An independent Data and Safety Monitoring Board of external advisors will also meet prior to the start of the study, annually during enrolment and follow-up and at trial end to review safety data. The risk of breach of confidentiality will be handled by emphasizing that information obtained during assessments and laboratory sessions is confidential and will be used solely for research purposes. All records will be kept in a locked file cabinet and will be available to research personnel who have been trained in human subjects’ protection guidelines.In addition, all data will contain only a numeric code, all assessment procedures will be closely supervised by the faculty sponsor, and staff will be trained and reminded of the need to keep all information confidential. No names will be used in presenting data in lectures, seminars, and papers. Individual study participants will not be identified in any way in any presentation or publication of the study results and analysis of the results will be based on aggregate data only. Medical information will be released only with the expressed written consent of the subject. Lastly, the PI has obtained a Certificate of Confidentiality in order to further protect participant confidentiality during the study.As outlined in exploratory aim 2, serum samples will be collected from all participants at randomization and at 4, 8, and 12-week follow-ups. Two lavender EDTA tubes will be collected for plasma to identify markers including innate immune receptors , cytokines , chemokines ,rolling flood tables and other inflammatory signaling molecules. In addition, one RNA PAXgene tube will be collected at randomization and week 12 to identify transcription factors that code for cytokines.

As outlined in exploratory aim 4, salivary cortisol samples will be collected from participants who choose to participate in the neuroimaging session at 3 points during the week 4 neuroimaging visit: at the beginning of the visit and immediately before and after the fMRI session. Saliva will be collected via Salivette swab. Biological samples will be stored in freezers. Serum samples will be assayed by a laboratory technician with extensive expertise processing biological samples for analyses of inflammatory markers. Salivary cortisol samples will be shipped to an outside lab for processing.Data analysis will utilize an intention-to-treat population that includes all randomized patients who took at least one dose of medication and provided valid post-randomization outcome data. The primary tests of hypotheses will use percent heavy drinking days measured by the TLFB at weeks 2, 4, 6, 8, 10, and 12 as a priori primary efficacy endpoint. Other outcomes will also be analyzed as described in the secondary and exploratory aims. Prior to statistical analyses, the data will be inspected to determine the advisability of scale transformations and to identify missing data, outliers, or other unusual features that may be influential. Preliminary analyses will also be performed to compare treatment groups on descriptive and clinical characteristics at baseline to ensure that randomization has succeeded. If confounding variables are found, they will be included as covariates in follow-up analyses.The a priori primary efficacy endpoint will be percent heavy drinking days, defined as 4+ drinks for women/5+ drinks for men, measured bi-weekly during the maintenance phase of the study. Patients who discontinued medication will be allowed to remain in the study and participate in study assessments.

The primary efficacy analysis will be performed using a repeated measures mixed effects model that includes treatment, time, treatment × time interaction, a random intercept and a random slope, and adjusts for other covariates such as demographic and baseline variables as appropriate. The mixed effects model approach permits testing of between group differences, within-group changes, and performance trends over time. It also uses all observed repeated measurements data, treating the missing data mechanism as ignorable. In addition to testing the treatment effects, a summary of least-square means, standard errors, and 95% confidence intervals will be presented for each treatment and will be derived from fully adjusted models on untransformed outcomes averaged across the maintenance period.In this aim, we plan on traditional analyses of the effects during the maintenance phase of the study on the following secondary alcohol consumption endpoints: drinks per day, drinks per drinking day, percent days abstinent, percent subjects with no heavy drinking days , and percent subjects abstinent. The analytical plan for the secondary outcomes with repeated measures are similar to that for the primary efficacy endpoint as discussed above for aim 1. For the dichotomous outcomes , logistic regression models will be used. Further, in light of recent research on AUD endpoints, we will examine secondary outcomes when allowing an optimal grace period of first 4 weeks and will evaluate the efficacy of IBUD over the maintenance period.Explanatory variables for the alcohol cues task will be created by convolving delta functions representing the onset of experimental events with a doublegamma hemodynamic response function in FEAT. Temporal derivatives will be included as covariates. Second-level group analyses will then be conducted. The main contrast of interest will be activation during alcohol vs. non-alcoholic beverage blocks. Explanatory variables for the MIST will be created by convolving delta functions representing the onset of experimental conditions with a double-gamma hemodynamic response function in FEAT. Temporal derivatives will be included as covariates.

