Conditions: Alcohol Use Disorder
Keywords: ibudilast, treatment, medication development
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 102
Healthy volunteers: no

Brief summary:
This study is a double-blind, placebo-controlled randomized clinical trial of Ibudilast (IBUD) (50mg twice a day) for the treatment of Alcohol Use Disorder (AUD). Eligible participants will undergo a 12-week medication treatment period and 5 in-person visits over 16 weeks.

Detailed description:
The study design consists of a 12-week, double-blind, placebo-controlled randomized clinical trial of IBUD (50mg twice a day) for the treatment of AUD. The investigators will randomize 132 treatment-seekers with current AUD over the course of 4 years. Participants will complete telephone screening, followed by in-person eligibility assessment, a physical exam for medical eligibility, randomization to study medication or matched placebo, and in-person follow-up visits at 4, 8, and 12 weeks of treatment. Timeline Followback (TLFB) assessment of drinking outcomes will also occur by telephone on weeks 2, 6, and 10. A final safety check visit will occur on week 16, consisting of repeated clinical labs and electrocardiography (ECG).

Arms:
arm 1: 10mg delayed-release capsules, target dose 50mg twice daily (5 x 10mg capsules twice daily) for 12 weeks arm 2: matched to experimental drug

Interventions: intervention 1: Ibudilast intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: targets neurotrophin signaling and neuroimmune function intervention 2: matched to active drug, ibudilast

Protocol document:
Prot_SAP_000.pdf: 
IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
1 
 
 
 
 
 
 
 
 
 
 
 
A RANDOMIZED CONTROLLED CLINICAL TRIAL OF THE NEUROIMMUNE MODULATOR 
IBUDILAST FOR THE TREATMENT OF ALCOHOL USE DISORDER 
 
STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
VERSION 10, MARCH 1, 2022 
 
NCT #03594435 
 
 
 
 
 
 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
2 
 
A RANDOMIZED CONTROLLED CLINICAL TRIAL OF THE NEUROIMMUNE MODULATOR 
IBUDILAST FOR THE TREATMENT OF ALCOHOL USE DISORDER 
 
STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
1. INTRODUCTION 
 
Alcohol use disorder (AUD) is a chronic and relapsing condition for which current 
pharmacological treatments are only modestly effective (1). The development of efficacious 
medications for AUD remains a high research priority with recent emphasis on identifying novel 
molecular targets for AUD treatment and to efficiently screen new compounds aimed at those 
targets (2, 3). To that end, modulation of neuroimmune function represents a promising novel 
target for AUD (4). Chronic alcohol consumption produces a sustained inflammatory state, such 
that individuals with AUD have increased neuroinflammation throughout the brain (5), and 
alcohol-induced neuroinflammation is thought to contribute to chronic alcohol seeking behavior 
and to the behavioral and neurotoxic effects of alcohol (6). In rodents, lipopolysaccharide-
induced neuroinflammation produces prolonged increases in alcohol consumption (7), and 
knocking out neuroimmune signaling genes attenuates alcohol preference and self-
administration (8). Therefore, a medication that reduces proinflammatory signaling may produce 
anti-alcohol and neuroprotective effects that may be beneficial for the treatment of AUD. 
 
Ibudilast (IBUD; aka, MN-166, previously AV411) has been advanced as a novel addiction 
pharmacotherapy that targets neurotrophin signaling and neuroimmune function. IBUD inhibits 
phosphodiesterases -4 (PDE4) and -10 (PDE10) and macrophage migration inhibitory factor 
(MMIF) (9). As PDE4 and MMIF are critically involved in proinflammatory signaling (10, 11), and 
PDE10 negatively regulates neurotrophin expression (12), the inhibition of these molecules by 
IBUD has been theorized to reduce neuroinflammation and promote neurotrophin expression 
(9). In support, IBUD enhances neurotrophin expression, reduces pro-inflammatory cytokine 
release, and attenuates neuronal death (13). In rodents, IBUD has been demonstrated to 
reduce ethanol intake by approximately 50% both under conditions of maintenance and relapse 
testing (14). These recent preclinical findings for IBUD support prior studies indicating 
pharmacological inhibition of PDE4 and PDE10 decreases alcohol intake (15-17).  
 
To advance medications development for AUD, our laboratory has recently completed a 
randomized, double-blind, placebo-controlled crossover laboratory study of IBUD in non-
treatment seeking individuals with AUD (R21 AA022214; NCT02025998) (18). This study tested 
the safety, tolerability, and initial human laboratory efficacy of IBUD (50mg BID) on measures of 
subjective response to alcohol, as well as cue- and stress-induced changes in craving and 
mood. Participants (N = 24) completed two separate 7-day intensive outpatient protocols which 
included daily visits for medication administration and testing. Upon reaching a stable target 
dose of IBUD (or matched placebo), participants completed a stress-exposure session, an 
alcohol cue-exposure session, and an IV alcohol administration session. Results indicated that 
IBUD was well tolerated and associated with mood improvements during stress- and alcohol-
cue exposures, and with reduction in tonic levels of alcohol craving. Exploratory analyses 
revealed that among individuals with higher depressive symptomatology, IBUD attenuated the 
stimulant and positive mood-altering effects of alcohol. 
 
Building upon the strong rationale and preclinical findings for IBUD, along with safety data and 
early efficacy in human testing conducted in our laboratory, this proposal seeks to advance 
medication development for AUD by conducting a 12-week, double-blind, placebo-controlled 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
3 
 
randomized clinical trial of IBUD (50mg BID). We propose to randomize 132 treatment-seeking 
men and women with current AUD (moderate or severe). To provide a standardized behavioral 
platform, all participants in the study will complete the NIAAA-developed web-based program 
Take Control during the study. 
 
2. BACKGROUND AND SIGNIFICANCE 
 
2.1. Better medications for alcoholism are needed and neuroimmune signaling 
represents a promising novel target. 
 
Pharmacotherapies for alcoholism are used less often than psychosocial interventions (19). The 
limited use of pharmacotherapy for alcoholism is due, in part, to the relative lack of 
pharmacological options to treat alcohol use disorders. The only pharmacotherapies currently 
approved by the Food and Drug Administration (FDA) for the treatment of AUD are disulfiram 
(Antabuse®), naltrexone, acamprosate, and Vivitrol, an injectable extended-release formulation 
of naltrexone. Given the dearth of available pharmacotherapies and their limited efficacy (20), 
medication development to treat AUD remains a top research priority (2). To that end, future 
directions in medication development emphasize the identification of new molecular targets and 
the development of novel compounds for these targets (2, 4). This is consistent with the 
phenotypic complexity of alcoholism, which calls for multiple targets that can effectively address 
multiple pathways of risk. The proposed study seeks to develop ibudilast (IBUD) for AUD, a 
novel compound that targets modulation of GDNF, PDE, and MIF. 
 
Neurotrophins, including glial (GDNF) and brain derived neurotrophic factor (BDNF), are 
essential for synaptic plasticity (21), neuron survival, and basic cell signaling, including midbrain 
dopamine transmission (22, 23). In rodent models of AUD, reductions in GDNF and BDNF 
expression underlie dysfunctional striatal dopamine signaling, increased motivation to consume 
alcohol, and heightened alcohol reward (24-27). Conversely, increases in GDNF and BDNF 
signaling restores mesolimbic dopamine function, reduces alcohol self-administration, and 
attenuates relapse to alcohol seeking (27-31). These results suggest that medications that 
increase GDNF and BDF expression may be useful treatments for AUD. 
 
Chronic alcohol consumption produces a sustained inflammatory state, and in turn, this alcohol-
induced neuroinflammation contributes to the behavioral and neurotoxic effects of alcohol (6). 
Individuals with AUD have increased neuroinflammation throughout the brain (5), and elevated 
peripheral levels of proinflammatory cytokines have been proposed as a biomarker for AUD 
(32). In rodents, neuroinflammation produces prolonged increases in alcohol consumption (7), 
and knocking out neuroimmune signaling genes attenuates alcohol preference and self-
administration (8). Proinflammatory signaling also mediates acute alcohol-induced motor 
impairment (33), and chronic alcohol exposure produces long-lasting neuroinflammation, which 
in turn is associated with sustained cognitive and behavioral impairment and brain damage (34). 
Finally, neuroinflammation is thought to increase vulnerability to stress-induced drug seeking 
and relapse (35). In sum, a medication that reduces proinflammatory signaling may produce 
anti-alcohol and neuroprotective effects that are beneficial for the treatment of AUD. 
 
2.2. Ibudilast is a neuroimmune modulator with robust safety data and early efficacy 
signal that warrants clinical investigation. 
 
