The Efficacy of Virtual Reality Exposure Therapy for the Treatment of Alcohol Use Disorder Among Adult Males: A Randomized Controlled Trial Comparing With Treatment-as-usual

The approval of the study was obtained from the Human Research Ethics Committee of Xinxiang Medical University. The study will be conducted according to the Declaration of Helsinki 1974 and its subsequent amendments and abide by the Good Clinical Practice Guidelines for Clinical Trial in Malaysia. If there is any amendments, for example in the eligibility criteria, study population, study procedures, interventions, data collection, data analysis; it will be informed in writing to the Human Research Ethics Committee of Xinxiang Medical University.

Prior to participation in the trial, participants will be informed of their right to withdraw from the trial at any time and the data collected will be discarded immediately and will not be used for the study. Participants will be reminded that all personal identifiable information will not be used and only group data will be analyzed and published. They will be assured of their anonymity for participating in the trial. The participants will be assured that the data collected will only be used for research purposes and the findings will not be recorded in their case files. All participants will be assigned a research number for identification purposes, for example "VT 001". All the data collected from the participants will be stored in the research file which will be locked in a file cabinet, whereby the key will be kept by the principal investigator. Data collected may also be stored in thumb drive and lap top which is only accessible by the research team and the principal investigator. Prior to participation, all the participants will also be informed regarding the study purposes, study procedures, and the risks and benefits of participating in the study. The findings of the study will be published in academic journals and presented in conferences or symposia. As for publication of research findings in academic journals, the principal investigator will be the corresponding author while the other authorship will be determined according to the the International Committee of Medical Journal Editors' recommendations. All the investigators in the research team declared that there is no competing interest in term of financial gain or the conduct of this study.

Participants who experienced any adverse effects (AE) will be withdrawn from the study. AE is any untoward medical events which occurred with or without causal relationship with the study's intervention. In order to monitor AE during the trial, all participants will be given a trial card which contains the name, contact number and email of the members of the research team. They are encouraged to contact the research team member in charge if there is any occurrence of AE. The occurrence of AE will then be reported to the "adverse effect" section of the trial's case report form. The details of the AE reporting will contain information, such as the name of the AE, the date of occurrence and date of resolution, severity, AE relationship with the study intervention, treatment of AE, and the outcome (resolve or still on-going). The AE which may lead to withdrawal of participants from the trial are: (1) adverse reaction which is not related to the study intervention but cause discomfort to the participants, (2) adverse reaction which is related to the study intervention (probiotic, ACT and/or placebo), and (3) any changes in behavior, temperament, personality, psychotic symptoms, and suicidal tendency that occurred after the study intervention began (VRET, ACT or TAU). All AE should be reported to the Human Research Ethics Committee of Xinxiang Medical University and investigation should be carried out. If there is any safety concerns regarding the administration of the study intervention (VRET, ACT, and TAU), such as deliberate self-harm, suicidal tendency, bacterial infection, sepsis, hospitalization due to psychological adverse effect arise from the intervention, or mortality; there it is an indication for premature termination of the trial after an interim analysis.

The principal investigator will lead the trial center and will coordinate closely with the research and site coordinators in a day-to-day basis involving in the conduct of the clinical trial, subject recruitment, and data collection. A trial monitoring unit will also be set up which will be chaired by the principal investigator, whereby weekly meeting will be held to discuss on the conduct of the trial, auditing of the trial, and prepare report to be submitted to the Human Ethics Committee of Xinxiang Medical University. The monitoring of trial data and auditing of the trial will be managed by the clinical trial coordination unit of the 2nd Affiliated Hospital of Xinxiang Medical University, which are independent of the funder. Interim analysis will be carried out if there is such necessity for premature termination of the trial based on assessment and auditing of the trial data.

The estimated sample size will be calculated using the G*Power 3.1.9.7 sample size calculator using the sample size calculation for repeated measure ANOVA, within-between interaction, whereby the type I error was 0.05, the power was 0.8, the number of groups was three, the number of measures was four, and the effect size was 0.14. The estimated total sample size needed was 80 (after inclusion of 30% drop out), in which 40 subjects per group is required.