Alcohol Use Disorder
Conditions
Brief summary
Alcohol use disorder (AUD) is a prevalent and disabling psychiatric disorder with few, and only moderately efficacious, treatment options. Consequently, the identification of novel treatment targets and the development of rigorous laboratory paradigms to screen and optimize novel therapeutics represents a research priority. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor. Recently in an AUD sample, IBUD was shown to decrease reactivity to a psychological stressor. Furthermore, IBUD was effective in blunting alcohol reward among participants with greater depressive symptoms, a hallmark symptom of protracted withdrawal. Recently, preclinical research in opiates has demonstrated that drug withdrawal is necessary for microglia activation and neuroinflammation in reward networks, suggesting that IBUD may be most effective among patients who experience withdrawal-related dysphoria. Therefore, this proposed study aims to examine withdrawal-related dysphoria as a moderator of IBUD efficacy in the natural environment measured using Daily Diary Assessment (DDA) approaches. To accomplish this aim, participants meeting criteria for AUD and balanced on the presence of withdrawal-related dysphoria will be enrolled in a double-blinded IBUD trial including consisting of two weeks randomized to medication and DDA assessment. The proposed research aims are: Aim 1: Test whether IBUD reduces basal negative affect in abstinence, and blunts alcohol-related negative reinforcement. It is hypothesized that IBUD will reduce basal levels of negative affect during alcohol abstinence, and in so doing will interfere with alcohol-induced blunting of negative affectivity as captured during naturalistic drinking episodes. Aim 2: Test whether IBUD attenuates neural alcohol cue-reactivity. It is hypothesized that IBUD will reduce BOLD activation to alcohol cues in mesocorticolimbic reward circuitry. Aim 3: Test whether withdrawal-related dysphoria moderates the effects of IBUD. It is hypothesized that IBUD will alleviate basal negative affect, interfere with alcohol-induced negative reinforcement and attenuate BOLD activation to alcohol cues only among participants who experience dysphoria in withdrawal. Aim 4: Test whether neural activation to alcohol cues is predictive of drinking outcomes. It is hypothesized that individuals with higher mesocorticolimbic activation to alcohol cues will report more drinking in the week following the neuroimaging session.
Interventions
DRUGIbudilast
Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.
OTHERPlacebo
Placebo is matched to ibudilast active medication.
Sponsors
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Age between 21 and 45 2. Meet DSM-5 criteria for current Moderate-to-Severe AUD 3. Current Heavy Drinking (\> 14 drinks per week for men; \> 7 drinks per week for women), as indicated by self-reported drinking for the 30 days prior to screening 4. Have reliable internet access
Exclusion criteria
1. Currently receiving or seeking treatment for AUD\* 2. Past year DSM-5 diagnosis of any substance use disorder other than alcohol or nicotine 3. A lifetime diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder 4. Current use of drugs, other than marijuana, verified by a urine toxicology screen\* 5. Pregnant, nursing, or refusal to use reliable birth control (if female)\* 6. A medical condition that may interfere with safe participation (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension, diabetes, or AST, ALT, or GGT ≥ 3 times upper normal limit) 7. Self-reported recent (i.e. past 30 day) use of medications that are contraindicated with ibudilast\* 8. Non-removable ferromagnetic objects in body 9. Claustrophobia 10. Serious head injury or prolonged period of unconsciousness (\>30 minutes) * Participants who meet these criteria at any point during the course of the study (i.e. after randomization) will be withdrawn from the study for safety purposes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Negative Affect | Assessed through daily prompts throughout the 2-week study period. | Negative affect as measured by self-reported ratings of Downhearted, Discouraged, Uneasy, and Anxious. Each item was rated on a scale from 0 (not at all) to 4 (extremely). The 4 items were summed for the total negative affect score for each day, ranging from 0 - 16. Higher scores indicate more negative mood. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heavy Drinking | 14 days | Medication effects on number of heavy drinking days. Heavy drinking is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as ≥5 drinks/day for men and ≥4 drinks/day for women. Values indicate estimated probability of a heavy drinking day across time for each group. |
| Any Drinking | 14 days | Medication effects on number of days where any drinking was reported. . Values indicate estimated probability of a drinking day across time for each group. |
| Ventral Striatum Activation | Day 8 | Medication effect on alcohol cue-induced ventral striatal activation. Participants completed an fMRI alcohol cue-reactivity paradigm where they viewed pictures of alcoholic beverages, non-alcoholic beverages, blurred images, and a plus sign. The mean percent signal change between the ALC and BEV blocks was extracted from an a priori defined region of interest: bilateral ventral striatum (VS), 6 mm-radius sphere centered at ±12 6 9 in MNI space. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at an outpatient research clinic in a medical center. Participants were recruited through social media and mass transit advertisements. Initial screening was conducted through telephone interview, with eligible participants invited for an in-person assessment.