Ibudilast (IBUD; aka, MN-166, previously AV411) has been advanced as a novel addiction 
pharmacotherapy that targets neurotrophin signaling and neuroimmune function. IBUD inhibits 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
4 
 
phosphodiesterases -4 (PDE4) and -10 (PDE10) and macrophage migration inhibitory factor 
(MMIF) (9). As PDE4 and MMIF are critically involved in proinflammatory signaling (10, 11), and 
PDE10 negatively regulates neurotrophin expression (12), the inhibition of these molecules by 
IBUD has been theorized to reduce neuroinflammation and promote neurotrophin expression 
(9). IBUD enhances neurotrophin expression, reduces pro-inflammatory cytokine release, and 
attenuates neuronal death (13). Most important to the present study, IBUD has been 
demonstrated to reduce ethanol intake by approximately 50% in selectively bred alcohol-
preferring (P) and high alcohol drinking (HAD1) rats both under conditions of maintenance and 
relapse testing (14). These recent preclinical findings for IBUD support prior studies suggesting 
that pharmacological inhibition of PDE4 and PDE10 is associated with decreases alcohol intake 
in rodents (15-17). These results suggest IBUD is a promising treatment for AUD, but the safety 
and efficacy of IBUD in combination with alcohol administration has only recently been studied 
in humans, as part of an NIAAA-supported R21 to test IBUD (50 mg BID) in the human 
laboratory. 
 
As shown in our preliminary studies section, results of the safety aim of our human laboratory 
trial suggested that IBUD (50 mg BID) was generally safe and well tolerated. Specifically, there 
were no study dropouts directly related to IBUD, as well as no dose reductions over the course 
of the protocol. Analyses of specific side effects revealed significant differences between IBUD 
and placebo for headaches and a trend-level effect for general gastrointestinal disorders. 
Furthermore, the co-administration of IBUD with alcohol (to a target Breath Alcohol 
Concentration or 0.08 g/dl) was not associated with significant changes in cardiovascular 
parameters, such as blood pressure and heart rate. A trend-level effect for nausea during 
alcohol administration suggested that IBUD may increase feelings of nausea at rising BrAC 
levels, compared to placebo. Together, these findings support the safety of IBUD, at the 50mg 
BID dose, in samples with mild-to-severe AUD. This is particularly noteworthy given that PDE-4 
inhibitors, such as rolipram, have yielded promising preclinical findings for AUD (36) while 
raising safety concerns during testing in humans. As reviewed elsewhere (37), PDE-4 inhibitors, 
including rolipram, are often associated with gastrointestinal distress, vertigo, nausea, and 
vomiting within their therapeutic window (38). These effects are believed to be due to increases 
in gastric acid secretion (39) as well as central effects in brain areas regulating emesis and the 
vestibular system (40). Although the effects of IBUD are not limited to PDE-4, and include 
inhibition of PDE-10 and macrophage migration inhibitory factor (13, 41-43), these results 
support the potential application of IBUD to AUD treatment in human clinical samples and are 
consistent with recent safety studies for opiate (44, 45) and methamphetamine (46, 47) use 
disorders.   
 
As recommended by Litten et al. (2, 3, 48), human laboratory models can be used to guide the 
identification of promising medications by collecting both safety and alcohol interaction data 
along with initial demonstration of medication effects on subjective responses to alcohol, cue-
reactivity, and alcohol self-administration. Such findings on safety and initial efficacy are vital to 
deciding whether to invest resources on efficacy testing for a novel AUD medication. Based on 
the results of our recently completed randomized, double-blind, placebo-controlled crossover 
laboratory study of IBUD in non-treatment seeking individuals with current AUD (R21 
AA022214; NCT02025998), we believe that the safety data are robust and that early efficacy 
results provide sufficient signal to warrant a clinical trial of IBUD (50 mg/BID) for alcoholism.  
 
2.3. Significance of the proposed project hinges on the development of IBUD for 
alcoholism, which is grounded on preclinical testing, safety, and initial efficacy in 
individuals with AUD. 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
5 
 
 
Alcoholism is a chronic and relapsing condition affecting 10 million Americans and causing a 
host of negative medical, psychosocial, and economic consequences to the individual and to 
society (49, 50). To date, only four pharmacotherapies are approved by the FDA for the 
treatment of alcoholism and their efficacy is modest (51). Therefore, medication development for 
AUD represents a high priority area. The significance of this proposal is grounded on the 
following recent developments: (A) this study focuses on novel molecular targets for AUD, 
namely GDNF modulation and PDE inhibition, and will test the clinical efficacy a novel 
compound targeting these systems (IBUD); (B) it is supported by compelling preclinical data 
validating its molecular targets and its effects on alcohol phenotypes (i.e., IBUD reduced ethanol 
intake by approximately 50% in animal models); (C) safety data for IBUD are robust and have 
been established in our own human laboratory study, as well as recent safety studies for opiate 
(44, 45) and methamphetamine (46, 47) use disorders; (D) the early efficacy data from our R21 
study provides sufficient signal to support additional testing of IBUD in treatment-seeking 
samples. Specifically, our human laboratory study found that IBUD was associated with mood 
improvements during stress- and alcohol-cue exposures as well as reductions in tonic levels of 
alcohol craving compared to placebo; and (E) the translation of findings from preclinical to 
clinical samples has been challenging in the AUD literature and often promising compounds 
with compelling preclinical data do not progress to testing in humans (described as the “valley of 
death” in AUD medication development)(2, 3); thus allowing for promising novel (and safe) 
compounds to progress to clinical trials represents a significant step forward in medications 
development for AUD. In sum, significant proposals are those that can have a transformative 
impact on the field and ultimately improve the standards of care for AUD. To that end, the 
successful completion of the proposed study will further develop IBUD, a safe and promising 
novel compound with strong preclinical and safety data for AUD. If IBUD proves superior to 
placebo in this study, it will set the stage for a confirmatory multi-site trial leading to FDA 
approval of a novel AUD treatment. 
 
3. STUDY OBJECTIVES 
 
3.1. Primary Aims 
 
Primary Aim 1: To test whether IBUD (50mg BID) will decrease percent heavy drinking days 
(PHDD; HDD defined as 5+ drinks for men and 4+ for women), as compared to placebo, over 
the course of the 12-week trial.  
 
Primary Aim 2: To test the efficacy of IBUD (50mg BID) on secondary alcohol consumption 
endpoints, namely (a) drinks per day, (b) drinks per drinking day, (c) percent days abstinent, (d) 
percent subjects with no heavy drinking days, and (e) percent subjects abstinent, as well as 
measures of alcohol craving and negative mood, over the course of the 12-week trial. It is 
hypothesized that IBUD will decrease drinking, improve mood, and attenuate alcohol craving 
over the course of the 12-week trial.  
 
3.2. Exploratory Aims 
 
Exploratory Aim 1: To test whether the effects of IBUD (50mg BID) on the primary and 
secondary endpoints (aims 1 and 2) are moderated by depressive symptomatology. This is 
based on our finding that IBUD attenuated the stimulant effects of alcohol among individuals 
with higher levels of depressive symptomatology. 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
6 
 
 
Exploratory Aim 2: To test whether IBUD (50mg BID), compared to placebo, reduces 
neuroinflammation, as indexed by circulating blood levels of proinflammatory markers over the 
course of the 12-week trial. 
 
4. STUDY DESIGN 
 
4.1. Design Overview 
 
The study design consists of a 12-week, double-blind, placebo-controlled randomized clinical 
trial of IBUD (50mg BID) for the treatment of AUD. We will randomize 132 treatment-seekers 
with current AUD over the course of 4 years. As a behavioral support platform, all participants 
will complete the NIAAA-developed and computer-delivered program “Take Control” during the 
study. Participants will complete telephone screening, followed by in-person eligibility 
assessment, a physical exam for medical eligibility, randomization to study medication or 
matched placebo, and an in-person follow-up visit at week 4, and in-person or remote follow-up 
visits at 8 and 12 weeks of treatment. A brain imaging session will take place at week 4 (if 
participant is eligible).  In addition, TLFB assessment of drinking outcomes will occur by 
telephone on weeks 2, 6, and 10. A final safety check visit will occur on week 16, consisting of 
repeated clinical labs and ECG. 
 
5. PHARMACOTHERAPY INTERVENTIONS 
 
5.1. Ibudilast (IBUD) 
 
Experimental medication and matched placebo will be supplied by MediciNova (see Letter of 
Support). The study drug is IBUD (MN-166, previously known as AV411) and the formulation is 
10 mg delayed-release Pinatos® capsules, the Japanese generic IBUD product produced by 
Taisho Pharmaceuticals and imported by MediciNova. The target dose of IBUD will be 50 mg 
BID (5 x 10 mg capsules twice daily). To minimize nausea, the most common side effect of 
IBUD, all participants will begin at 20 mg BID for 2 days increasing to 50 mg BID on day 3 and 
remaining at the 50mg BID dosing until week 12. For the last three days of week 12, participants 
will reduce the dose (step down procedure) to 20 mg BID prior to stopping the medication at the 
end of the study. This is consistent with the ongoing trial of IBUD for MAUD; NCT01860807).  
 
