Study setting and population
Study data will be collected in day hospitals (DH) within the addiction departments of public hospitals. For this research, four centers in the Paris area will be involved in recruiting patients. The four recruiting centers are: 1) Department of Addictions - Hôpital Albert Chenevier - CHU Henri Mondor - APHP – Créteil, 2) Department of Addictions - Hôpital Fernand Widal - Nord - Université de Paris - APHP – Paris, 3) Department of Addictions - Centre hospitalier des Quatre Villes – Sèvres, 4) Department of Addictions - Tolbiac Day Clinic – Paris. Recruitment will be done by the investigating physician at the time of admission to the DH during an individual consultation. If the patient is eligible for the study, the full protocol will be presented and reviewed during an individual consultation at the DH enrollment visit.
The following inclusion criteria apply: i) 18 to 80 years of age at the time of enrolment; ii) patients with a diagnosis of AUD according to DSM-5 criteria (American Psychiatric Association, 2013); iii) patients who had been abstinent for at least 15 days; iv) patients who can speak, understand and read French; v) patients who have signed an informed consent form and who are affiliated to a health insurance plan.
Subjects are not included if they are: i) adults under legal protection or deprived of liberty by judicial or administrative decision; ii) pregnant or breast-feeding women; iii) patients with decompensated psychiatric disorders (psychotic disorders, mood disorders and anxiety disorders); iv) patients relapsing from their AUD; v) patients with severe cognitive impairment as defined by the MOCA Cognitive Assessment Test (score < 10) (24); vi) visually impaired patients; vii) patients with contraindications to virtual reality exposure, due to epilepsy or history of photoparoxysmal EEG response, or vestibular disorders; viii) recent cardiovascular accident less than 3 months old, current nausea/vomiting, claustrophobia and moderate or severe myopia (greater than − 3. 5 diopters); ix) patients wearing any of the following medical devices (due to the risk of interference with the virtual reality headset): pacemaker, implanted defibrillator or implanted hearing aid (non-implanted prostheses are not contraindicated if the patient agrees to remove them during VR-CET); x) participation in another study or being in the exclusion period after previous research involving human subjects; xi) and patients benefiting from State Medical Assistance (defined as access to healthcare for people in an irregular situation).
Treatment groups
The first four CBT group sessions focus on understanding the effects of alcohol, assessing motivation to change, behavioral and emotional strategies, cognitive strategies, relapse prevention and assertiveness strategies. These sessions are conducted in a group setting by a trained psychologist and a trainee.
Participants are then randomized into two groups (M1): i) VR-CET + BT group, ii) CBT group only. Allocation is centralized, individualized and randomized according to the following factors: center, presence of pharmacological treatment to maintain alcohol abstinence (2 modalities), history of AUD treatment in the last five years (2 modalities), alcohol consumption goals (2 modalities) and severity of alcohol dependence according to DSM-5 criteria (3 modalities).
Secondary outcomes
Craving is assessed by the Transaddiction Craving Triggers Questionnaire (TCTQ) (28). This is an instrument designed to assess what triggers craving. The questionnaire is completed at inclusion, M2, M5, and M8. Craving is also assessed using a VAS (0 to 10) at each exposure session (29) and on a monthly basis after M2, in the same way as for the primary outcome.
The frequency of hazardous drinking episodes is assessed with the AUDIT-C (Alcohol Use Disorders Identification Test) questionnaire (30), an abbreviated version of the AUDIT self-report questionnaire (31) that includes three questions about the patient's alcohol consumption. These data are collected at enrollment and at treatment phases M2, M5, and M8. Finally, reported alcohol consumption is correlated with weekly DH toxicology monitoring, if this is routinely performed at the recruiting centers. Weekly toxicology screenings for ethyl glucuronide (EtG), if performed as part of the routine care at the recruiting centers, will be recorded in the logbook.
Anxiety is assessed by the Generalized Anxiety Disorder-7 (GAD-7) questionnaire (32). This instrument is designed to screen for generalized anxiety disorder and may also help to identify panic disorder, social anxiety disorder, and posttraumatic stress disorder. It is administered at inclusion, M2, M5, and M8.
Depression is assessed by the Patient Health Questionnaire-9 (PHQ-9) (33). This instrument collects information on the presence and intensity of depressive symptoms. Data is collected at inclusion, M2, M5, and M8.
Self-efficacy is assessed by the Sense of Self-Efficacy Questionnaire, originally developed in German by Matthias Jerusalem and Ralf Schwarzer (34). It is administered at inclusion, M2, M5, and M8.
Rumination is assessed by the 15-item Perseverative Thinking Questionnaire (PTQ). This is a widely used self-report measure of repetitive negative thinking (35). It is administered at inclusion, M2, M5, and M8.
The state of presence in virtual reality is measured by the QEP questionnaire (Questionnaire sur l'État de Présence) developed by the UQO Cyberpsychology Laboratory (2002) (36, 37). This survey is conducted at M2 for the participants randomly assigned to the VR-CET group.
Cybersickness risk is assessed after each VR-CET session using the Cybermalaise Questionnaire from the UQO Cyberpsychology Laboratory (38).
All questionnaires are completed by DH patients at inclusion and M2. The scheduled assessments from M3 to M8 are conducted by telephone (Cf. Table 1).
