegm) as a consequence of reduced tobacco cigarette
consumption. Secondary objectives were to (1) assess the
success rate of smoking cessation attempts in the three groups;
(2) monitor safety and toxicity during the study; (3) evaluate
psychological and behavioral (ie, lifestyle) effects of
e-cigarettes; (4) assess the impact of e-cigarette use on quality
of life; and (5) identify cognitive/behavioral patterns as
e-cigarettes success predictors in reducing tobacco cigarette
smoking.
More specifically, the main aim of the project concerns the
effectiveness of e-cigarettes in improving lung health in the
heavy smokers involved in the COSMOS II program. If proven
safe and effective, e-cigarettes should be included in lung cancer
screening programs as a standard tool to reduce smoking-related
risks for lung diseases. Naturally, this aim requires a scientific
approach, since e-cigarettes should not increase nicotine
dependence. Another fundamental aim of the project regards
the effectiveness of e-cigarettes in reducing tobacco
consumption. In particular, no studies to date have tested the
feasibility and effectiveness of these tools in limiting risky
behaviors (eg, tobacco smoking) among heavy smokers enrolled
in a lung cancer screening program. Consequently, we want to
determine whether providing e-cigarettes to participants in a
controlled protocol reduces tobacco consumption, as well as
related health and breathing problems. We also aim to analyze
the psychological characteristics and needs of the subjects
enrolled in the COSMOS II program, in order to evaluate how
risk perception (eg, the premise of risky behavior adoption) is
associated with a psycho-cognitive profile. We argue that an
important and successful screening project, such as COSMOS,
should incorporate a comprehensive approach to the individual.
Design
This is a prospective, randomized, placebo-controlled,
double-blind, three-parallel group study. The study protocol
was designed using the recommendations of the Consolidated
Standards of Reporting Trials statement (Figure 1).
For this study, we opted for the VP5 electronic cigarettes kit,
which offered a good quality/price ratio and proven reliability
and safety. Nicotine and nicotine-free liquids are produced by
BioFumo, which fully collaborated with us and provided liquids
in nicotine concentrations of 8 mg/mL and packages that were
not distributed for commercial use.
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Figure 1. CONSORT flow diagram.
Participants
Volunteer smokers are recruited from among COSMOS II
participants at the IEO hospital. Details on the inclusion and
exclusion criteria are provided in the “Selection Criteria” section
below.
The main inclusion criterion is adult healthy smokers who
voluntarily choose to take part in a lung cancer screening
program. This screening program includes both a low-dose
computed tomography (CT) scan and blood tests in order to
detect early signs of lung cancer. Consequently, all of our
participants agree to undergo these examinations and are over
the age of 55 at the beginning of the study. To be included in
the study, COSMOS II participants must have smoked an
average of 10 cigarettes or more a day for at least the past 10
years. Furthermore, they also must report strong motivation to
stop smoking as measured by a motivational questionnaire (see
the “Instruments and Measures” section).
Since we are interested in assessing the effect of a specific
e-cigarettes-based treatment, we exclude smokers already using
e-cigarettes, which we define as smokers who had ever regularly
used e-cigarettes for more than 1 week alone or in combination
with tobacco cigarettes. Thus, all participants are inexperienced
with the use of e-cigarettes (full instructions are provided by
the researcher in charge of the study during the briefing). Also,
smokers who at the moment of the interview are undergoing
NRT or underwent NRT in the previous 6 months are excluded.
In this way, we tried to prevent any psychological and
physiological confounding effects due to previous treatments.
Furthermore, people with a history of psychiatric, severe
dyspnea, and cardiovascular diseases are also excluded.
All the including and excluding criteria are evaluated during
the first clinical examination of the COSMOS II program. Only
after the clinical examination, which includes objective tests
and an anamnestic interview by a physician in charge, is a
smoker considered for possible inclusion in the protocol.