5.1.1. IBUD Safety Data 
 
IBUD has been used clinically for 20 years in Asia for the treatment of bronchial asthma, and 
more recently for post-stroke dizziness and ocular allergies during which it has proven to be 
safe and well tolerated (90). Of note, IBUD is prescribed without any alcohol use restrictions. As 
IBUD is not currently clinically available in the US, information concerning possible adverse 
events come from results of phase I trials conducted by the US developer (Avigen/MediciNova) 
and from experience with clinical use in Asia. In Avigen phase I trials (AV411-009, -010, -016, -
026), doses up to 100 mg of IBUD (as a single 100 mg dose and at 50 mg BID [dose used in 
this study] for up to 2 weeks in diabetics and healthy controls) were well tolerated. In total, ~425 
subjects have been treated in the clinical development of IBUD with no SAEs clearly linked to 
IBUD and one severe AE of hepatic steatosis (possibly-related) at 30 mg/d IBUD and one 
moderate hepatotoxicity deemed related to IBUD (at 60 mg/d); both at 20-23 months of 
treatment. There were no serious adverse events in any of these trials. Frequencies of the most 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
7 
 
common mild-moderate severity adverse events were (IBUD vs. Plac): headache (18 vs. 21%), 
nausea (12 vs. 8%), dyspepsia, diarrhea (12 vs. 8%), and emesis (6 vs. < 1%). According to the 
package insert for Ketas® (IBUD market name in Asia), the most frequently observed adverse 
reactions are anorexia (weight loss; <1%), nausea (<1%), increased AST (GOT) levels (<1%), 
increased ALT (GPT; <1%), and thrombocytopenia (<1%). In addition, there have been no 
significant drug-drug interactions observed to date in clinical studies of IBUD among patients 
being treated for diabetes, neuropathic pain, opioid dependence, or multiple sclerosis. To date, 
over 200 subjects have received the proposed 50 mg BID dose without SAEs (in diabetes, AUD, 
opiate, and MAUD studies).  
 
5.1.2. Medical Monitoring and Side Effects 
 
The study physician (Dr. Miotto) will be available to the study participants for the entire duration 
of the study. Participants will have access to her 24-hr pager and will report on adverse events 
at each monthly visit. Dr. Miotto will call every participant at the end of the first week on the 
study medication (or placebo) to discuss and manage any adverse events. The study staff will 
notify Dr. Miotto of any adverse events recorded during the follow-up visits. Side effects will be 
collected as an open-ended question such as “How have you been feeling since your last visit?” 
at each follow-up visit. A follow-up safety visit will also be conducted 4 weeks after medication is 
terminated (Week 16) and will consist of clinical labs and ECG, which will be reviewed and 
managed by the study physician. Dr. Irwin (Co-I), a licensed physician, will be available to Dr. 
Miotto for consultation on clinical care issues. Any significant escalation in drinking (defined as ≥ 
50% increase in drinking from baseline) will prompt an intervention by the PI and /or study 
physician, aimed at assessing safety and discussing alternative treatment options (e.g., 
detoxification programs). Lastly, the C-SSRS assessing for suicidal ideation and behaviors will 
also be conducted at each in-person visit and clinically significant findings will trigger further 
evaluation by the PI (psychologist) and/or the study physician (Dr. Miotto) and Co-I (Dr. Irwin). 
 
5.1.3. Medication Compliance 
 
Compliance will be monitored by the study staff using participant self-report verified by the pill 
count method at each in-person follow-up visit.  
 
5.1.4. Medication Stopping Rules 
 
Pre-specified criteria for discontinuation of study medication are:  
(a) development of agitation, hostility, depressed mood, or changes in behavior or thinking 
not typical of alcohol use or withdrawal (more severe and/or temporally un-related to 
alcohol use/withdrawal;  
(b) severe nausea and vomiting;  
(c) systolic blood pressure greater than 160, or a diastolic blood pressure greater than 100 
(i.e. cutoffs for stage 2 hypertension), or a heart rate greater than 70% of the maximum 
heart rate expected for their age [0.70(220-age)];  
(d) females who become pregnant;  
(e) any circumstances that, in the opinion of the investigators, compromise participant 
safety. Medication stopping criteria will be evaluated at each follow-up visit (4, 8, and 12-
weeks post randomization) and each time a participant calls the study physician to report 
an adverse event.  
 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
8 
 
 
 
5.1.5. Dose Justification 
 
Selecting 100 mg/day (50 mg BID) as the single target dose in this study is based on safety 
considerations, preclinical, and clinical data. Additionally, all in vitro (13, 94, 95), in-vivo animal 
(96, 97), and clinical neuropharmacology studies of IBUD, found efficacy to be dose- or 
concentration-incremental - at least up to 80-100 mg/day doses and plasma concentrations (44, 
61). In essence, ‘more is better’ up to the current clinical maximum safe and well-tolerated high 
dose of 50 mg bid correlates with ~100 ng/ml or ~0.5 uM steady-state plasma concentration 
(with daily AUC ~1500 ng*hr/ml) and ~1.5 uM brain concentration. The target dose reflects 
experience in recent MediciNova safety trials, where 50 mg BID has been well tolerated, 
adverse events being easily managed and 50mg BID representing the upper limit of what the 
manufacturer believes is the maximal tolerated and potentially efficacious dose for an addiction 
indication. The half-life of IBUD is estimated at approximately 19 hours (98) justifying BID 
dosing. Lastly, discussions with MediciNova have reassured the study team that the 50 mg BID 
dose represents the best balance between obtaining consistent efficacy in a host of clinical 
studies (for addition and MS) while producing a manageable side effect profile.  
 
6. BEHAVIORAL INTERVENTIONS 
 
6.1. Take Control Program 
 
Take Control is easy-to-use tool, developed by NIAAA (2009) that helps participants analyze 
their own drinking. Take Control offers evidence-based information to help participant reduce 
their risk for alcohol problems. In this study, participants will be asked to complete the Take 
Control program for 30 minutes at the randomization visit and at all in-person follow-ups. This 
approach is consistent with that of NCIG6, which used Take Control in computer-delivered 
format. A recent study comparing computer-delivered Take Control to therapist-delivered 
platforms (TDP) found comparable drinking outcomes and higher medication adherence in the 
Take Control trials (81), suggesting that Take Control is cost-efficient behavioral platform for 
AUD trials. Regarding the role of mutual support groups in the Take Control platform, the 
“Treatment Options” module reviews various treatment resources including mutual support 
groups, addiction specialist, and medications commonly used to treat problem drinking. 
 
7. STUDY PROCEDURES 
 
7.1. Recruitment of Subjects 
 
Participants will be recruited from the community through radio, TV, online, and newspaper 
advertisements. Campaigns in local buses and print publications (e.g., LA Weekly) will also be 
implemented. Consistent with our efforts to identify treatment-seeking individuals with AUD, all 
recruitment materials will invite individuals who wish to change their drinking and who indicate 
they have a drinking problem.  
 
 
 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
9 
 
7.2. Eligibility Criteria 
 
7.2.1. Inclusion Criteria 
 
To be included in the study, participants must:  
(1) 
Be between the ages of 18 and 65  
(2) 
Meet current (i.e., past 12 months) DSM-5 diagnostic criteria for alcohol use disorder 
moderate or severe  
(3) 
Be treatment-seeking for AUD  
(4) 
Report drinking at least 14 drinks per week if male (7 drinks per week if female) in the 28 
days prior to consent 
 
7.2.2. Exclusion Criteria 
 
To be included in the study, participants must not:  
(1) 
Have a current (last 12 months) DSM-5 diagnosis of substance use disorder for any 
psychoactive substances other than alcohol and nicotine  
(2) 
Have a lifetime DSM-5 diagnosis of schizophrenia, bipolar disorder, or any psychotic 
disorder 
(3) 
Have a positive urine screen for narcotics, amphetamines, or sedative hypnotics;  
(4) 
Have clinically significant alcohol withdrawal symptoms as indicated by a score ≥ 10 on 
the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-R)  
(5) 
Be pregnant, nursing, or planning to become pregnant while taking part in the study; and 
must agree to one of the following methods of birth control (if female), unless she or 
partner are surgically sterile:  
• 
Oral contraceptives 
• 
Contraceptive sponge 
• 
Patch 
• 
Double barrier 
• 
Intrauterine contraceptive device 
• 
Etonogestrel implant  
• 
Medroxyprogesterone acetate contraceptive injection 
• 
Complete abstinence from sexual intercourse 
• 
Hormonal vaginal contraceptive ring 
(6) 
Have a medical condition that may interfere with safe study participation (e.g., unstable 
cardiac, renal, or liver disease, uncontrolled hypertension or diabetes)  
(7) 
Have AST, ALT, or GGT ≥ 3 times upper normal limit  
(8) 
Have attempted suicide and/or have had serious suicidal intention or plan in the past 
month  
(9) 
Currently be on prescription medication that contraindicates use of IBUD, including alpha 
or beta agonists, theophylline, or other sympathomimetic  
(10) 
Currently be on any medications for AUD or any psychotropic medications (e.g., 
psychostimulants and benzodiazepines) with the exception of stable antidepressants 
(stable dose for ≥4 weeks) 
(11) 
Have any other circumstances that, in the opinion of the investigators, compromises 
participant safety.  
 
