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THIS IS A PRE-PRINT PARTIAL VERSION
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Full article may be find in:
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Nicotine & Tobacco Research, nty047,https://doi.org/10.1093/ntr/nty047
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Nicotine & Tobacco Research (2018). DOI: 10.1093/ntr/nty047.
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Nicotine & Tobacco Research, nty175, https://doi.org/10.1093/ntr/nty175
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CORRECTED PROOF
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E-Cigarettes May Support Smokers With High
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Smoking-Related Risk Awareness to Stop
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Smoking in the Short Run: Preliminary
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Results by Randomized Controlled Trial
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Marianna Masiero Claudio Lucchiari Ketti Mazzocco Giulia VeronesiPatrick
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Maisonneuve Costantino Jemos Emanuela Omodeo Salè Stefania SpinaRaffaella
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Bertolotti Gabriella Pravettoni
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Abstract
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Method: The main focus of this article is on a secondary outcome of the study, that is,
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the assessment of effectiveness and safety of e-cigarettes in achieving smoking cessation
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in a group of chronic smokers voluntarily involved in long-term lung cancer screening.
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Participants were randomized into three arms with a 1:1:1 ratio: e-cigarettes (arm 1),
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placebo (arm 2), and control (arm 3). All subjects also received a low intensity
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counseling.
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Results: Two hundred ten smokers were randomized (70 to nicotine e-cigarettes, 70 to
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nicotine-free placebo e-cigarettes, and 70 to control groups). About 25% of participants
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who followed a cessation program based on the use of e-cigarettes (arms 1 and 2) were
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abstinent after 3 months. Conversely, only about 10% of smokers in arm 3 stopped. A
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Kruskal–Wallis test showed significant differences in daily cigarettes smoking across the
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three arms (K-W = 6.277, p = .043). In particular, participants in arm 1 reported a higher
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reduction rate (M = −11.6441, SD = 7.574) than participants in arm 2 (M =
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−10.7636, SD = 8.156) and arm 3 (M = −9.1379, SD = 8.8127).
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The primary outcome of this trial was the assessment of the impact of a 3-month e-
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cigarettes program to reduce smoking-related respiratory symptoms (dry cough, breath
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shortness, mouth irritation, and phlegm) as a consequence of reduced tobacco cigarette
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consumption. The secondary outcomes included the assessment of the success rate of
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smoking cessation attempts and daily smoking reduction in the three arms, and the
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monitoring of safety and toxicity during the study in arms 1 and 2. The present work
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illustrates data at 3 months, where the primary outcome was not measured yet. So, we
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focused here on smoking stopping, smoking reduction, and safety issues.
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We hypothesized that e-cigarette filled with nicotine liquid (arm 1) would be more
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effective than nicotine-free e-cigarette (arm 2) and the control group (arm 3) for smoking
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reduction and would have no greater risk of side-effects.
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A sample size of 210 participants was chosen to assess smoking reduction. Starting with
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the expected intrinsic motivation of participants, the study aimed to have at least 80%
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retention at 6 months and 70% at 12 months. Considering these figures, we expected to
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maintain a statistical power to detect a reduction of 5 cigarettes/day in our smokers
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(being the cigarettes per day mean about 20 in the COSMOS population). Thus, using a
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two-sided two-sample t-test with a significance level (alpha) of 0.05, a sample size of 49
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participants per arm we expected to achieve 80% power to detect a mean reduction of 5
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cigarettes/day between any of the two experimental arms and the control arm, assuming
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a mean consumption of 20 cigarettes/day in the control arm and common standard
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deviation within group of 8.7.
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…
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Results
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At the baseline, the levels of anxiety and depression were not significantly different
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between the three groups. Generally, participants reported normal values, indicating the
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absence of clinical depression. Likewise, no differences among groups were found in the
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physical and psychological domains based on the LCQ scores. Some common e-
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cigarette side effects were reported.
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At month 3, we collected complete data about 170 participants. No statistical differences
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in the number of missing data were present between arms (χ2(2) = .835, p = .659).
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Participants in Arm 1 and Arm 2 had a similar compliance in the use of e-cigarettes. In
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fact, considering the number of empty flacons they gave back at the end of the study we
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dind’t find any significant difference, though the placebo group used on average less
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liquid (Arm 1 M = 10.9 empty flacons; Arm 2 M = 9.8 empty flacons).
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Across study arms, 20% of participants (N = 34) stopped smoking at month 3. The
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percentage was significantly higher in the nicotine (N = 15; 25.4%) and nicotine-free (N
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= 13; 23.4%) e-cigarette groups than in the control group (N = 6; 10.34%) (χ2(2) =
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4.899, p = .044).
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Next, we compared reduction of cigarette consumption in participants who had used e-
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cigarettes (Arm 1 and Arm 2) and those who only received counseling (Arm 3). The
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Mann-Whitney U test reported significant differences between conditions (e-cigarettes
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vs. control) at month 1 (U = 2.508, p < .010) and at month 3 (U = 2.130, p < .022). The
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use of the electronic device actually helped participants reduce daily cigarettes. At
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month 3, also the reduction rate showed interesting results. Participants in Arm 3
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reported smoking an average of 10.034 cigarettes/day, while participants in Arm 1 and
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Arm 2 showed a lower consumption (7.671 and 9.091, respectively). However, while the
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difference between Arm 1 and Arm 3 was statistically significant, differences between
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Arms 1 and 2 and between Arms 2 and 3 were not.
