In an initial safety and efficacy trial, ibudilast improved mood resilience following stress exposure and reduced tonic levels of craving . Mood resilience was defined as a faster recovery of positive mood to baseline levels in the treatment condition following exposure to a stressful personal narrative. However, as noted above, ibudilast did not robustly alter subjective response during an alcohol administration paradigm. Yet, this study had a relatively small sample size , and findings could not be extended to subjective effects of alcohol in real-world settings, as participants were required to maintain abstinence during the trial for safety reasons. Extending medications development to naturalistic settings, particularly for novel pharmacotherapies like ibudilast, is needed, as it enables researchers to assess medication effects with far greater ecological validity and to examine dynamic within-person processes through repeated assessments. Electronic real-world data capture is a cost-effective way to collect numerous occasions of alcohol self administration and related subjective effects in participants’ natural environment . As such, work testing ibudilast’s ability to modulate subjective response in naturalistic drinking settings has the potential to further our understanding of its bio-behavioral mechanisms, particularly in the context of powerful natural reinforcers and cues. For this reason, the present study will extend findings published from a two-week clinical trial of ibudilast in our laboratory, which utilized daily diary methods . DDAs of subjective alcohol response were collected during this trial to identify bio-behavioral mechanisms of ibudilast,mobile vertical rack but had yet to be analyzed. The present study sought to test the effect of neuroimmune modulation by ibudilast on subjective response to alcohol in the naturalistic environment.
This secondary analysis leveraged DDAs from a two-week experimental medication RCT of ibudilast, stratified on sex and withdrawal-related dysphoria, that enrolled non-treatment seeking participants with AUD. The DDAs included reports of alcohol use and subjective response measures of stimulation, sedation, mood, and craving. Each morning, participants retrospectively reported on their mood and craving levels both before and during the previous day’s drinking episodes, as well as stimulation and sedation levels during the previous day’s drinking episodes. We hypothesized that ibudilast would significantly reduce average levels of alcohol-related stimulation and increase average levels of alcohol-related sedation compared with placebo during participant naturalistic drinking episodes. Second, we hypothesized that ibudilast would significantly attenuate daily alcohol-induced changes in craving and mood compared with placebo. Two sets of exploratory analyses were also undertaken in which we tested if ibudilast moderated the effect of alcohol-related stimulation and sedation on same-day number of drinks consumed and if the presence of withdrawal-related dysphoria moderated ibudilast’s effects on daily alcohol-induced changes in mood and craving.The current study is a secondary analysis of data collected during a two-week clinical trial of ibudilast for heavy drinking reduction and negative mood improvement in a sample of non-treatment seeking individuals with AUD .Fifty-two eligible participants were randomized to either ibudilast or matched placebo. Randomized participants were asked to attend in-person study visits on Day 1 , Day 8 , and Day 15 , and complete electronic DDAs to report on previous day craving, mood, and alcohol and cigarette use. When participants endorsed previous day alcohol consumption, they also reported on levels of stimulation and sedation. Participants completed a neuroimaging scan at study midpoint.
The clinical trial was approved by the University of California, Los Angeles Institutional Review Board [UCLA IRB#17–001741]. Prior to completing study procedures, all participants provided written informed consent after receiving a full study explanation. A community-based sample of individuals with current DSM-5 AUD was recruited for the trial through social media and mass transit advertisements in the greater Los Angeles area. Study inclusion criteria were: between 21 and 50 years of age; meet current DSM-5 diagnostic criteria for mild-to-severe AUD ; and report heavy drinking levels 30 days prior to their screening visit, as defined by the National Institute on Alcohol Abuse and Alcoholism as >14 drinks per week for men and >7 drinks per week for women. Exclusion criteria were: currently receiving or seeking treatment for AUD; current DSM-5 diagnosis of another substance use disorder ; lifetime DSM-5 diagnosis of bipolar disorder or any psychotic disorder; current use of psychoactive drugs, other than cannabis, as verified by a urine toxicology screen; if female: pregnancy, nursing, or decision to not use a reliable method of birth control; presence of non-removable ferromagnetic objects, claustrophobia, serious head injury, or prolonged period of unconsciousness ; medical condition that could interfere with safe study participation; and recent use of medications contraindicated with ibudilast treatment . Participants were also required to have reliable internet access to complete electronic DDAs. A total of 190 individuals consented to participate in the initial in-person screening visit. Of those, 81 individuals were deemed clinically eligible and were invited to complete a physical screening to determine medical eligibility. A total of 52 participants were randomized to study medication or placebo . Included in the present analyses are 50 participants who completed at least one daily diary report after randomization. Participants were compensated up to $250 for their participation in the study and received an additional $100 bonus if all study visits and ≥80% of DDAs were completed. The clinical trial was conducted at an outpatient research clinic in an academic medical center. Interested individuals completed an initial telephone-screening interview and eligible callers were then invited to the laboratory for an in-person behavioral screening visit.
