Medication will be stopped based on pre-specified criteria for discontinuation of study medication: development of agitation, hostility, depressed mood, or changes in behavior or thinking not typical of alcohol use or withdrawal severe nausea and vomiting; have a systolic blood pressure greater than 160, or a diastolic blood pressure greater than 100 , or a heart rate greater than 70% of the maximum heart rate expected for their age [0.70]; females who become pregnant; > 50% increase in AST/ALT at any of the LFT assessments ; and any circumstances that, in the opinion of the investigators, compromise participant safety. Four weeks after medication is terminated a follow-up safety visit will be conducted and will consist of clinical labs and ECG, which will be reviewed by the study physician.To assist with adherence to intervention protocols, participants receive a detailed medication log that lists the date, study day blister pack number, and AM/PM tablet number for everyday of the study in order for the participant to keep track of medication consumption. In addition, participants are provided a document with tips on how to remember to take medication twice a day. Compliance will be monitored by the study staff using the pill count method at each follow-up visit. Finally, participants will work with the same research staff member throughout the trial and will complete regular check-ins with that staff member.In the event that significant medical problems are encountered, the blind will be broken and appropriate medical treatment will be provided. Significant medical problems are defined as any of the following severe adverse events defined per the US FDA as any fatal event, any immediately life-threatening event, any permanent or substantially disabling event, any event that requires or prolongs inpatient hospitalization,cannabis grow set up or any congenital anomaly, or any unexpected adverse drug experiences that have not previously been observed.
In addition, any other important medical event that a study investigator judges to be severe because it may jeopardize the subject’s health in some manner or require intervention to prevent one of the above outcomes, or which would suggest a significant hazard, contraindication, side effect, or precaution. The PI will promptly report all severe adverse events or unexpected adverse drug experiences as required by the UCLA Institutional Review Board , the NIAAA Program Officer, the study’s DSMB, and the FDA. A decision to break the blind will be determined by the severity of the medical problem and its relevance to study medication.A battery of measures designed to provide a comprehensive assessment of medical safety, alcohol and cigarette use, other drug use, and psychological measures are included. In order to substantially decrease the task of managing the data stream, most self-reported study measures will be collected using Qualtrics. The following interviews and self-report measures will be administered during the initial screening visit for the purposes of assessing eligibility and measuring relevant individual differences: The 30-day timeline follow-back interview measures quantity and frequency of drinking; the Structured Clinical Interview for DSM-5 will be performed by a master’s level clinician using under the supervision of the PI. The SCID-5 will be used to assess current AUD diagnosis as well as exclusionary diagnoses ; Clinical Institute Withdrawal Assessment for Alcohol is a brief 10-item measure that assesses for the emergence of alcohol withdrawal symptoms. The CIWA-AR has been used both in clinical and research applications and has demonstrated both reliability and validity; the Columbia Suicide Severity Rating Scale, interview assess suicide ideation, intensity of ideation, and suicidal behavior.
C-SSRS is intended for use by trained administrators who have completed the required online training certification and who will be supervised by the PI; smoking is assessed by number of cigarettes per day/any form of tobacco and the Fagerstrom Test for Nicotine Dependence; Cannabis Use Disorder Identification Test to identify persons with hazardous and harmful patterns of cannabis consumption; the Graded Chronic Pain Scale , a 7- item measure used to evaluate an individual’s overall severity of chronic pain from pain that has lasted at least 6 months; the Profile of Mood States for measuring dimensions of mood; the Beck Anxiety Inventory a self-report assessment to measure anxiety and depression levels used widely in clinical trial; The Beck Depression Inventory, Revised captures depressive symptomatology ; the Adverse Childhood Experience Questionnaire , a 10-item self-report measure developed to identify childhood experiences of abuse and neglect; information on family history of alcohol problems will be collected using the Family Tree Questionnaire ; the Penn Alcohol Craving Scale will provide an assessment of tonic levels of craving for alcohol; the Alcohol Dependence Scale , a scale measuring alcohol dependence symptoms over the past 12 months; the Alcohol Purchase Task , a 16-item scale that uses hypothetical situations regarding alcohol purchases and consumptions at varying prices in order to generate several indices of alcohol-related reinforcement; the Alcohol Use Disorders Identification Test to identify persons with hazardous and harmful patterns of alcohol consumption; Readiness to Change ladder is a measure with 11 responses items to assessmotivation to reduce or cut back on drinking; the Reward-Relief Drinking Scale is a 4-item scale that measures an individual’s reward drinking tendencies; the Insomnia Severity Index measures sleep quality; and the ImBIBe is a 15-item questionnaire in which the subject responds on a 5-point scale responses to questions on the consequences of alcohol use. Breath alcohol concentration , urine drug screen, and pregnancy test will be administered at each study visit.