Selection Criteria
Inclusion Criteria
1. Subjects are involved in the COSMOS II study
2. Subjects have smoked at least ten cigarettes a day for the
past 10 years
3. Subjects wish to reduce tobacco smoking (motivational
score higher than 10) who are not treated at a smoking
center
4. Signed informed consent
Exclusion Criteria
1. Symptomatic cardiovascular disease
2. Symptomatic severe respiratory disease
3. Regular psychotropic medication use
4. Current or past history of alcohol abuse
5. Use of smokeless tobacco or NRT
6. Participation in another antismoking program in the current
year
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Treatments
Group 1 Treatment (E-Cigarette and Support)
The participants receive an e-cigarettes kit and 12 10-mL liquid
cartridges containing an 8 mg/mL concentration of nicotine.
They are instructed to use the electronic cigarette ad libitum
during the first week before their quitting day (determined at
the first contact) in order to familiarize themselves with its use.
Starting at Week 2 (soon after the designated quitting day), the
participants are asked to stop smoking tobacco cigarettes and
use the e-cigarettes exclusively for the next 11 weeks.
E-cigarette use is monitored through a weekly paper diary and
regular telephone interviews. Since it is not possible to exclude
tobacco-cigarette smoking after the quit day, the weekly diary
also contains items related to cigarette smoking. Tobacco
smoking is also addressed during the periodic calls.
During treatment, a low-intensity remote (by phone) counseling
program is provided to maintain motivation and monitor any
psychological and/or physical problems related to the study
protocols. This program includes 4 calls in total, 1 at the ends
of Week 1, Week 4, Week 8, and Week 12. Each call will last
about 10 minutes; will address concerns about any ongoing
psychological, physical, and behavioral changes; and will
support the participants’ continued motivation by providing
practical suggestions.
The participants also receive an electronic fitness bracelet in
order to assess their physical activity and sleep quality during
treatment.
Group 2 Treatment (Placebo)
The participants receive an e-cigarettes kit and 12 10-mL
nicotine-free liquid cartridges. This liquid has the same
manufacturer, flavor, and components (except for nicotine) as
the one used in Group 1. All other procedures and measures
used for Group 2 are the same as those for Group 1.
Group 3 Treatment (Control/Support-Only)
The participants are provided only with low-intensity remote
(by phone) antismoking counseling to motivate and support
cigarette smoking cessation and abstinence. Scheduling, aims,
and structure are the same as those of Group 1. The participants
also receive an electronic fitness bracelet in order to assess their
physical activity and sleep quality during treatment. All
measures and procedures are identical to Groups 1 and 2.
Treatments Common to All Groups
•A complete explanation of the project and informed
participant consent
•Baseline behavioral, motivational, and psycho-cognitive
evaluation (set of questionnaires)
•Baseline clinical parameter assessment
•Initial and final face-to-face interview
•Regular telephone interviews
•Explanation of the weekly short-diary procedure
•Briefing on and delivery of the e-bracelet
•Low-intensity remote smoking cessation counseling
program
Instruments and Measures
Clinical Parameter Evaluation
•Anamnesis
•Clinical examination
•CO measurement
•Low-dose CT scan
•Circulating micro-RNA examination
•Respiratory examination
Instruments
•Self-reported measures are used for cough and other
respiratory symptoms assessment. We opted for Likert
scales to measure cough, breath shortness, mouth irritation,
and phlegm frequency as well as the Leicester Cough
Questionnaire.
•Fagerstrom Test for Nicotine Dependence: a 6-item
self-reporting questionnaire assessing nicotine dependence.
It requires a few minutes to complete [12]. This test is
administered to all COSMOS II participants.
•Motivational questionnaire [13]: a 4-item self-reporting
questionnaire assessing motivation to quit smoking. The
total classifies the patient into 1 of 4 motivational categories
(from “not ready to quit” to “highly motivated”). This test
is administered to all COSMOS II participants.
•Hospital Anxiety and Depression Scale (HAD): The HAD
is a self-administered questionnaire composed of two 7-item
scales, 1 for anxiety and 1 for depression, which should be
used as 2 separate measures of emotional distress. The scale
has been validated for Italian culture by Costantini and
showed high internal consistency with Crohnbach alpha,
ranging from .83 to .85 [14]. The HAD evaluates symptoms
of anxiety and depression, avoiding misattribution due to
the physical aspects of the illness. The values range from
0 to 21 for each scale. Cutoff scores are preliminarily
defined as normal (0-5), mild (6-8), moderate (9-11), and
severe (greater than 11) for both anxiety and depression
patients [15].