Second-level analyses averaging over the three task runs will be conducted on the contrast images transformed into standard space. Third-level group analyses will then be conducted on the second-level images. The main contrast of interest will be activation during the stress vs. control blocks. For both tasks, Z-statistic images will be thresholded with cluster-based corrections for multiple comparisons based on the theory of Gaussian Random Fields with a cluster-forming threshold of Z > 2.3 and a cluster-probability threshold of p < 0.05.We will examine if the effects of IBUD on the efficacy outcomes are moderated by depressive symptomatology. A moderator identifies for whom or under what conditions a treatment works. It may suggest which participants will respond most to treatment or identify subgroups with possibly different causal pathways. We will study moderators based upon criteria given in Kraemer et al.. For the repeated measured efficacy outcomes, we will include depressive symptomatology in the analyses, using the mixed effects analysis designs described above,flood and drain tray and testing the interactions of × treatment as well as × treatment × time. For the dichotomous outcomes , we will include depressive symptomatology in the logistic regression analyses and test the interactions of depressive symptomatology × treatment. To reduce confounding of main effects with these interaction terms and increase the interpretability of the regression coefficients, the variables will be centered as recommended by Kraemer and Blasey. If interactions are significant, we will estimate treatment effects at low, middle, and high values of the moderator. Further, we will test whether physiological dependence serves as a moderator of medication effects in this trial.An annual summary of adverse events will be submitted to the FDA, the IRB, the DSMB, and NIAAA. The analysis of all adverse events accumulated-to-date will include a listing of all adverse events. Participants’ descriptions of adverse events from AE Forms will be grouped in some reasonable way, counted, and compared by treatment groups. A designation of “more common and drug-related” will be given to events occurring at an incidence of least 5% in subjects assigned to active drug, and for which the active drug incidence is at least twice the placebo incidence. Other significant adverse events that will be reported include the following: marked abnormalities in laboratory, vital signs, electrocardiograms or other parameters, and adverse dropouts and adverse events that lead to dose adjustments or to the addition of concomitant therapy. The study physician will be available to participants for the entire duration of the study. Participants will have access to her 24-h pager and will report on adverse events at each monthly visit. The study physician will call every participant at the end of the first week on the study medication to discuss and manage any adverse events. Study staff will notify the study physician of any adverse events recorded during the follow-up visits. Side effects will be collected through an open-ended question asking participants to report of any adverse events they may be experiencing and a questionnaire-based assessment, the Systematic Assessment for Treatment Emergent Events, which will be administered at the 4, 8, and 12-week follow-up visits.

To continuously monitor safety, clinical labs will be repeated at each in-person follow-up visit and abnormal results will be discussed with the study physician.The PI will designate appropriately qualified personnel to periodically perform quality assurance checks at mutually convenient times during and after the study. These monitoring visits provide the opportunity to evaluate the progress of the study and obtain information about potential problems. The monitor will assure that data are accurate and in agreement with any paper source documentation used, verify that subjects’ consent for study participation has been properly obtained and documented, confirm that research subjects entered into the study meet inclusion and exclusion criteria, verify that study procedures are being conducted according to the protocol guidelines, monitor review AEs and SAEs, perform drug accountability, and assure that all essential documentation required by Good Clinical Practices guidelines are appropriately filed. At the end of the study, they will confirm that the site has the appropriate essential documents on file, advise on storage of study records, and inspect the return and destruction records for unused study medication. An independent Data and Safety Monitoring Board of external advisors will meet prior to the start of the study, bi-annually during enrollment and follow-up and at trial end to review safety data. In addition to bi-annual meetings, the DSMB will meet after half the subjects have been randomized to review safety data and the integrity of the study and make a formal recommendation to the PI on the continuation or early stopping of the study due to safety concerns. The DSMB will provide periodic review of the protocol, which is consistent with current practices at the UCLA CTRC, where this study will take place. The DSMB will provide comprehensive and regular input into whether there are appreciable changes to subjects’ risks to participation while the study is ongoing. The DSMB will monitor the following six aspects of study execution: Administrative/ Regulatory Updates, Study Updates, Quality Assurance and Safety Monitoring Procedures, Study Accrual, Protocol Violations/Deviations, and Safety and Outcomes. After reviewing all these elements of the study, the DSMB will provide recommendations regarding safety/ethical concerns, study continuation, and protocol modifications. In addition, the DSMB will assist the PI and Study Physician to evaluate whether an active subject should be discontinued from further participation in the study for safety reasons.The PI will promptly inform the NIAAA Program Officer of any changes in recruitment or in the protocol that are relevant to safety, as well as any actions taken by the IRB as a result of its continuing review of the study. All necessary protocol changes will be submitted in writing as protocol amendments to the IRB by the PI for approval prior to implementation. In the event of any major changes in the status of any ongoing protocol, the PI will inform the NIAAA Program Officer, DSMB, IRB, CTRC, etc., immediately. Such changes would include amendments to the protocol, temporary suspension of patient accrual or of the protocol, any changes in informed consent or IRB approval status, and termination of patient accrual or of the protocol.IBUD is a promising treatment for AUD as a neuroimmune modulator that has shown robust safety and early efficacy. In a preliminary study conducted by our lab , IBUD was generally safe and well-tolerated, with no study dropouts or dose reductions over the course of the protocol, in a population with mild-to-severe AUD. The current study is supported by these early clinical results, as well as by compelling preclinical data validating its molecular targets and effects on alcohol phenotypes in animal models. To the best of our knowledge, from a search of ClinicalTrials.gov as of May 16, 2020, at present the only registered trials of ibudilast for the treatment of alcohol use disorder have come from our lab, and the current study is the only interventional large-scale randomized clinical trial, testing IBUD in 132 treatment-seeking participants with AUD. This single-center trial is double-blinded vs placebo, with 1:1 randomization.