7.3. Screening Period 
 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
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7.3.1. Telephone Screen 
 
Individuals who call the lab (in response to flyers and advertisements) expressing interest in the 
study will receive detailed information about the study procedures, and if they remain interested 
they will complete a telephone screen performed by a trained research assistant for self-
reported inclusion and exclusion criteria. Those who appear eligible will be invited to the 
laboratory for an initial in-person screening session.  
 
7.3.2. Initial Screening Visit 
 
Prior to conducting any research related procedures, research staff will conduct the informed 
consent process which details the procedures to take place during the screening visit. Informed 
consent will be a three-part process. First, participants will be asked to read and provide verbal 
consent for breathalyzer. If the breathalyzer is above 0.000, the visit will be stopped and the 
participant will not be compensated. The participant will be given an opportunity to reschedule 
the visit for another day.  If the breathalyzer test is negative, the written informed consent form 
will be reviewed and signed by the participant and study staff outlining procedures for the initial 
screening visit.  A second written consent form will be reviewed and signed in the presence of 
the study physician at the medical screening visit if the participant is found eligible to continue to 
that visit.  
 
At the initial screening visit, subjects will be asked to provide a urine to test for drugs of abuse 
and pregnancy (if female), and will complete a series of individual differences measures 
(described in detail below). This visit should take 1 to 2 hours.  
 
Following the initial in-person screening, the study coordinator will meet with the PI to determine 
if the participant is eligible to continue to the medical screening based on study 
inclusion/exclusion criteria. 
 
7.3.3. Medical Screening Visit 
 
Those participants who appear to be eligible after the initial screening visit, will then be 
scheduled for a second screening visit, which will be conducted with the study physician.  The 
visit will start with a breathalyzer test. If the breathalyzer is above 0.000, the visit will be stopped 
and the participant will not be compensated.  The participant will be given an opportunity to 
reschedule the visit for another day.  If the breathalyzer test is negative, the physician will meet 
with the participant in-person or via telemedicine to conduct the second written (experimental) 
consent, medical history interview, and physical exam.  The participant will then be walked to 
the UCLA Clinical and Translational Research Center (CTRC) for blood specimen collection 
including Comprehensive Metabolic Panel and Complete Blood Count to evaluate overall 
health; and EKG to screen for medical conditions that contraindicate taking ibudilast.  In 
addition, urine drug screen test and pregnancy test (if female) will be repeated. The study 
physician will review each participant’s medical history, vital signs, weight, review of systems, 
and laboratory tests, including liver function tests (LFTs), drug screen, chemistry screen, and 
urine pregnancy screen to determine if it is medically safe for the participant to take the study 
medication.  
 
Any subject who is excluded from the study will be compensated for their time in the screening 
session and will be offered referrals for alcohol treatment in the community. 
 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
11 
 
 
7.4. Randomization Visit 
 
Participants who are eligible after the medical screening visit will be scheduled to come into the 
lab to be randomized and start study medication.  Randomization will be done in a 1:1 ratio, to 
either IBUD or placebo using a stratified block randomization procedure, gender and drinking 
status (moderate drinking defined as  ≥ 14 drinks/week for men and ≥ 7 drinks/week for women 
versus heavy drinking defined as ≥ 28 drinks/week for men and ≥ 21 drinks/week for women) as 
the stratification factors. Participants will be asked to provide a urine specimen for drug testing 
and pregnancy for female participants, perform an alcohol breathalyzer test, and complete 
measures as described in the Schedule of Assessments below.  In addition, blood will be drawn 
to collect baseline neuroinflammation data. Participants will be dispensed enough medication to 
last until the next scheduled visit. 
 
7.5. Follow Up Period 
 
Follow-up visits will occur at the UCLA Addictions Lab on weeks 4, 8, 12, and 16.  Data 
collection for the week 8 and week 12 follow-up visits may be conducted remotely if needed.  
Telephone follow-up interviews will be conducted at weeks 2, 6 and 10 to collect Timeline 
Follow Back data as described below. At each in-person follow up visit, participants will be 
asked to provide a urine specimen for drug testing and pregnancy for female participants, 
perform an alcohol breathalyzer test, and complete measures as described in the Schedule of 
Assessments below.  In addition, blood will be drawn to monitor participant safety (week 16) and 
collect neuroinflammation data (all in-person visits through week 12). Participants will be asked 
to bring all study medication and used packaging to each visit to assess for medication 
compliance and will be dispensed study medication to last until the next scheduled visit.   
 
7.5.1. Brain Imaging Session 
 
Participants found to be eligible for an MRI, as determined by the MRI Safety Screening form, 
will be asked to complete a brain imaging session as part of the week 4 in-person visit. 
 
Participants will be asked to abstain from drinking alcohol prior to coming into the lab for the 
brain imaging session, which will be verified through a breathalyzer. Only participants with a 
blood alcohol concentration of zero will be allowed to complete the scanning visit. Female 
participants will be given a pregnancy test to make sure that they are not pregnant. We will also 
collect a urine sample on that day to verify compliance with the study medication. We will then 
ask participants to fill out a few questionnaires including information about your use of alcohol 
and tobacco.  
 
After the initial questionnaires, participants will receive some training on how to complete 
questionnaires in the scanner. 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.  In the scanner, participants will view 
alcohol and neutral cues and will be asked to rate their urge drink. Additionally, in the scanner, 
participants will complete the Montreal Imaging Stress Task. In this task participants are asked 


IBUD for AUD 
Protocol V10, March 1, 2022 
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12 
 
to solve mental arithmetic problems of varying degrees of difficulty and are given feedback on 
their performance.  Subjective and biological measures of stress will be administered before and 
after the stress task.   
 
7.6. Compensation for Participation 
 
Participants will be compensated up to a total of $385 for their time and effort according to the 
following schedule: 
 
Initial Screening Visit:  
$40 
Medical Screening Visit: 
$40 
Randomization: 
 
$40 
Follow Up Week 4: 
 
$40 
Brain Imaging Session: 
$50 (if eligible) 
Follow Up Week 8: 
 
$40 
Follow Up Week 12:  
$45 
Follow Up Week 16:  
$40 
Completion Bonus: 
 
$50 
 
All participants will be provided with free parking validation or bus fare for attendance to each 
study visit.  Participants are free to discontinue participation at any time and will receive 
compensation for the amount of time they participated. 
 
8. SAFETY MONITORING PLAN 
 
Safety monitoring will be conducted throughout the study; therefore safety concerns will be 
identified by continuous review of the data by the PI and study physician, internal quality 
assurance monitor, and DSMB. 
 
8.1. PI and Study Physician Safety Monitoring 
 
Participants will be given a 24-hour telephone number for calling the physician to discuss side 
effects, and physician office hours will be available as needed. Adverse events, including side 
effects will be collected in an open-ended way at each in-person study visit. In the event that an 
adverse event is spontaneously reported during a telephone interview at weeks 2, 6, or 10, 
research staff will note general information to provide to the study physician and will have the 
physician follow up with the participant via phone to gather more information and address safety 
issues as needed.  Vital signs, weight, and neuropsychiatric side effects, including depression 
and suicidal ideation, will be monitored at each study visit. Alcohol withdrawal will be monitored 
at each visit through administration of the CIWA, and any significant withdrawal, as indicated by 
a score of 10+ on the CIWA will be reported to the study physician immediately.  The study 
physician will repeat all the clinical labs at the week 16 follow-up in order to verify that there 
were no changes associated with the 12-week medication regimen (+ 2 week titration/ 
stabilization period). In the event that significant medical problems are encountered, the blind 
will be broken and appropriate medical treatment will be provided.  
 
8.2. Internal Quality Assurance Monitoring 
 


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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 to 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 (GCP) 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. 
 
8.3. Data and Safety Monitoring Board (DSMB) 
 
An independent DSMB of external advisors will meet prior to the start of the study, annually 
during enrollment and follow-up and at trial end to review safety data. The Board will be blinded 
to subjects’ actual randomized group assignments but may request at any time that the blind be 
broken by the data center, if concerns arise from the blinded data. In addition to annual 
meetings, the DSMB will meet after half of the subjects (66) have been randomized to review 
safety data and the integrity of the study (i.e., an evaluation of the dropout rate and impact on 
the planned statistical analysis of the data) and make a formal recommendation to the PI on the 
continuation or early stopping of the study due to safety concerns. Ad hoc meetings will be 
convened if SAEs occur that are considered at least possibly related to the study medication. 
 