•BIS/BAS Scale [16]: a 20-item self-reporting questionnaire
evaluating the behavioral inhibition system (BIS) and BAS.
Each of the items is rated on a 5-point scale, ranging from
1 (does not describe me at all) to 5 (describes me very well).
•Barratt Scale [17]: an 11-item self-reporting questionnaire
designed to measure impulsiveness. All items are measured
on a 4-point scale (Rarely/Never; Occasionally; Often;
Almost Always/Always), where a 4 generally indicates the
most impulsive response, although some items are scored
in reverse order to avoid a response bias [18].
•The Leicester Cough Questionnaire: a valid, self-reported
cough-specific health status measure. It is a 19-item
questionnaire that has been validated in acute and chronic
cough [19]. The overall score ranges from 3 to 21 with a
higher score indicating a better quality of life.
•Electronic bracelet (the Flex FitBit): a device that allows
lifestyle monitoring of physical activity and sleep
characteristics, including: sleeping and napping (hours slept,
light vs deep sleep, and waking periods); activity (distance,
calories burned, activity time, and activity intensity);
nutrition (food and beverage intake); mood (assessment of
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the affect state); and an insight engine that identifies hidden
connections and patterns in day-to-day activities.
•The exhaled CO is measured by the The Micro+
Smokerlyzer, which has less than 5% H2cross-sensitivity.
•Ad hoc questionnaire: measures demographic data,
self-perceived quality of life (analogue scale), physical
activity, and smoking-related issues (characteristics of the
smoking experience).
Recruitment and Follow-Up
All inclusion and exclusion criteria are checked during the
registration procedure and initial assessment for inclusion in
COSMOS II. Eligible participants are asked to provide informed
consent. The informed consent form is signed and dated by both
the participant and the physician. Enrolled participants receive
a chronological number and are assigned to a treatment group
(e-cigarettes with nicotine, e-cigarettes without nicotine, or
control).
A randomization list using a permuted block design (40 blocks
of 6 subjects randomly assigned to 1 of the 3 treatment groups)
have been previously prepared by an independent personnel
unit and labeled with the progressive number applied to the
packaging containing e-cigarettes and liquid cartridges with or
without nicotine (Group 1 and Group 2).
Neither the participant nor the researcher in charge knows
whether the liquid in the e-cigarettes kit contains nicotine. Only
the statistician who prepared the randomization list and the
person labeling the e-cigarettes packaging know the actual
treatment.
Each participant is then assigned to one of the three groups and
receives the related treatment, as illustrated above.
Follow-up: 6 months (at the IEO)
•Behavioral psycho-cognitive questionnaires
•Clinical parameters assessment (respiratory symptoms)
•Smoking status assessment (questionnaire and CO level).
The nonsmoking status is established by self-report items
and the CO level (ppm<5).
•Debriefing, during which we also ask participants of Group
1 and Group 2 to guess if they used a nicotine-free or a
nicotine-based e-cigarette.
End-point: 12 months (at the IEO, during the annual assessment
of COSMOS II)
•Clinical parameter assessment (respiratory symptoms)
•Final behavioral and psycho-cognitive assessment
•Smoking status assessment (questionnaire and CO level)
•Debriefing and collection of comments
Timeline (Figure 2):
•Distribution of e-cigarettes: 3 months (ends at Week 12)
•Data tracking (e-bracelet) and active monitoring: 6 months
(ends at Week 24)
•End point: 12 months
Figure 2. Protocol plan.
Endpoints/Evaluation Criteria
Primary Outcome Measures
•Change in respiratory symptoms (eg, dry cough, breath
shortness, mouth irritation)
To evaluate the impact of a 3-month e-cigarettes program to
reduce smoking-related respiratory symptoms (dry cough, breath
shortness, mouth irritation, and phlegm) through reduced
tobacco cigarette consumption. The primary outcome is
measured at Month 6 and then at the follow-up at Month 12.