Participants by arm
| Arm | Count |
|---|---|
| Ibudilast 20mg BID Days 1-2 50mg BID Days 3-14
Ibudilast: Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor. | 24 |
| Placebo Matched to active
Placebo: Placebo is matched to ibudilast active medication. | 28 |
| Total | 52 |
Baseline characteristics
| Characteristic | Placebo | Ibudilast | Total |
|---|---|---|---|
| Age, Continuous | 31.07 years STANDARD_DEVIATION 7.81 | 34.46 years STANDARD_DEVIATION 9.24 | 32.63 years STANDARD_DEVIATION 8.58 |
| Alcohol Dependence Scale Total Score | 12.07 score on scale STANDARD_DEVIATION 7.01 | 13.00 score on scale STANDARD_DEVIATION 6.1 | 12.50 score on scale STANDARD_DEVIATION 6.56 |
| Alcohol Use Disorder Identification Test Total Score | 16.71 score on scale STANDARD_DEVIATION 6.42 | 16.38 score on scale STANDARD_DEVIATION 5.9 | 16.56 score on scale STANDARD_DEVIATION 6.12 |
| Alcohol Use Disorder Symptom Count | 4.86 symptoms STANDARD_DEVIATION 2.27 | 5.29 symptoms STANDARD_DEVIATION 2.37 | 5.06 symptoms STANDARD_DEVIATION 2.3 |
| Beck Depression Inventory-II Total Score | 8.64 score STANDARD_DEVIATION 7.2 | 12.42 score STANDARD_DEVIATION 8.47 | 10.38 score STANDARD_DEVIATION 8.27 |
| Cannabis Days | 8.15 number of days used in prior 30 days STANDARD_DEVIATION 8.24 | 11.38 number of days used in prior 30 days STANDARD_DEVIATION 9.99 | 9.64 number of days used in prior 30 days STANDARD_DEVIATION 9.14 |
| Cigarette Smokers | 14 Participants | 11 Participants | 25 Participants |
| Cigarettes Per Day | 5.06 cigarettes STANDARD_DEVIATION 6.76 | 7.39 cigarettes STANDARD_DEVIATION 8.7 | 6.14 cigarettes STANDARD_DEVIATION 7.73 |
| Drinking Days | 20.25 number of days in the prior 30 days STANDARD_DEVIATION 6.51 | 22.21 number of days in the prior 30 days STANDARD_DEVIATION 6.87 | 21.15 number of days in the prior 30 days STANDARD_DEVIATION 6.68 |
| Drinks Per Day | 3.81 average drinks over prior 30 days STANDARD_DEVIATION 3.62 | 4.10 average drinks over prior 30 days STANDARD_DEVIATION 2.15 | 3.94 average drinks over prior 30 days STANDARD_DEVIATION 3.01 |
| Drinks Per Drinking Day | 5.34 drinks STANDARD_DEVIATION 3.57 | 5.70 drinks STANDARD_DEVIATION 2.58 | 5.51 drinks STANDARD_DEVIATION 3.13 |
| Education | 15.21 years STANDARD_DEVIATION 1.75 | 15.25 years STANDARD_DEVIATION 2.64 | 15.23 years STANDARD_DEVIATION 2.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 19 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fagerstrom Test for Nicotine Dependence Score | 1.07 score on scale STANDARD_DEVIATION 1.54 | 2.82 score on scale STANDARD_DEVIATION 2.82 | 1.96 score on scale STANDARD_DEVIATION 2.27 |
| Heavy Drinking Days | 8.68 number of heavy drinking days STANDARD_DEVIATION 8.04 | 10.79 number of heavy drinking days STANDARD_DEVIATION 8.29 | 9.65 number of heavy drinking days STANDARD_DEVIATION 8.15 |
| Obsessive Compulsive Drinking Scale Total Score | 13.93 score STANDARD_DEVIATION 8.07 | 14.54 score STANDARD_DEVIATION 6.05 | 14.21 score STANDARD_DEVIATION 7.15 |
| Penn Alcohol Craving Scale Total Score | 12.11 score STANDARD_DEVIATION 7.04 | 12.79 score STANDARD_DEVIATION 5.14 | 12.43 score STANDARD_DEVIATION 6.18 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 12 Participants | 17 Participants | 29 Participants |
| Reasons for Heavy Drinking Questionnaire - Normalizing | 8.29 score STANDARD_DEVIATION 7.34 | 9.67 score STANDARD_DEVIATION 7.1 | 8.92 score STANDARD_DEVIATION 7.2 |
| Reasons for Heavy Drinking Questionnaire - Reinforcing | 22.82 score STANDARD_DEVIATION 4.88 | 23.29 score STANDARD_DEVIATION 3.51 | 23.04 score STANDARD_DEVIATION 4.27 |
| Region of Enrollment United States | 28 participants | 24 participants | 52 participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Male | 18 Participants | 16 Participants | 34 Participants |