 
 


IBUD for AUD 
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14 
 
9. ASSESSMENTS 
 
9.1. Schedule of Assessments Table 
Study Visit: 
Procedure  
Initial 
Screen 
Med 
Screen 
Rand. 
Visit 
Wk 4 
F/U 
Wk 8 
F/U 
Wk 12 
F/U 
Wk 16 
F/U 
Informed Consent: Initial Screen 
x 
 
Informed Consent: Experimental/Medical 
 
x 
 
 
 
 
 
Adverse Childhood Experience Questionnaire (ACE) 
 
 
x 
 
 
 
 
Adverse Events/Serious Adverse Events (AE/SAE) 
x 
x 
x 
x 
x 
 
Alcohol Breathalyzer 
x 
x 
x 
x 
x 
x 
 
Alcohol Dependency Scale (ADS) 
 
 
x 
x 
x 
x 
 
Alcohol Purchase Task (APT) 
 
 
x 
x 
x 
x 
 
Alcohol Use Disorders Identification Test (AUDIT) 
 
 
x 
 
 
 
 
Beck Anxiety Inventory (BAI) 
 
 
x 
x 
x 
x 
 
Beck Depression Inventory (BDI-II) 
x 
 
x 
x 
x 
x 
 
Birth Control Assessment 
x 
 
 
 
 
 
 
Brain Imaging (if eligible) 
 
 
 
x 
 
 
 
Brief Trauma Questionnaire (BTQ) 
 
 
x 
 
 
 
 
Brief AUD Severity Scale (BASS 
 
 
x 
 
 
 
 
Clinical Institute W/D Assessment for Alcohol (CIWA-AR) 
x 
 
x 
x 
x 
x 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
x 
 
x 
x 
x 
x 
 
Safety Labs CMP/CBC (blood sample) 
 
x 
 
 
 
 
x 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
 
Cannabis Use Disorder Identification Test (CUDIT) 
 
 
x 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
Drinking Goal 
 
 
x 
 
 
 
 
Drug Compliance/Accountability 
 
 
 
x 
x 
x 
 
Drug Screen (urine sample) 
x 
x 
x 
x 
x 
x 
 
Electrocardiogram (ECG) 
 
x 
 
 
 
 
x 
Fagerstrom Test for Nicotine Dependence (FTND) 
 
 
x 
 
 
 
 
Family Tree Questionnaire (FTQ) 
 
 
x 
 
 
 
 
Graded Chronic Pain Scale (GCPS) 
 
 
x 
x 
x 
x 
 
ImBIBe 
 
x 
x 
x 
x 
 
Inflammation and Behavior Questionnaire 
 
 
x 
x 
x 
x 
 
Insomnia Severity Index (ISI) 
 
 
x 
x 
x 
x 
 
Locator Form  
x 
 
 
 
 
 
 
Medical History 
 
x 
 
 
 
 
 
NIH Toolbox 
 
 
x 
 
 
x 
 
Neuroimmune assays (blood sample)* 
 
 
x 
x 
x 
x 
 
Penn Alcohol Craving Scale (PACS) 
x 
x 
x 
x 
 
Physical Exam 
 
x 
 
 
 
 
 
Pregnancy Test (urine sample) 
x 
 
x 
x 
x 
x 
 
Profile of Mood States (POMS) 
 
x 
x 
x 
x 
 
Readiness to Change (RTC) Ladder 
 
 
x 
 
 
 
 
Reward-Relief Drinking Scale 
 
 
x 
 
 
 
 
Risky Families Questionnaire  
 
 
x 
 
 
 
 
Salivary Cortisol Testing 
 
 
 
x 
 
 
 
Spielberger State-Trait Anxiety Scale (STAI) 
 
 
 
x 
 
 
 
Structured Clinical Interview for DSM-5 (SCID-5) 
x 
 
 
 
 
 
 
Subjective Distress Units Scale (SUDS) 
 
 
 
x 
 
 
 
Take Control (Computer-delivered) 
 
 
x 
x 
x 
x 
 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
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Timeline Follow Back (TLFB)** 
x 
x 
x 
x 
x 
x 
x 
Vital Signs (including weight) 
x 
x 
x 
x 
x 
x 
x 
*RNA sample collected only at Randomization and Week 12 visits. 
**TLFB assessment will also be conducted by phone at weeks 2, 6, and 10. 
 
9.2. Adverse Childhood Experiences Questionnaire (ACE) 
 
The Adverse Childhood Experiences Questionnaire (ACE) is a 10-item self-report measure 
developed to identify childhood experiences of abuse and neglect.  The ACE will be completed 
electronically at the randomization visit. 
 
9.3. Adverse Events (AE) and Serious Adverse Events (SAE) 
 
The study physician and study site staff are responsible for the detection, documentation, 
classification, reporting, and follow up of events meeting the definition of an AE or SAE.  
Adverse Events will be assessed at the medical screening visit and at each subsequent visit 
through the week 12 follow up visit.  However, SAEs will be collected from the time of informed 
consent onward. General symptoms will be collected via an open ended question: “How have 
you been feeling since your last visit or the last time we spoke?” 
 
Adverse Events will be recorded on the AE Log using accepted medical terms and/or the 
diagnoses that accurately characterize the event. When a diagnosis is known, the AE term 
recorded on the eCRF will be the diagnosis rather than a constellation of symptoms. The study 
physician will assess all AEs for seriousness, relationship to study medication, and severity. 
When an event has not resolved by study closure, it will be documented on the AE Log as 
“ongoing”. 
 
If a woman has a positive or borderline pregnancy test after enrollment, the pregnancy will be 
recorded as an AE. The site will contact the subject at least monthly and document the subject’s 
status until the pregnancy has been terminated or completed. The outcome of the pregnancy 
(e.g., normal birth, death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn) will be recorded. 
 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless of 
severity, will be followed by study physicians until satisfactory resolution (the event either 
resolved or stabilized and is not expected to resolve in the near term).  All SAE’s will be 
reported per requirements.  
 
9.3.1. Adverse Event (AE) Definition 
 
An AE is any untoward medical occurrence in a participant who has been administered a 
pharmaceutical product and may not necessarily have a causal relationship with the 
administered treatment. An AE can therefore be any unfavorable and unintended sign (including 
a clinically significant laboratory abnormality), symptom, or disease temporally associated with 
the use of the study medication, whether or not related to the medication. Pre-existing 
conditions, diseases, or disorders are not considered AEs unless there is a change in severity 
or frequency. 
 
9.3.1.1. 
Classification of Adverse Event Intensity and Relationship to Study 
Medication 


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For each recorded AE or SAE, the physician must make an assessment of severity based on 
the following criteria: 
 
• 
Mild: An event that is usually transient, requiring no special treatment, and does not 
generally interfere with the subject’s daily activities. 
• 
Moderate: An event that interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the subject. The event is usually 
ameliorated with additional specific therapeutic intervention. 
• 
Severe: An event that interrupts usual activities of daily living or significantly affects 
clinical status. The event poses a significant risk of harm to the subject and 
hospitalization may be required, and typically requires intensive therapeutic intervention. 
• 
Life-threatening: An event that puts the subject into imminent risk of death without 
intervention. 
 
The physician must also make an assessment of relationship to the investigational product 
based on the following criteria: 
 
• 
Unrelated: The subject did not receive the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational product is 
not reasonable, or there is another obvious cause of the AE/SAE. 
• 
Unlikely: There is evidence of exposure to the investigational product but there is 
another more likely cause of the AE/SAE. 
• 
Possible: There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational product is 
reasonable, but the AE/SAE could have been due to another equally likely cause. 
• 
Probable: There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational product is 
reasonable, and the AE/SAE is more likely explained by the investigational product than 
by any other cause. 
• 
Definite: There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational product is 
reasonable, the AE/SAE is more likely explained by the investigational product than by 
any other cause, and the AE/SAE shows a pattern consistent with previous knowledge 
of the investigational product or investigational product class. 
 
9.3.1.2. 
Outcomes and Actions Taken 
 
All unresolved AEs will be followed for a minimum of 14 days (unless the AE is an ongoing 
pregnancy which must be followed to conclusion) after the subject’s final study visit, unless the 
investigator’s judgment dictates otherwise, the event has resolved or stabilized prior to the 14-
day period, or the subject is lost to follow-up. Investigators are not obligated to actively seek 
AEs or SAEs in former study subjects that occur following the follow-up period. 
 
For each recorded AE or SAE, the investigator must make an assessment of outcome at the 
time of last observation, as follows: 
 
• 
Fatal: The subject died. 
• 
Resolved without Sequelae: The AE or SAE has ended. 


