Withdrawal-Related Dysphoria as a Moderator of Ibudilast for Alcohol Use Disorder
Phase: PHASE2
Conditions: Alcohol Use Disorder
Sponsor: University of California, Los Angeles

IBUD Withdrawal Protocol 
Version 4, 05/10/18  
 
 
Withdrawal-Related Dysphoria as a Moderator of Ibudilast for 
Alcohol Use Disorder 
NCT #: NCT03489850 
Protocol version 4 
May 10, 2018 
 
 

IBUD Withdrawal Protocol 
Version 4, 05/10/18  
Ibudilast Withdrawal Protocol 
Study Design 
 
Specific Aims 
 
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. It is still unknown how neuroimmune modulation impacts brain processes that 
underlie alcohol reward processing. 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, DDA assessment, and fMRI. 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. 
 
Participants 
Participants (N = 50) will be men and women ages 21 to 45 recruited in Los Angeles. Participants will be 
screened for inclusion and exclusion criteria by online and telephone screens which will also assess for 
withdrawal-related dysphoria. Eligible participants will then complete an in-person behavioral screen 
where they will complete self-report assessments of demographics, psychological state/history, and 
alcohol and drug use. A Masters level clinician will complete a structured diagnostic interview (SCID) and 
assess for physiological withdrawal (CIWA).  
 
Inclusion Criteria 
(1) Age between 21 and 45  

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(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. 
 
Stratification 
To test the role of withdrawal-related dysphoria, participants will be balanced on their yes/no response 
to the item “I drink because when I stop, I feel bad (I am nervous, irritable, and I sleep poorly)" taken 
from the Reasons for Heavy Drinking Questionnaire (RHDQ). 
 
Medication Administration 
Study medication and matched placebo will be provided by Medicinova Inc. and dispensed by the UCLA 
Health Pharmacy Investigational Drug Section who will also maintain the blind. After establishing 
eligibility, participants will be provided with their first medication dosage in a blister-pack. IBUD will be 
provided in 10 mg capsules and participants will be titrated as follows: 20 mg BID during days 1-2, 50 mg 
BID during days 3-14, or matched placebo. All capsules will contain a riboflavin (50 mg) tracer to verify 
compliance. EMA assessment will begin on Medication Day 1 and will continue through Day 15 (one day 
post medication termination). 
 
Measures 
Behavioral Screen Measures 
1. Breathalyzer 
2. Urine toxicology screen and pregnancy test (if female) 
3. The Structured Clinical Interview for DSM-5 (SCID)  
4. Drink Years Assessment (DYA) 
5. The Clinical Institute Withdrawal Assessment for Alcohol Scale – Revised (CIWA-Ar).   

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6. A 30-day alcohol, cigarette, and marijuana timeline follow-back (TLFB)  
7. Reasons for Heavy Drinking Questionnaire (RHDQ)  
8. Reward-Relief Drinking Scale (RRDS) 
9. The Alcohol Dependency Scale (ADS) 
10. The Alcohol Use Disorders Identification Test (AUDIT) 
11. Family Tree Questionnaire (FTQ) 
12. Fagerstrom Test for Nicotine Dependence (FTND) 
13. Beck Depression Inventory-II (BDI-II) 
14. Pain Catastrophizing Scale (PCS) 
15. Graded Chronic Pain Scale (GCPS) 
16. RTC Ladder 
17. Snaith-Hamilton Pleasure Scale (SHAPS) 
18. Penn Alcohol Craving Scale (PACS) 
19. Obsessive Compulsive Drinking Scale (OCDS) 
20. Concomitant Medications Assessment 
21. Center for Cognitive Neuroscience MRI Safety Screening Form 
 
Physical Exam Measures 
1. Breathalyzer 
2. Urine toxicology screen and pregnancy test (if female) 
3. The Clinical Institute Withdrawal Assessment for Alcohol Scale – Revised (CIWA-Ar).   
4. Timeline follow-back (TLFB) 
5. Concomitant Medications Assessment  
 
Baseline Visit Measures 
1. Breathalyzer 
2. Urine toxicology screen and pregnancy test (if female) 
3. The Clinical Institute Withdrawal Assessment for Alcohol Scale – Revised (CIWA-Ar).   
4. Timeline follow-back (TLFB)  
5. Beck Depression Inventory-II (BDI-II) 
6. Graded Chronic Pain Scale (GCPS) 
7. Snaith-Hamilton Pleasure Scale (SHAPS) 
8. Penn Alcohol Craving Scale (PACS) 
9. Obsessive Compulsive Drinking Scale (OCDS) 
10. Side Effects Checklist (SAFTEE) 
11. Open Ended Side Effects Interview 
12. Concomitant Medications Assessment 
 