Secondary Outcome Measures
•Change in psychological well-being (HAD scale)
•Change in number of cigarettes smoked daily
•Change in the concentration of exhaled air CO
•Change in daily activity (mean number of daily steps)
•Change in lifestyle as measured by ad-hoc questionnaires
Statistical Considerations
Sample Size
Starting with data provided by previous studies on the effect of
smoking discontinuation, whether using or not using e-cigarettes
[2,20,21], we expected to find a reduction between 20% and
30% of respiratory symptoms reported by participants. We used
cough as the measure to power the trial on. Using a two-sided
Ztest, a sample of 70 participants in either of the experimental
groups (e-cigarettes with or without nicotine) and 70 in the
control group (counseling alone) will reach 80% power, at .05
significance level, to detect a 20% reduction in the frequency
of symptoms from the baseline in either of the e-cigarette groups
(with or without nicotine) compared to a 5% reduction in the
control group (counseling alone).
Statistical Plan
The main analysis will consist of comparing the reduction in
symptoms after 6 months for the three groups: e-cigarettes with
nicotine vs control; e-cigarettes without nicotine vs control; and
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e-cigarettes with nicotine versus e-cigarettes without nicotine.
Analyses will be based on two-sided Ztests.
A secondary analysis will assess the reduction of the
consumption of tobacco-containing cigarettes after 6 months
among the groups. Analysis will be based on paired Student’s
t-test or the Wilcoxon signed rank tests.
No interim monitoring is planned since, given the sample size,
any interim analysis would have too few events to be interpreted.
Efforts will be made to maximize retention by maximizing trust
at the baseline assessment and collecting multiple means to
contact and commit participants, including email and phone
contact details, and by assertive follow-up. Starting with our
previous experience with a similar population coming from the
COSMOS I program, we expect that our participants will be
compliant with and committed to the aims of the study. Giving
the expected intrinsic motivation of participants and thanks to
the above strategies, the study aims to have at least 80%
retention at 6 months and 70% at 12 months. Considering these
figures, we expect to maintain a statistical power to detect a
reduction of 5 cigarettes/day in our smokers (the cigarettes per
day mean is about 20 in the COSMOS population). Thus, using
a two-sided two-sample t-test with a significance level (alpha)
of .05, a sample size of 49 participants per arm will achieve
80% power to detect a mean reduction of 5 cigarettes/day
between any of the 2 experimental arms and the control arm,
assuming a mean consumption of 20 cigarettes/day in the control
arm and a common standard deviation of 8.7.
Ethical Considerations
This study is performed in accordance with the principles stated
in the Declaration of Helsinki and subsequent amendments, and
in accordance with the Good Clinical Practice Guideline. This
protocol was assessed and certified by the ethical board of
Fondazione Umberto Veronesi, the ethical committee of
Università degli studi di Milano, and the ethical committee of
the European Institute of Oncology. The ClinicalTrials.gov
identifier is NCT02422914. Informed consent will be obtained
from all subjects.
Results
At the time of manuscript submission, the trial’s status is
“recruiting.”
Discussion
Principal Findings
Cigarette smoking is a major risk factor for a variety of diseases.
The World Health Organization states that tobacco kills nearly
6 million people each year and that an annual death toll of more
than 8 million is expected by 2030.
Despite the availability of approved medications and smoking
cessation aids (ie, NRT, bupropion, varenicline, and counseling
programs), long-term quitting rates are relatively low. Most
smokers try to quit without professional help even when they
see their doctor on a regular basis. Indeed, smoking status is
rarely documented and smoking cessation treatments are offered
even less frequently [22], wasting an opportunity provided by
the doctor-patient relationship.
The failure of tobacco control is clear in developing countries.
However, in most rich countries, tobacco control also is
problematic due to a number of factors. Economic and ethical
issues often conflict in antismoking research and strategies [23],
and the relatively recent availability on the market of e-cigarettes
has added further confusion [24]. Consequently, independent
studies are needed in this field to avoid any possible external
influence. Furthermore, we believe that lung cancer screening
programs (like COSMOS II, where this project is nested) have
an ethical obligation to provide participants access to all the
information and strategies that could help them to reduce their
risk. Stopping or reducing tobacco consumption, then, should
be a primary goal. However, traditional antismoking programs
are expensive and not always effective. Therefore, favoring a
partial or complete shift to e-cigarettes in heavy smokers (eg,
persons at high risk for a number of diseases) could be
considered a moral imperative. However, to follow this path,
sound and reliable data is required on a large sample and in a
variety of contexts.