IBUD for AUD 
Protocol V10, March 1, 2022 
PI: Lara Ray, PhD 
 
17 
 
• 
Resolved with Sequelae: The AE or SAE has ended but changes are noted from 
baseline. 
• 
Unresolved – Ongoing: The AE has not ended and is ongoing at the end of the reporting 
period (i.e., 14 days after the final Follow-up visit) and the investigator deems that further 
follow up is not medically required 
• 
Unknown – Lost to Follow-up: Lost to follow-up after repeated unsuccessful attempts to 
contact the subject. 
 
Actions taken with respect to study medication (discontinuation or not) will also be recorded. In 
addition, if the AE was treated (medications or other physical measures), this will also be 
recorded. 
 
9.3.2. Serious Adverse Event (SAE) Definition 
 
An SAE is any untoward medical occurrence that meets one of the following: 
 
• 
Results in death 
• 
Is life-threatening (at the time of the event) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
 
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or frequency in 
the risk information included in the Product Label for the drug. Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be considered a 
serious adverse event when, based upon appropriate medical judgment, they may jeopardize 
the study subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition. 
 
9.4. Alcohol Breathalyzer 
 
An alcohol breathalyzer will be administered at consent, and at every in-clinic visit as a safety 
measure. BrAC must be equal to 0.000 prior to performing any study assessments.  Results will 
be recorded on the paper checklist, and later entered into the database. 
 
9.5. Alcohol Dependency Scale (ADS) 
 
The Alcohol Dependency Scale is a 25-item scale that measures alcohol dependence 
symptoms over the past 12-months. The ADS assesses problems that are relevant for alcohol 
dependent drinkers. The ADS is a self-report measure that will be completed by the participant 
electronically at the randomization visit, and at each follow-up visit.  
 
9.6. Alcohol Purchase Task (APT) 
 
The Alcohol Purchase Task is a 16-item scale that uses hypothetical situations regarding 
alcohol purchases and consumption at varying prices in order to generate several indices of 
alcohol-related reinforcement. The APT is a self-report measure that will completed by the 
participant electronically at the randomization visit, and at each follow-up visit. 
 
 


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9.7. Alcohol Use Disorders Identification Test (AUDIT) 
 
The Alcohol Use Disorders Identification Test is used to identify persons with hazardous and 
harmful patterns of alcohol consumption. The AUDIT was developed by the World Health 
Organization (WHO) as a simple method of screening for excessive drinking.  The AUDIT is a 
self-report measure that will be completed by the participant electronically at the randomization 
visit. 
 
9.8. Beck Anxiety Inventory (BAI) 
 
The Beck Anxiety Inventory (BAI) surveys anxiety symptomatology including physical and 
cognitive indicators of anxious mood. The BAI will be completed electronically at randomization, 
and all follow up visits. 
 
9.9. Beck Depression Inventory (BDI-II) 
 
The Beck Depression Inventory, Revised (BDI-II) captures depressive symptomatology (and is 
needed to test exploratory aim #1).  The BDI-II will be completed at the initial screening, 
randomization, and all follow up visits.  
 
9.10. 
Birth Control Assessment 
 
The Birth Control Assessment is designed to confirm a female subject’s compliance with the 
birth control specifications detailed in the inclusion criteria.  Birth Control Assessment 
information will be recorded on the checklist at the initial screening visit for participant safety 
purposes. 
 
9.11. 
Brief Trauma Questionnaire (BTQ) 
 
The Brief Trauma Questionnaire (BTQ) is a 10-item questionnaire derived from the Brief 
Trauma Interview (BTI) and is used to assess traumatic exposure according to Criterion A in the 
PTSD module of the DSM-V. The BTQ will be administered electronically at the randomization 
visit.  
 
9.12. 
Brief AUD Severity Scale (BASS) 
 
The Brief AUD Severity Scale (BASS) is a 9-item self-report measure used to assess alcohol use 
disorder severity.  The BASS will be completed at the randomization visit. 
 
9.13. 
Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) 
 
The CIWA-AR is a brief 10-item measure used to provide a quantitative index of the severity of 
the alcohol withdrawal syndrome. The CIWA-AR has been used both in clinical and research 
applications and has demonstrated both reliability and validity.  This questionnaire will be 
administered on paper by appropriately trained staff during screening, at the randomization visit, 
and at each follow-up visit.  Participant responses will then be entered electronically. 
 
9.14. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 


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The C-SSRS is a 4-page form asking questions about suicidal ideation, intensity of ideation, and 
suicidal behavior developed by Posner and collaborators at the New York State Psychiatric 
Institute. This scale is intended for use by trained administrators. The questions contained in the 
C-SSRS are suggested probes. Ultimately, the determination of the presence of suicidality 
depends on clinical judgment. Training is required before administering the C-SSRS through a 
30-minute interactive slide presentation followed by a question-answer session through the 
Columbia University Medical Center. Those completing the training are certified to administer 
the C-SSRS, and will receive a training certificate. This scale will be used to assess current 
suicidal ideation at screening, randomization, and at each follow up visit and will be 
administered by a trained staff member with responses recorded on paper first, then entered 
electronically. 
 
9.15. 
Comprehensive Metabolic Panel/Complete Blood Count 
 
Blood will be drawn for a comprehensive metabolic panel and complete drug count during the 
medical screening and follow up visit at week 16 to assess for participant safety.  The total 
blood volume to be collected is approximately 8 mL. Additional laboratory samples may be 
taken at the discretion of the study physician if the results of any tests fall outside reference 
ranges or clinical symptoms necessitate testing to ensure safety.  
 
9.16. 
Concomitant Medications 
 
All medications taken by the participant 2-weeks prior to the start of screening and through the 
final follow-up at week 12, collected via participant self-report will be recorded recorded on a 
source document and later entered electronically. 
 
9.17. 
Cannabis Use Disorder Identification Test (CUDIT) 
 
The Cannabis Use Disorders Identification Test is used to identify persons with hazardous and 
harmful patterns of cannabis consumption. The CUDIT was developed a simple method of 
screening for excessive cannabis use. The CUDIT is a self-report measure that will be 
completed by the participant electronically at the randomization visit. 
 
9.18. 
Demographics 
 
Demographics data include the participant’s age, gender, race/ethnicity, marital status, 
education, employment pattern, occupation, and income level. These data will be collected 
electronically at the initial screening visit. 
   
9.19. 
Drinking Goal 
 
Drinking Goal is 1-item questionnaire that assesses for the subject’s treatment goal in regards 
to alcohol. The responses are categorized into a controlled drinking goal, complete abstinence, 
or conditional abstinence. This questionnaire will be completed electronically at the 
randomization visit.  
 
9.20. 
Drug Compliance/Accountability 
 


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Drug Accountability and Compliance will be monitored by the study staff using participant self-
report verified by the pill count method at each follow-up visit.  Participants will be asked to bring 
all unused medication and any packaging, including used blister-packs, to each in-person visit. 
 
9.21. 
Drug Screen 
 
An FDA cleared, CLIA waived urine drug test card will be used at all visits to assess for recent 
use of opioids, cocaine, amphetamines, methamphetamine, THC, buprenorphine, methadone or 
benzodiazepines. Subjects must be negative for all substances except THC.  Results will be 
recorded on the visit checklist first and then entered into the database. 
 
9.22. 
Electrocardiogram (ECG) 
 
A 12-lead resting ECG will be obtained at the medical screening visit and repeated at week 16. 
Any abnormalities will be noted and an assessment of clinical significance will be made by the 
study physician. 
 
9.23. 
Fagerström Test for Nicotine Dependence (FTND) 
 
The Fagerström Test for Nicotine Dependence will be used to assess smoking status and 
motivation to change smoking behavior. This questionnaire will be completed by the subject 
electronically at the randomization visit. 
 
9.24. 
Family Tree Questionnaire (FTQ) 
 
Information on family history of alcohol problems will be collected using the Family 
Tree Questionnaire. The questionnaire provides subjects with a family tree listing of relatives to 
identify blood relatives with alcohol problems. This questionnaire will be completed by the 
subject electronically at the randomization visit. 
 
9.25. 
Graded Chronic Pain Scale 
 
The Graded Chronic Pain scale is a 7-item measure used to evaluate an individual’s overall 
severity of chronic pain if they have suffered from chronic pain that has lasted at least six 
months. The measure assesses on two dimensions: pain severity, and pain-related disability. 
This questionnaire will be completed by participants electronically at the randomization visit, and 
at each follow-up visit.  
 
9.26. 
ImBIBe 
 
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. This scale was adapted from the Drinker 
Inventory of Consequences (Drinc) questionnaire based on FDA recommendations on patient 
reported outcomes. This questionnaire will be completed by the participant electronically at 
randomization and at each follow-up visit. 
 
9.27. 
Inflammation and Behavior Questionnaire 
 
The Inflammation and Behavior Questionnaire will be used to collect relevant inflammatory 
information, including if the subject has recently been ill, had any vaccinations, taken any anti-


IBUD for AUD 
Protocol V10, March 1, 2022 
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21 
 
inflammatory medications, consumed caffeine, and exercised. This questionnaire will be 
completed in conjunction with the blood draw for neuroimmune markers, and will be completed 
at the randomization and all in-person follow up visits. 
 