| THC+ Urine | 8 Participants | 7 Participants | 15 Participants |
| Total Cigarettes | 133.07 number of cigarettes smoked prior 30 day STANDARD_DEVIATION 205.78 | 52.28 number of cigarettes smoked prior 30 day STANDARD_DEVIATION 79.85 | 102.44 number of cigarettes smoked prior 30 day STANDARD_DEVIATION 197.18 |
| Total Drinks | 114.9 drinks over prior 30 days STANDARD_DEVIATION 108.72 | 122.89 drinks over prior 30 days STANDARD_DEVIATION 64.58 | 118.20 drinks over prior 30 days STANDARD_DEVIATION 90.32 |
| Withdrawal Related Dysphoria | 11 Participants | 9 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 28 |
| other Total, other adverse events | 14 / 24 | 18 / 28 |
| serious Total, serious adverse events | 0 / 24 | 0 / 28 |
Outcome results
Primary
Negative Affect
Negative affect as measured by self-reported ratings of Downhearted, Discouraged, Uneasy, and Anxious. Each item was rated on a scale from 0 (not at all) to 4 (extremely). The 4 items were summed for the total negative affect score for each day, ranging from 0 - 16. Higher scores indicate more negative mood.
Time frame: Assessed through daily prompts throughout the 2-week study period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ibudilast | Negative Affect | 2.91 units | Standard Error 0.55 |
| Placebo | Negative Affect | 2.47 units | Standard Error 0.41 |
p-value: 0.6295% CI: [-1.01, 1.69]Generalized Estimating Equation
Secondary
Any Drinking
Medication effects on number of days where any drinking was reported. . Values indicate estimated probability of a drinking day across time for each group.
Time frame: 14 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibudilast | Any Drinking | 59.25 predicted probability in percent |
| Placebo | Any Drinking | 63.63 predicted probability in percent |
p-value: <0.0595% CI: [0.47, 1.48]Generalized Estimating Equation
Secondary
Heavy Drinking
Medication effects on number of heavy drinking days. Heavy drinking is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as ≥5 drinks/day for men and ≥4 drinks/day for women. Values indicate estimated probability of a heavy drinking day across time for each group.
Time frame: 14 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibudilast | Heavy Drinking | 24.16 predicted probability in percent |
| Placebo | Heavy Drinking | 36.80 predicted probability in percent |
p-value: <0.0595% CI: [0.3, 0.98]Generalized Estimating Equation
Secondary
Ventral Striatum Activation
Medication effect on alcohol cue-induced ventral striatal activation. Participants completed an fMRI alcohol cue-reactivity paradigm where they viewed pictures of alcoholic beverages, non-alcoholic beverages, blurred images, and a plus sign. The mean percent signal change between the ALC and BEV blocks was extracted from an a priori defined region of interest: bilateral ventral striatum (VS), 6 mm-radius sphere centered at ±12 6 9 in MNI space.
Time frame: Day 8
Population: Participants were excluded from neuroimaging analyses for the following reasons: participant missed mid-point study visit (n=1, placebo); participant could not be scanned due to COVID-19 safety restrictions (n=1, placebo); participant began scan but ended early due to claustrophobia (n=1, ibudilast); scanner issues prevented the collection of alcohol cue reactivity data (n=1, ibudilast); and participant was found to be not safe for MRI scanning on the day-of the study visit (n=1, ibudilast).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibudilast | Ventral Striatum Activation | -0.08 percent signal change | Standard Deviation 0.2 |
| Placebo | Ventral Striatum Activation | 0.14 percent signal change | Standard Deviation 0.32 |
p-value: <0.05ANCOVA