A 12-month randomised, double-blind, controlled, multicentre trial comparing changes in Cigarette consumption after switchinG to high or low nicotine strENght E-cigaretteS In smokers with Schizophrenia spectrum disorders: Protocol for the GENESIS Trial

Background Smoking prevalence among people with mental disorders is about two to four times higher than in the general population. As a result of high smoking rates, people with a mental health condition also have high rates of morbidity and mortality from smoking-related diseases compared with the general population. Progress in reducing smoking prevalence in people with mental health diagnoses has been very slow compared to the general population. Consequently, there is a pressing need for alternative and more efficient interventions to reduce or prevent morbidity and mortality in smokers with schizophrenia spectrum disorders. Methods A volunteer population of 258 adult smokers with Schizophrenia Spectrum Disorder will be recruited for the GENESIS study, a randomized, double blind, smoking cessation trial comparing effectiveness, safety and subjective effects between 5% and 1.5% nicotine e-cigarette. The study duration will be 12-month. The primary endpoint of this study will be the continuous quit rate defined as the proportion of study participants who self-report that they had stopped smoking at 6-month, biochemically verified by exhaled CO measurements of ≤ 7 ppm. These participants will be referred to as “Quitters”. The differences in continuous variables between the two groups for normally distributed data will be evaluated by one-way analysis of variance (ANOVA). The differences between the two groups for not normally distributed data will be evaluated by the Mann-Whitney U test. Any correlation between the variables under evaluation will be assessed by Spearman r correlation. To analyze differences in frequency distribution of categorical variables we will use the Chi-square test with the Yates correction or the Fisher exact test. All statistical tests are two-tailed and are considered to be statistically significant at a P value <0.05. The consistency of effects for pre-specified subgroups will be assessed using tests for heterogeneity. Subgroups will be based on age, sex, education, level of nicotine dependence. Discussion This will be the first multicenter randomized trial directly comparing high (JUUL 5% nicotine) with low nicotine strength devices (JUUL 1.5% nicotine) in term of reduction in cigarette consumption, adoption rates, product acceptability, tolerability, and tobacco harm reduction potential. This knowledge can contribute to a better understanding of e-cigarette with high nicotine content as a pragmatic and much less harmful alternative to tobacco smoking with the possibility of significant health gains in smokers with schizophrenia spectrum disorders. Trial registration [ClinicalTrials.gov][1] ID: [NCT04452175][2]. Registered June 29, 2020. ### Competing Interest Statement DECLARATION OF COMPETING INTEREST MS, DS, EA and RP are full-time employee of the University of Catania, Italy. PC, and MM are fixed-term researcher at University of Catania, Italy. FB is fixed-term researcher at Centro per la Prevenzione e Cura del Tabagismo, University of Catania. RC is full time employee of the Vita-Salute San Raffaele University, Milan, Italy. LI is full-time employee of the University of Rome La Sapienza, Rome, Italy. CM is is full time employee of Department of Mental Health, ASP n.3, Catania, Italy. RA is full-time employee of the CTA-Villa Chiara Psychiatric Rehabilitation Clinic and Research, Mascalucia, Italy. BI is full-time employee of Bashkir State Medical University, Ufa, Russia. EK is full-time employee of First Pavlov State Medical University, V. M. Bekhterev National Research Medical Center for Psychiatry and Neurology, St. Petersburg, Russia. RN is full-time employee of Abraham Cowley Unit, Surrey and Borders Partnership NHS Foundation Trust, Redhill, UK; FC is is full-time employee of National Research Council of Italy, Institute for Biomedical Research and Innovation, Palermo, Italy. In relation to his work in the area of tobacco control and respiratory diseases, Riccardo Polosa has received lecture fees and research funding from Pfizer, Inc., GlaxoSmithKline plc, CV Therapeutics, NeuroSearch A/S, Sandoz, MSD, Boehringer Ingelheim, Novartis, Duska Therapeutics, and Forest Laboratories. He has also served as a consultant for Pfizer, Inc., Global Health Alliance for treatment of tobacco dependence, CV Therapeutics, NeuroSearch A/S, Boehringer Ingelheim, Duska Therapeutics, Forest Laboratories, ECITA (Electronic Cigarette Industry Trade Association, in the UK), and Health Diplomat (consulting company that delivers solutions to global health problems with special emphasis on harm minimization). Lecture fees from a number of European EC industry and trade associations (including Federation Interprofessionnelle de la VAPE in France and Federazione Italiana Esercenti Svapo Elettronico in Italy) were directly donated to vaper advocacy no-profit organizations. He is currently Head of the European Technical Committee for standardization on Requirements and test methods for emissions of electronic cigarettes (CEN/TC 437; WG4). He is also founder of the Center of Excellence for the acceleration of Harm Reduction at the University of Catania (CoEHAR), which has received a grant from the Foundation for a Smoke Free World to support 8 independent investigator-initiated research projects on tobacco harm reduction, and scientific advisor for LIAF, Lega Italiana Anti Fumo (Italian acronym for Italian Anti-Smoking League). The other authors have no conflict of interests to declare. ### Clinical Trial NCT04452175 ### Funding Statement This research is supported by an Investigator-Initiated Study award by Juul Labs, Inc. (Juul Science Programme). The study protocol was written by PC and RP who were also respectively the principal investigator and the scientific director of the study. Juul Labs, Inc had no role in the design of the study protocol and will not have any role during its execution, analysis, data interpretation or writing of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Internal Ethic Review Board IERB Dipartimento di Scienze della Formazione Sezione di Psicologia 16.06.2020 All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes NA * AE : Adverse Event ANOVA : One-way analysis of variance APR : Annual progress report AR : Adverse Reaction BP : Blood pressure CI : Chief Investigator CO : Carbon Monoxide in exhaled breath CRF : Case Report Form CRO : Contract Research Organisation CST : Chester step test DMC : Data Monitoring Committee EQ VAS : Quality of Life scale FTCD : Fagerstrom test for cigarette dependence GCP : Good Clinical Practice HR : Heart rate IB : Investigator Brochure mCEQ : Modified Cigarette Evaluation Questionnaire PI : Principal Investigator REC : Research Ethics Committee SAE : Serious Adverse Event PANSS : Positive and negative symptoms of Schizophrenia SAR : Serious Adverse Reaction SmPC : Summary of product characteristics SOP : Standard Operating Procedure SRMH : Self-rated mental health SUSAR : Suspected Unexpected Serious Adverse Reaction TC : Telephone Contact TSC : Trial Steering Committee [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04452175&atom=%2Fmedrxiv%2Fearly%2F2020%2F10%2F26%2F2020.10.15.20141457.atom