9.28. 
Insomnia Severity Index (ISI) 
 
The Insomnia Severity Index ISI) is a 7-item measure used to assess symptoms of insomnia. 
The questionnaire probes for the participant’s perception and severity of their quality of sleep. 
This questionnaire will be completed electronically at randomization, and all follow up visits.  
 
9.29. 
Locator Form 
 
The Locator Form asks participant to provide his/her name, address, and phone number and to 
provide names, addresses, and phone numbers of friends and family members who can be 
contacted if the subject cannot be located. This information is essential and will be collected 
during the initial screening, and will be updated throughout the study as necessary.  
 
9.30. 
Medical History 
 
A Medical History interview will be conducted by the study physician at the medical screening 
visit and will screen for medical conditions that contraindicate the study medication, Ibudilast. 
 
9.31. 
NIH Toolbox 
 
The NIH Toolbox is a platform that provides comprehensive assessment tools for researchers, 
providing measures that assess from four primary batteries – cognition, sensation, motor and 
emotion. This platform was developed by HealthMeasures and the NIH. The participants will 
complete questionnaires electronically from the cognition domain at the randomization visit, and 
at the 12-week follow-up visit (if visit is completed in-person).  
 
9.32. 
Neuroimmune Assays 
 
Identifying the effects of IBUD on inflammatory marker levels has the potential to elucidate the 
biological mechanisms of action of this neuroimmune modulator. Blood samples will be 
collected at randomization and at in-person follow-ups to address exploratory aim #2.  Two 
lavender EDTA tubes will be collected for plasma to identify markers including innate immune 
receptors (TLR2, TLR4), cytokines (TNF-α, IL-1α, IL-1β, IL-2, IL-6, IL-10, IL12p70, GM-CSF, 
IFNγ), chemokines (MCP-1, MIP-1α, and MIP-1β), and other inflammatory signaling molecules 
(reactive oxidative species, NO, substance P, C-reactive protein). In addition, one RNA 
PAXgene tube will be collected at randomization and week 12 (if visit is completed in-person) to 
identify transcription factors that code for cytokines.  Due to the diurnal rhythm of cytokine 
production (117), attempts will be made to collect samples in the early afternoon for all subjects. 
 
9.33. 
Penn Alcohol Craving Scale (PACS) 
 
The PACS is a five-item, self-report measure that includes questions about the frequency, 
intensity, and duration of craving, the ability to resist drinking, and asks for an overall rating of 
craving for alcohol for the previous week. Each question is scaled from 0 to 6.  Participants will 
complete this scale at randomization, and at each follow up visit. 
 


IBUD for AUD 
Protocol V10, March 1, 2022 
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22 
 
9.34. 
Physical Exam 
 
A physical examination of the oral cavity, head, eyes, ears, nose, and throat, cardiovascular 
system, lungs, abdomen, extremities, skin, neuropsychiatric mental status and sensory/motor 
status, musculoskeletal system and general appearance will be performed during the medical 
screening visit.  Abnormal findings will be reported as AEs, if appropriate. 
 
9.35. 
Pregnancy Test 
 
An FDA approved rapid result urine pregnancy test will be used (i.e., dipstick test) to assess for 
pregnancy in female participants at the initial screening, randomization, and in-person follow-up 
visits.  If applicable, participants will be asked to sign a release of information form for study 
personnel to access medical records to obtain information regarding the outcome of a 
pregnancy that occurred during the study. 
 
9.36. 
Profile of Mood States (POMS) 
 
The POMS measures dimensions of mood and will be completed electronically at 
randomization, and follow up visits.  
 
9.37. 
Readiness to Change (RTC) Ladder 
 
The Readiness to Change Ladder is a measure with 11 response items designed to assess 
motivation to reduce or cut back on drinking.  This assessment will be completed at the 
randomization visit. 
 
9.38. 
Reward-Relief Drinking Scale 
 
The Reward-Relief Drinking Scale is a 4-item scale that measures an individual’s reward 
drinking tendencies. This measure was adapted from the Inventory of Drinking Situations. The 
participants will complete this measure electronically at randomization.  
 
9.39. 
Risky Families Questionnaire 
 
The Risky Families Questionnaire is a 13-item self-report that assesses the relation of childhood 
experiences to mental and physical health outcomes in adulthood. This measure was adapted 
from the Adverse Childhood Experiences (ACE). This questionnaire will be completed 
electronically at the randomization visit.  
 
9.40. 
Salivary Cortisol Testing 
 
Saliva samples will be collected for testing of cortisol levels as a biological measure of stress 
response at 3 time points during the week 4 follow up visit (at the beginning of the visit, 
immediately before the fMRI stress task, and immediately after the fMRI stress task). 
    
9.41. 
Spielberger State-Trait Anxiety Inventory (STAI) 
 
The STAI is a commonly used measure of trait and state anxiety.  For this study, the short form, 
which has 6 items for assessing state anxiety will be completed before and after the stress task, 
which takes place during the fMRI session at week 4. 


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9.42. 
Structured Clinical Interview for DSM-5 Disorders (SCID-5) 
 
The SCID is a semi-structured interview for making the major DSM-5 diagnoses.  It will be 
performed by a master’s level clinician under the supervision of the PI. The SCID-5 will be used 
to assess current (past 12-month) AUD diagnosis (moderate or severe) as well as exclusionary 
diagnoses (e.g., lifetime psychosis) at the initial screening visit.  
 
9.43. 
Subjective Units of Distress Scale (SUDS) 
 
The SUDS is a scale of 0-10 for measuring the subjective intensity of disturbance or distress 
currently experienced by an individual.  This measure will be collected before and after the 
stress task, which takes place during the fMRI session at week 4.   
 
9.44. 
Take Control Behavioral Platform 
 
The behavioral platform “Take Control” will consist of a series of 11 computerized modules. 
Participants will view 2 modules of “Take Control” at randomization and at each in-person follow 
up visit. If a visit is missed, missed modules will be reviewed at the next visit. The intervention is 
derived from a self-help approach developed by NIAAA that provides evidence-based, field 
tested information for individuals with alcohol problems, and suggestions for making changes in 
their drinking. The NIAAA material is publicly available in a NIAAA booklet entitled “Rethinking 
Drinking” and on a NIAAA website http://rethinkingdrinking.niaaa.nih.gov. Delivering these 
materials in a computerized method in this trial has the advantage of standardizing the amount 
of educational material received by the subject. 
 
9.45. 
Timeline Follow Back (TLFB) 
 
The Time Line Follow Back will be administered to assess quantity and frequency of alcohol, 
cigarette and marijuana use and will be completed at the initial screening (for the 30 days prior 
to that visit) and at each subsequent visit to gather data for every day prior to and including the 
last visit.  The TLFB interview will be conducted at all in-person visits and by telephone on 
weeks 2, 6, and 10 (and any other remote visits) to shorten the duration between drinking 
outcomes assessment.  Information obtained in this interview will be recorded on the TLFB 
Calendar and transcribed to the database.   
 
9.46. 
Vital Signs 
 
Vital signs assessed at each visit include sitting blood pressure and pulse rate (after sitting for at 
least 3 minutes) and weight.  Values will be recorded on the visit checklist and entered into the 
database. 
 
10. STATISTICAL METHODS AND POWER CONSIDERATIONS 
 
The experimental design is a two-arm Phase II, randomized, double-blind, placebo-controlled 
12-week clinical trial of IBUD (50mg BID) for the treatment of AUD. We plan to randomize 132 
treatment-seekers with current moderate-to-severe AUD. Participants will complete telephone 
screening, followed by in-person eligibility assessment, a physical exam for medical eligibility 
assessment, randomization to study medication or matched placebo, and in-person follow-up 
visits at 4, 8, and 12 weeks and telephone interviews for drinking outcomes (i.e., TLFB) at 2, 6, 


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24 
 
and 10 weeks. Randomization will be done in a 1:1 ratio, to either IBUD or placebo using a 
stratified block randomization procedure, gender and drinking status (moderate drinking defined 
as  ≥ 14 drinks/week for men and ≥ 7 drinks/week for women versus heavy drinking defined as 
≥ 28 drinks/week for men and ≥ 21 drinks/week for women) as the stratification factors.  
 
Data analysis will utilize a modified Intention-to-Treat (mITT) 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 (4+ drinks for women/ 5+ drinks for men) 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. Power analyses have been performed to ensure that the study 
has sufficient power to detect a small to medium effect size for testing the primary hypothesis 
using a mixed effects model that takes into account of the repeated measures design. 
Strategies for handling missing data and performing sensitivity analyses are outlined below.  
 