Midpoint Measures 
1. Breathalyzer 
2. Urine toxicology screen and pregnancy test (if female) 
3. The Clinical Institute Withdrawal Assessment for Alcohol Scale – Revised (CIWA-Ar).   
4. Timeline follow-back (TLFB)  
5. Beck Depression Inventory-II (BDI-II) 

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6. Graded Chronic Pain Scale (GCPS) 
7. Snaith-Hamilton Pleasure Scale (SHAPS) 
8. Penn Alcohol Craving Scale (PACS) 
9. Obsessive Compulsive Drinking Scale (OCDS) 
10. Side Effects Checklist (SAFTEE) 
11. Open Ended Side Effects Interview 
12. Concomitant Medications Assessment 
13. Center for Cognitive Neuroscience MRI Safety Screening Form 
 
Midpoint Functional Brain Imaging 
After the midpoint measures (above) are collected, participants will complete a brain functional 
magnetic resonance imaging (fMRI) scan. The scanning will be performed at the Brain Mapping Center 
or at the Center for Cognitive Neuroscience, both located on the UCLA campus. They will be asked to lie 
down on a padded table, with their head placed in the center of a large, metal doughnut-shaped 
magnet.  While the machine is running, the participant will hear loud banging noises and will be offered 
earplugs to reduce the noise made by the magnet.  Head and back support will also be provided to 
minimize discomfort.   
 
Participants will be asked to have a normal night’s sleep the night before the scan, have no more than 
one alcoholic drink, and abstain from drinking coffee within 2 hours prior to the scan. Breath alcohol 
concentration must be zero and for female participants the pregnancy test must be negative 
immediately prior to the scanning session. Prior to scanning, subjects will practice the task in front of a 
computer monitor with headphones and a button response box using the same stimulus delivery 
software as for fMRI scanning. The subjects will practice until it can be ascertained that they understand 
the task. 
 
During the imaging session we will utilize several structural and functional scans. The structural protocol 
will consist of a high-resolution, matched-bandwidth (MBW) scan and a structural magnetization-
prepared rapid-acquisition gradient echo (MPRAGE) scan. The functional scan will include a fMRI 
alcohol-cue reactivity paradigm previously reported to elicit blood oxygen level dependent (BOLD) 
response in mesocorticolimbic regions (Schacht et al., 2011).  
 
The visual alcohol cue reactivity paradigm is a well-validated, with strong reliability and within-
participant stability (1). The alcohol cues task consists of viewing alcohol and neutral cues, developed 
based on work by Schacht and colleagues (2011). There are five types of visual cues: alcoholic 
beverages, non-alcoholic (neutral) beverages, blurred alcoholic beverages, blurred non-alcoholic 
beverages, and a fixation cross. Stimuli are presented in six 120-s epochs (total scan duration: 12 
minutes), with each epoch consisting of four 24-s blocks (one block of alcohol cues, one block of neutral 
cues, one block of blurred images, and one block of fixation). During each 24-s block, 5 individual 
pictures will be displayed for ~4.8 seconds each. Alcohol blocks will be specific to beverage type (beer, 
wine, or liquor), with two blocks of each beverage type. Each block will be followed by a 6-s washout 
period, which allows the hemodynamic response from the previous block to decline.  

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Prior to scanning, participants will be shown how to provide ratings of their cravings using an optically 
isolated universal serial bus (USB) interface, which consists of a four-button (1= low to 4= high) response 
box. Subjects will provide ratings of their craving immediately following each cue block. 
 
Example Epoch of Alcohol Cue Reactivity Paradigm 
 
Final Measures 
1. Breathalyzer 
2. Urine toxicology screen, ETG test, and pregnancy test (if female) 
3. The Clinical Institute Withdrawal Assessment for Alcohol Scale – Revised (CIWA-Ar).   
4. Timeline follow-back (TLFB)  
5. Beck Depression Inventory-II (BDI-II) 
6. Graded Chronic Pain Scale (GCPS) 
7. Snaith-Hamilton Pleasure Scale (SHAPS) 
8. Penn Alcohol Craving Scale (PACS) 
9. Obsessive Compulsive Drinking Scale (OCDS) 
10. Side Effects Checklist (SAFTEE) 
11. Open Ended Side Effects Interview 
12. Concomitant Medications Assessment 
 
DDA Measures  
• 
See attached IBUD DDA Codebook 
 
 
 
 
 

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Study Design and Flow Chart