At the start of all in-person visits, participants were required to have a BrAC of 0.00g/dl and a urine toxicology test negative for all drugs excluding cannabis. Eligible participants were asked to complete an in-person physical screening visit consisting of laboratory tests and physical exam by a study physician. Participants meeting all study eligibility criteria who attended the in-person randomization visit were randomly assigned to receive either 50 mg BID of ibudilast or matched placebo. Randomization was stratified by sex and participant report of experiences with withdrawal-related dysphoria. This a-priori stratification variable was intended to capture the “dark side of addiction” , whereby individuals reporting withdrawal-related dysphoria were estimated to experience greater dysfunction of the immune system. MediciNova, Inc. supplied ibudilast and placebo for the trial but did not provide any financial support for the study. The UCLA Research pharmacy prepared and dispensed all study medication in blister packs. Research staff, participants,vertical grow rack and providers remained blind to medication condition during the trial. Participants were titrated on ibudilast as follows: 20 mg BID during days 1–2 and 50 mg BID during days 3–14. Target medication dose was selected based on safety considerations as well as preclinical and clinical data . Medication compliance was monitored through pill counts and self-report via DDA. Side effects were closely monitored and reviewed by study physicians. During the in-person screening visit, participants completed a set of assessments for individual differences and eligibility screening. Assessments included collection of demographic information , substance use characteristics and history, and psychological functioning and diagnoses. Surveys used to characterize the sample included the Beck Depression Inventory to assess levels of depression symptomatology, the Snaith-Hamilton Pleasure Scale to measure anhedonia , the Alcohol Use Disorders Identification Test to capture alcohol problem severity, Penn Alcohol Craving Scale to measure tonic craving levels, and the Reasons for Heavy Drinking Questionnaire to capture one’s motivations for heavy drinking. In addition, the RHDQ determined the presence of withdrawal-related dysphoria for randomization stratification as follows: raw scores ranging from 0 – 10 on the RHDQ question #6: “I drink because when I stop, I feel bad ”, were dichotomized into yes /no, based on a cut-off of 6+ points. Interviews used to determine eligibility criteria and determine baseline quantity and frequency of alcohol use were administered by clinical graduate students or trained research staff and included the Timeline Follow Back measuring alcohol, cigarette, and cannabis use over the previous 30 days , the Clinical Institute Withdrawal Assessment for Alcohol Scale – Revised assessing clinically significant alcohol withdrawal, and the Structured Clinical Interview for DSM-5 to determine current AUD diagnosis and severity and to screen for exclusionary psychiatric diagnoses.Each morning throughout the two-week trial, participants were asked to retrospectively report on their previous day experiences by completing an electronic DDA survey . Study staff provided instructions on DDA completion and participants practiced filling out the survey at their randomization visit. Daily text messages or emails containing links to DDAs were sent to participants at 8am each morning during their 14-day medication period. Additional telephone or text reminders were sent by study staff as needed.
At the start of each daily survey, participants were asked, “Did you drink any alcohol yesterday?” If participants endorsed alcohol use the previous day, they reported on drink type and quantity, and then completed two sets of items: 1) ratings of mood, craving, and urge before drinking, and 2) ratings of mood, craving, urge, stimulation, and sedation while drinking. For example, participants were asked: “Before you drank, how strong was your urge to drink alcohol yesterday?” and “While drinking, how strong was your urge to drink alcohol yesterday?” The current analyses focus primarily on drinking days, given our interest in medication-related changes in subjective response to alcohol. Mood states were assessed via the short form of the Profile of Mood States survey . POMS-SF is a standard, validated psychological rating scale that measures dimensions of transient mood states by asking subjects to indicate how well each item describes their mood on a 5-point Likert scale . To keep the survey brief and thus reduce the burden on participants, only select items from POMS-SF were chosen for DDAs . Reports of stimulation and sedation were assessed via the validated Brief Biphasic Alcohol Effects Scale . The B-BAES is a six-item measure on the acute stimulant and sedative effects of alcohol on an 11-point scale . Urge to drink was captured via the item, “How strong was your urge to drink alcohol yesterday” , in line with previously published reports . Phasic craving was assessed using the first and last items from the validated Alcohol Urge Questionnaire on a 7-point Likert scale . Participants reported the quantity of standard alcoholic drinks consumed according to established guidelines and provided details about non-standard drinks . Drink entries were reviewed and verified by study staff.DDA Item Scoring—All descriptive and statistical analyses were completed in SAS Version 9.4 on the sample of participants who completed at least one DDA. Select items from the POMS-SF tension and depression sub-scales , were summed to form a negative mood state score and select items from the vigor sub-scale were summed to form a positive mood state score for each time point, consistent with previous reports . The two AUQ items were summed to form a craving score . Stimulation and sedation sub-scales from B-BAES were calculated using standard methods . Multilevel Models—Models were fit in SAS using the MIXED procedure and a multilevel framework, unstructured covariance matrix, residual maximum likelihood estimation, and random intercepts with observations nested within subjects to account for clustering and to preserve suitable Type-1 error rates . Kenward-Rogers degrees of freedom were chosen to reduce bias and obtain more accurate p-value estimates. Main and simple effects were probed by recentering dichotomous variables and using the simple slopes approach. Daily alcohol use quantity, mood states, craving, and urge data from non-drinking days were treated as missing. Comparable three-level models were fit for variables having both before and during drinking observations , such that these observations were nested within day and days were nested within subjects. All models were tested with the following level-2 covariates: sex, AUD severity , and baseline drinks per drinking day . In addition, daily number of drinks consumed during the trial was included as a predictor with random effect in all subjective response models to account and control for potential day-level drink quantity effects on subjective response. To examine both between- and within-subject effects and interactions, covariates were centered at the grand mean and focal within-subject variables were centered within cluster . Specifically, to assess the effect of medication on the acute stimulant and sedative effects of alcohol, one model for each B-BAES sub-scale was estimated in which stimulation or sedation served as the outcome and medication condition served as the focal predictor.