Last, the question of the use of e-cigarettes and their regulation
concerns not only physiological and toxicity aspects (eg, the
association between cancer and smoking), but also certain
relevant behavioral and psychological aspects as well. Thus, it
is necessary not only to understand the toxicity of these new
ways of smoking, but also their impact on smokers’ minds and
lifestyles.
Conclusions
E-cigarettes-based intervention could provide a gateway to
boosting health-related behavior changes, in order to reduce
tobacco consumption and positively impact smokers’ quality
of life. Indeed, reducing tobacco consumption or supporting
abstinence could be considered a fundamental aim of a screening
program, since a change in smoking habits reduces the risk of
smoking-related diseases.
Recent studies [2,3,25] show that e-cigarettes must be
considered safe devices that are potentially useful both for
reducing clinical symptoms (eg, cough, phlegm, breath
shortness) and enhancing the impact of antismoking
interventions. Consequently, the use of e-cigarettes is
particularly important in prevention programs and for high-risk
subjects. Many aspects are currently unclear and debated [25].
Hence, the outcome of this study will provide important data
on the possible role of e-cigarettes as tools for use in screening
and prevention programs. We argue that e-cigarettes apply a
medicalized substitution logic in which nicotine dependence
becomes a route to health in addition to a disorder to be treated.
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Acknowledgments
This work is supported by Fondazione Umberto Veronesi. The sponsor of the study is the University of Milan (Università degli
studi di Milano, Italy), which monitors the scientific, legal, and ethical aspects of the study. Subjects are recruited at an Italian
cancer center, the IEO, located in Milan. Methodological support is provided by the Interdisciplinary Research and Intervention
Centre of the University of Milan and the IEO Division of Epidemiology and Biostatistics. IEO’s central pharmacy is responsible
for assigning, allocating, and delivering e-cigarettes liquids. This work is supported by a grant from Fondazione Umberto Veronesi
(FUV).
Nicotine and nicotine-free liquids are produced by BioFumo, which offered full collaboration to meet the study demands. In
particular, BioFumo provided us with the liquids with nicotine concentration of 8 mg/mL in packages that were not distributed
for commercial use. All devices and products (eg, e-cigarettes, liquids, electronic bracelets) are purchased thanks to economic
support provided by the FUV. No support is provided to the study by tobacco industries or other for-profit corporations.
We are grateful to IEO personnel for their help in organizing and managing the study, as well as for their contribution to
methodological and ethical aspects.
Authors' Contributions
CL, MM, GP, PM, and GV conceived of and designed the study. CL coordinated the study, CL and CP acquired legal authorizations,
and MM and SS managed participants. Statistical support and data management were provided by PM and RB, while e-cigarettes
and liquids were managed by JC and EOS. Drafting and writing of the manuscript was handled by CL, MM, and PM. All authors
have read and approved the final manuscript.
Conflicts of Interest
None declared.
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Abbreviations
BAS: behavioral approach system
BIS: behavioral inhibition system
CT: computed tomography
CO: carbon monoxide
COSMOS: Continuous Observation of SMOking Subjects
HAD: Hospital Anxiety and Depression Scale
IEO: European Institute of Oncology
NRT: nicotine replacement therapy
Edited by G Eysenbach; submitted 05.06.15; peer-reviewed by P Krebs, N Walker; comments to author 16.07.15; revised version
received 07.08.15; accepted 07.10.15; published 03.02.16
Please cite as:
Lucchiari C, Masiero M, Veronesi G, Maisonneuve P, Spina S, Jemos C, Omodeo Salè E, Pravettoni G
Benefits of E-Cigarettes Among Heavy Smokers Undergoing a Lung Cancer Screening Program: Randomized Controlled Trial Protocol
JMIR Res Protoc 2016;5(1):e21
URL: http://www.researchprotocols.org/2016/1/e21/
doi:10.2196/resprot.4805
PMID:26842790
©Claudio Lucchiari, Marianna Masiero, Giulia Veronesi, Patrick Maisonneuve, Stefania Spina, Costantino Jemos, Emanuela
Omodeo Salè, Gabriella Pravettoni. Originally published in JMIR Research Protocols (http://www.researchprotocols.org),
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