A BrAC = 0.00 g/dl will be required for participation in each study visit. Medical eligibility will be determined by the study physicians using the following assessments: review of participant’s medical history; laboratory tests , glucose, drug screen, chemistry screen, and pregnancy test); physical examination, including vital signs, weight, and review of systems; and electrocardiogram. For safety reasons,grow rack systems clinical lab tests will be repeated at weeks 4, 8, and 12. And the ECG will be repeated at week 12. Lastly, participants will return 1 month post medication discontinuation to repeat all clinical labs and ECG as a final safety check. Several individual differences measures obtained during the initial screening visit will be repeated during randomization visit as well as the monthly assessments to allow for analyses of change overtime and as a function of study medication. The TLFB interview will be conducted by telephone on weeks 2, 6, and 10 to complement the in-person assessments on weeks 4, 8, and 12 and to shorten the duration between drinking outcomes assessment. This will improve data quality and maintain contact with research participants on a more frequent basis in order to prevent dropout. In addition to the measures testing the study outcomes, measures of neuroinflammation and brain imaging will be collected. Serum samples will be collected at randomization and at 4, 8, and 12-week follow-ups to address exploratory aim 2. Due to the diurnal rhythm of cytokine production, samples will be collected at the same time of day for all subjects. Assayed markers will include innate immune receptors , cytokines , chemokines , and other inflammatory signaling molecules. The neuroimaging session, completed during the week 4 follow-up visit, includes 2 neuroimaging paradigms: the alcohol cues task and the Montreal Imaging Stress Task. The neuroimaging paradigms will be presented in counterbalanced order between participants.Neuroimaging will be conducted using a 3-T Siemens Prisma Fit MRI scanner at the UCLA Center for Cognitive Neuroscience. Scanning parameters for functional magnetic resonance imaging scanning will be as follows: TR, 2 s; TE, 30 ms; flip angle, 90°; FOV, 192 mm; matrix, 64 × 64; voxel size, 3 × 3 × 4mm3 ; slice thickness, 4 mm; and 34 slices. A T2-weighted, high resolution, matched bandwidth, anatomical scan , and a magnetization-prepared rapid-acquisition gradient echo will be acquired to enable registration. The orientation for MBW and functional scans will be oblique axial to maximize brain coverage. During data acquisition, head restraints will be placed using a foam pillow. The alcohol cues task is well-validated, with strong reliability and within-participant stability. There are four types of cues: alcoholic beverages, non-alcoholic beverages, blurred images, and a fixation cross. Stimuli are presented in six 120-s epochs , with each epoch consisting of four 24-s blocks. During each 24-s block, 5 individual pictures will be displayed for ~ 4.8 s each. Alcohol blocks will be specific to beverage type , with 2 blocks of each beverage type. Each block will be followed by a 6-s washout period.
The MIST is a block design fMRI paradigm in which participants solve mental arithmetic problems. There are three conditions: stress induction, control, and rest, which are presented pseudo-randomly. During the control and stress induction conditions, participants are asked to solve mental arithmetic problems of varying degrees of difficulty and are given feedback on their performance. During the stress induction condition, 2 performance indicators are displayed on a colored bar to induce social evaluative threat: the participant’s overall performance and the “average” performance of all participants. In the stress induction condition, the time limit, represented by a blue progress bar, is dynamically modulated to be 10% shorter than the participant’s average time required to complete previous trials. In the control condition, participants complete arithmetic problems of a comparable difficulty level without the time restriction or social evaluative performance displays. During the rest condition, the visual interface is displayed but no arithmetic problems are presented. The task is administered in three 5-min runs consisting of six 50-s blocks. After each run, participants are given scripted, negative feedback of their performance. After the task is complete, participants are debriefed and informed that the task was designed to increase their stress level. Participants who participate in the neuroimaging session will complete subjective and biological measures of stress response immediately prior to and following the fMRI paradigm as described in exploratory aim 4. The Subjective Distress Units Scale is a scale of 0 to 10 for measuring the subjective intensity of disturbance or distress currently experienced by an individual. The short-form Spielberger State-Trait Anxiety Inventory has 6 items assessing state anxiety. Salivary cortisol samples will be collected at 3 time points during the week 4 visit.Source documents include but are not limited to original documents, data, and records such as hospital/ medical records , clinic charts, laboratory results, data recorded in automated instruments, and pharmacy records, etc. This study will use an electronic data capture eCRF system and paper source documents. Data will be transcribed from source documentation directly into a statistical program such as SPSS and will be subsequently double checked by another member of the research staff. Only questionnaire data will be entered directly into eCRF. Paper copies of the eCRFs will be available in the event that the EDC is not accessible at the time the questionnaire is being completed. The transcribed data will be consistent with the source documents, or the discrepancies will be explained. All entries, corrections, and alterations will be made by the investigator or other authorized study personnel. Subjects will be identified on eCRFs and paper source documents by a unique subject number. The subject number will be used if it becomes necessary to identify data specific to a single subject. Regulatory bodies, such as the study sponsor, Food and Drug Administration , and Institutional Review Board , are eligible to review medical and research records related to this study as a part of their responsibility to protect human subjects in clinical research. Personal identifiers will be removed from photocopied or electronic medical and research records. To maintain subject confidentiality, research and clinical records will be stored in a locked cabinet. Only research staff, sponsor officials, and other required regulatory representatives will have access to the records. Subject information will not be released without written permission. The PI has received a Certificate of Confidentiality for this study. In order to ensure compliance with protocol and regulatory guidelines, the PI will review study documents to verify their accuracy, completeness, and timeliness of collection and will provide feedback to staff on findings and on how to correct any errors found during the review. The PI will also designate appropriately qualified personnel to periodically perform quality assurance checks during and after the study.