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Considering the mean difference in cigarette consumption between the baseline and
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month 3, the Kruskal-Wallis H test for 3 independent samples showed a significant
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difference among Arms 1, 2, and 3 (see table 2): Participants in Arm 1 reported a higher
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reduction rate (M = -11.644, SD = 7.574) than participants in Arm 2 (M = -10.763, SD =
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8.156) and Arm 3 (M = -9.138, SD = 8.8127).
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Table 2 here
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However, excluding from the reduction analysis the participants who discontinued
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smoking, we failed to find any statistical difference, even though in Arm 1 we found the
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highest reduction (M = - 9.164 in Arm1; M = -8.262 in Arm2; M = -7.875 in Arm3).
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Considering respiratory symptoms, a significant reduction in all conditions was found,
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probably due to the decreased number of daily cigarettes smoked by most participants,
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independent of study arms. In particular, about 21.5% of participants reported a decrease
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in coughing, about 18.50% reported less catarrh, and about 14.5% reported an
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improvement in breathing.
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Focusing on e-cigarettes tolerability, our participants reported few side effects (see table
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3). In particular, at month 1 the most relevant complain was “burning throat”. It was
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reported by about 23% of participants using liquid containing nicotine (while only about
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4% of participant reported the same complain using nicotine-free liquid). However, at
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month 3 we observed a drastic decrease of the symptom. Cough was also reported at
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month 1 by about 10% of participants, both using nicotine and nicotine-free liquid. Also
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in this case, the symptom decreased during time.
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Discussion
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In this study, we tested the efficacy of e-cigarettes as cessation treatment in a sample of
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chronic smokers involved in a screening program. Our main result is that the use of e-
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cigarettes helped participant stop smoking since about one-quarter of participants who
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followed a cessation program based on e-cigarettes (both with and without nicotine) and
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a low-intensity counseling were abstinent after three months. Conversely, about 10% of
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smokers stopped following a program based only on a low-intensity counseling.
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Furthermore, e-cigarettes increased the reduction rate in participants who continued
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smoking. In fact, although all participants reported a significant reduction of daily
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cigarette consumption compared to the baseline, the use of e-cigarettes (including those
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without nicotine) allowed smokers achieving a better result. The few side effects
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reported, which were also reported in other studies,36-39 were well managed by
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participants and showed no increase during the treatment. Consequently, our findings
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confirm the efficacy as well as the safety of e-cigarettes in a short-term period.
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Although participants in Arm 1 generally achieved better results, the placebo condition
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was effectively as well, in some case leading to comparable outcomes. This result has
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not been described before and provides suggestions for potentially fruitful new lines of
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research.
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Future studies should analyze costs and benefits related to the use of nicotine-free e-
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cigarettes in high-risk patients who smoke. In particular, the efficacy of combining
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clinical counseling and nicotine-free e-cigarettes for high-risk patients should be
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discussed. In our view, it could have pivotal implications in clinical practice. We believe
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that nicotine-free e-cigarettes might be a first-line choice, particularly for subjects who
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have severe diseases (for example, those with heart problems) and cannot use nicotine or
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receive other medical treatments. However, the lack of differences between nicotine and
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nicotine-free device effects on smoking might also be linked to the low dosage of
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nicotine we adopted. In fact, using a device working at 10 W with an 8 mg/mL nicotine
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concentration we obtained quite a low dosage (less than 0.1 mg per puff) with respect to
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the nicotine normally assumed daily by a chronic smoker40. This may explain why
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results in Arm 1 (nicotine e-cigarettes) and Arm 2 (nicotine-free e-cigarettes) are so
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similar. Increasing nicotine concentration probably may enlarge this difference, although
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we need targeted research to establish which protocol may optimize the risk/benefits
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ratio.
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In conclusion, taking into consideration the perspective of personalized medicine, e-
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cigarettes based protocols associated with new ICT-driven models of self-management
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may be implemented to support people to better handle behavioral changes and side
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effects.41-45 This is true for ready-to-quit smokers (such as our participants) but could
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also be advantageous for less motivated smokers engaged in clinical settings.
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Limits of the Study
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The number of initial dropouts, i.e., participants who explicitly declared the willingness
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not to continue within the first month (1 participant in Arm 1, 2 in Arm 2, and 6 in Arm
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3) was particularly high in in the control group. It might suggest that motivation to
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participate to the study was related to the possibility of using the e-cigarettes rather than
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an actual willingness to stop smoking. During the study we had some missing data
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(12.4% at month 1; 21.9% at month 2; 18.1% at month 3) that limit our results.
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Monthly, we monitored the use of e-cigarettes during the counseling calls and the
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follow-up to manage potential problems. However, we didn’t assess systemically any
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quantitative measure about the actual use. For this reason, only qualitative considerations
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can be done about the different use of e-cigarettes between subjects in Arm 1 and Arm 2.
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Furthermore, the number of smoked cigarettes was recorded as participants’ self-reports,
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which might have led to a measurement bias. The impossibility of assessing carbon
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monoxide in an expired breath at month 3 because of the study design cannot
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disambiguate the aforementioned possible explanation. However, if present, this effect
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was constant in all 3 arms, thus not affecting the exhibited effects. Finally, this paper
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focused on a secondary outcome, since the primary one was supposed to be assessed at
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six months.
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Protocol
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Clinicaltrials.gov NCT02422914; https://clinicaltrials.gov/ct2/show/NCT02422914
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Funding
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This study was supported by a grant from Fondazione Umberto Veronesi (FUV).
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