Sample size
To determine the number of participants needed for the study, we randomly selected 15 patients with alcohol-related disorders (AUD) who were already being treated at the Albert Chenevier Day Hospital's addiction department. Their cumulative alcohol consumption was monitored at two, five and eight months after admission to estimate the average daily consumption over eight months. The target consumption was calculated on the basis of the recommendations of the European Medicines Agency (39), aiming at a reduction of at least two risk levels according to the World Health Organization. To achieve a statistical power of 0.8, considering a risk α of 0.05 with a two-sided hypothesis, 65 patients per group are required. Assuming a drop-out rate of 20%, 78 patients per group need to be recruited, for a total of 156 patients for both groups.
Table 2
| Number of subjects |
Total number of subjects selected | 156 |
Number of centers | 4 |
Inclusion period (months) | 24 |
DATA COLLECTION, MANAGEMENT, AND ANALYSIS
Data management
Data are collected on paper and in an observation notebook (with all questionnaires), then entered by the research team on the secure CleanWEB® platform. This platform enables data to be downloaded, anonymized, stored and randomized.
Statistical methods
The characteristics of all patients will be described globally and according to their randomization group, using the number of patients (%) for qualitative variables and the median [interquartile range] or mean (± standard deviation) for quantitative variables, depending on the normality of their distribution. A patient flow diagram will be generated. Results are reported according to CONSORT recommendations. Tests will be two-tailed, and a significance level of p < 0.05 will be considered statistically significant. The primary outcome (self-reported cumulative number of standard drinks consumed at 8 months) will be compared between the two groups using Student's t-test for independent samples. Complementary analyses will be conducted using generalized linear regression models adjusted for minimization factors and number of sessions per setting. Given the repeated measurement of outcomes and the multicenter design of the study, additional analysis will be performed including Cox and mixed models. To consider Survival analysis will also be conducted using a linear mixed model. Secondary endpoints will be analyzed using the same methodology as for the primary endpoint, i.e. a comparison of the mean using the usual tests. primary endpoint, i.e. a comparison of means using standard tests at 8 months. Secondary analyses to assess changes in secondary endpoints will be performed using evaluated using linear mixed models.
Methods for accounting for missing, unused, or invalid data
Patients who withdraw consent or discontinue follow-up during the study are not replaced. Missing data will be systematically searched for and checked in the patients' medical records. Analyses may be performed after imputation of missing data. Missing data will be handled using multiple imputation as recommended by the National Research Council Panel on Handling Missing Data in Clinical Trials (40).
Selection of participants for analyses
The intention-to-treat population will include all patients who signed the informed consent form and were randomized to one of the two study arms and will be analyzed according to the initial randomization group. The per-protocol (PP) population will include patients enrolled in the study without major deviations from the current protocol, including erroneous inclusion of patients, changes or noncompliance with the treatment assigned at randomization. The primary endpoint will be analyzed by ITT and secondarily by PP analyses. PP analyses. Secondary endpoints will be analyzed according to ITT and PP principles to ensure robustness of results.
Data monitoring
Two committees work together to monitor the data and guide the research.
The Steering Committee meets quarterly. Its purpose is to define the general organization, determine the methodology, monitor the progress of the research, coordinate information, initially determine the methodology, validate the applications of persons recruited under the protocol, and define any relevant modifications to the protocol necessary for the continuation of the trial. At the end of the meeting, the sponsor will be informed of any decision that requires rapid action by the sponsor.
The Scientific Committee meets quarterly. Its purpose is to define the objectives of the protocol, to draft the protocol and to propose modifications during the research. Decisions taken at these meetings are validated after discussion and majority vote.
Audit
All data, documents and reports may be audited without invoking medical confidentiality. Audits can be carried out at any stage of the research process, by independent persons appointed by the sponsor. The aim is to guarantee the quality of the research, the validity of the results, and compliance with applicable laws and regulations.
ETHICS AND DISSEMINATION
Research ethics approval
This research is conducted in accordance with the World Medical Association's Declaration of Helsinki. The study was approved by the French ethic committee (Comité de Protection des Personnes Sud-Est VI) on 07/07/2023 (National ID 2022-A02797-36). Any substantial modification of the protocol by the coordinating investigator must be approved by the sponsor. Once approved, the sponsor must obtain a favorable opinion from the ethic committee before implementation.
Consent or assent
Patients in addictology DH receive initial information from a trained investigator. Informed consent is obtained by the principal investigator, an attending physician, or a qualified person, with a two- to four-week cooling-off period. The investigator documents participation in the patient's medical record, retains a copy of the consent form, and a tamper-proof envelope is archived by the sponsor at the end of the study. No exclusion period is defined at the end of participation. No anticipated harm or compensation to subjects is foreseen, as the research will be organized as part of their routine care. However, participants in the CBT group will be offered the opportunity to receive virtual reality exposure sessions as part of their routine care once participation in the study has ended.
Confidentiality and access to data
Quality control personnel ensure confidentiality, making data non-identifiable, using initials and a coded ID. The sponsor ensures that each participant has given written consent to access data. APHP Cleanweb® data will be stored on dedicated servers. Physical documents will be kept in a locked cabinet during the research, then archived in accordance with regulations. Documents specific to minimal-risk research will be archived by the investigator and sponsor for 15 years after the end of the research, including sealed envelopes, files, successive versions of the protocol, ethic committee opinions, correspondence, inclusion list, special appendices, final report, and documents relating to data collection. Study results will be communicated to investigators at all centers, to patients and to the scientific community in general. APHP is the owner of the data. Additionally, a contract has been established with the University of Nanterre. This agreement allows for further statistical analyses to be conducted in collaboration with the CLIPSYD laboratory from the Faculty of Psychology at the University of Nanterre, under the direction of Prof. Lucia Romo. For this purpose, pseudonymized research data will be securely transmitted to the team to facilitate these analyses. All data necessary to support the protocol can be provided upon request to APHP.