 
 
10.1. 
Statistical Power 
 
We performed power analyses using the PASS 14 software for the primary hypothesis under 
the mixed effect model design. Because the lack of preliminary data on IBUD for the primary 
outcome, we used a similarly designed clinical trial of varenicline (125) as a reference for the 
anticipated effect size in our power calculations. Specifically, the varenicline study (125) showed 
that the percent heavy drinking days was 39.6 (SE=3.7) for the varenicline versus 50.2 (SE=3.6) 
for placebo (difference=10.6; Cohen’s d=0.31). With a total of 132 participants (66 subject/group 
* 2 groups), our repeated measures mixed effect model design will have 93.73% power to 
detect an effect size of 0.3 (between a small effect size of 0.2 and medium effect size of 0.5 
(126)) for the treatment group difference with 12 repeated measurements assuming a 
compound symmetry covariance structure when the standard deviation is 35.0, the correlation 
between observations on the same subject is 0.2, and the alpha level is 0.05. We also 
investigated the power under a variety of other scenarios by varying the covariance structure 
(Compound Symmetry, Simple, AR(1), and Banded(1)) and the within-subject correlation (from 
0.1 to 0.4), all yielded satisfactory power (ranging from 79% to 99%). Importantly, power 
analyses have been performed to ensure that the study has sufficient power to detect a small to 
medium effect size for testing the primary hypothesis using a mixed effects model that takes into 
account of the repeated measures design. The varenicline trial by Litten et al. (2013) was used 
merely as a reference point and no effect sizes from that trial were used in our analyses. 
 
10.2. 
Aim 1: To test the primary hypothesis that IBUD (50mg BID) will reduce 
percent heavy drinking days, as compared to placebo, over the course of the 
12-week trial 
 
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 


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25 
 
(Weeks 1-12). 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 (GLIMMIX with PROC GLIMMIX in SAS) that includes 
treatment,  time,  treatment x 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 (see the discussion of attrition below). 
In addition to testing the treatment effects, a summary of least-square means, standard errors, 
and 95% confidence intervals (CIs) will be presented for each treatment and will be derived from 
fully adjusted models on untransformed outcomes averaged across the maintenance period. 
 
10.3. 
Missing Data and Sensitivity Analysis 
 
The intent to treat (ITT) principle requires all randomized participants to be included in the 
analyses, but one has to deal with missing outcome measures due to loss to follow-up. First of 
all, we will minimize the extent of missing data by attempting to follow up all randomized 
participants event if they withdraw from allocated treatment, and to collect information on 
reasons of loss to follow-up which can help to determine whether it is related to the outcome. 
Secondly, we plan to perform sensitivity analyses to explore the effect of departures from the 
missing data assumptions made in the efficacy analyses. Our primary efficacy model, the linear 
mixed effects model, assumes missing at random (MAR), which is plausible if the reason for 
missing data is administrative but implausible if missing data is outcome related. Sensitivity 
analyses choices will include, but are not limited to, imputation methods as well as the joint 
modeling approach. Imputation will be done in different ways including a) imputing missing 
values as heavy drinking days and b) multiple imputation similar to Litten et al. (2013) (125). In 
addition, we will consider joint models that permits non-ignorable intermittent and monotone 
missing values (127). Dr. Li is an expert on joint modeling of longitudinal data with non-ignorable 
missing data and co-author of a recent monograph on joint models (Elashoff, Li, and Li, 2016). 
All randomized participants will be accounted for in the sensitivity analyses. 
 
10.4. 
Aim 2: To test the efficacy of IBUD (50mg BID) on secondary alcohol 
consumption endpoints 
 
In this secondary aim, we plan on traditional analyses of the effects during the maintenance 
phase of the study (Weeks 1-12) on the following secondary alcohol consumption endpoints: (1) 
drinks per day, (2) drinks per drinking day, (3) percent days abstinent, (4) percent subjects with 
no heavy drinking days (PSNHDD), and (5) 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 (PSNHDD and percent 
subject abstinent), 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 (Weeks 5-12) 
(128). 
 
10.5. 
Exploratory Aim 1: To test whether the effects of IBUD (50mg BID) on the 
primary and secondary endpoints (aims 1 and 2) are moderated by 
depressive symptomatology. 
 


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Based on our finding that IBUD attenuated the stimulant effects of alcohol among individuals 
with higher depressive symptomatology, 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 (2002) (129). For the repeated measured 
efficacy outcomes, we will include depressive symptomatology in the analyses, using the mixed 
effects analysis designs described above, and testing the interactions of (depressive 
symptomatology) x treatment as well as (depressive symptomatology) x treatment x time. For 
the dichotomous outcomes (PSNHDD and percent subject abstinent), we will include depressive 
symptomatology in the logistic regression analyses, and testing the interactions of depressive 
symptomatology x 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 (2004) (130). If interactions are significant, 
we will estimate treatment effects at low, middle and high values of the moderator (Littell et al., 
1996, p. 175) (131). Further, as recommended by the reviewer, we will test whether 
physiological dependence (marked by tolerance and withdrawal) serves as a moderator of 
medication effects in this trial, using the framework proposed herein. 
 
10.6. 
Exploratory Aim 2 
 
In this exploratory aim, we will test whether IBUD (50mg BID) reduces neuroinflammation, as 
indexed by circulating blood levels of proinflammatory markers over the course of the 12-week 
trial, using the mixed effect model design. The statistical considerations are similar to aim 1 and 
thus not repeated here. 
 
11. ETHICS 
 
11.1. 
IRB Review 
 
 
The study will be conducted under a protocol reviewed by the UCLA IRB; the study is to be 
conducted by scientifically and medically qualified persons; the benefits of the study are in 
proportion to the risks; the rights and welfare of the subjects will be respected; the physicians 
conducting the study will ensure that the hazards do not outweigh the potential benefits; the 
results to be reported will be accurate; subjects will give their informed consent and will be 
competent to do so and not under duress; and all study staff will comply with the ethical 
principles in 21 Code of Federal Regulations (CFR) Part 50 and the Belmont Principles. 
 
11.1.1. Protocol Modifications 
 
All necessary protocol changes will be submitted in writing as protocol amendments to the IRB 
by the PI for approval prior to implementation.  
 
 
11.1.2. Protocol Deviation Reporting Procedures 
 
All subject-specific deviations from the protocol are to be documented. The PI or designee will 
be responsible for identifying and reporting all deviations, which are occurrences involving a 
procedure that did not follow the study protocol. Any protocol deviation that adversely affects the 


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safety or rights of a subject or scientific integrity of the study is considered a major deviation and 
will be reported immediately to the UCLA IRB. 
 
 
11.2. 
Ethical Conduct of the Study 
 
This study will be conducted in accordance with all applicable Federal human research 
protections requirements and the Belmont Principles of respect for persons, beneficence, and 
justice.  The procedures set out in this study are designed to ensure that all study personnel 
abide by the principles of the ICH GCP Guideline and the Code of Federal Regulations (CFR). 
The PI confirms this by signing FDA Form 1572. 
 
 
11.2.1. Confidentiality of Data and Subject Records  
 
To maintain subject confidentiality, all laboratory specimens, eCRFs, reports and other records 
will be identified by a subject number only. 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. 
 
 
11.2.2. Compensation for Participation 
 
 
Subjects will be compensated for travel expenses and for time contributed to this research study 
in the form of cash. Compensation will be provided at each subject visit and is detailed in the 
informed consent form. 
 
11.2.3. Written Informed Consent 
 
 
The informed consent process and document will be reviewed and approved by the IRB and 
prior to initiation of the study. The consent document contains a full explanation of the possible 
risks, advantages, and alternate treatment options, and availability of treatment in the case of 
injury, in accordance with 21 CFR Part 50. The consent document indicates that by signature, 
the subject, permits access to relevant medical records as described above. A written informed 
consent document, in compliance with 21 CFR Part 50, 32 CFR Part 219, and the Belmont 
Principles, and HIPAA Authorization will be signed by the subject before any study-related 
procedures are initiated for each subject. All potential subjects for the study will be given a 
current copy of the Informed Consent Form to read. All aspects of the study and informed 
consent will be explained in lay language to the subject by either the investigator, or a medically 
trained designee. Any subject who is unable to demonstrate understanding of the information 
contained in the informed consent will be excluded from study participation. 
All study subjects will be given a copy of the signed informed consent. 
 
11.2.4. Delegation of Responsibilities and Adequate Resources 
 
 
The PI should have adequate time to conduct the study properly and should have an adequate 
number of qualified staff to assist with the conduct of the study. The term “investigator” used 
throughout this protocol refers to the PI and/or qualified Sub-investigators. The PI may delegate 
responsibilities to other study site personnel. The PI shall delegate tasks only to individuals 
qualified by education, training, and experience to perform the delegated tasks. The PI shall 
have direct oversight of all delegated activities and shall document delegation of responsibilities. 
The PI is responsible for ensuring all delegated staff has been properly trained on the protocol 


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and their assigned study responsibilities. A delegation log identifying all delegated duties and 
the individual to whom they have been delegated will be maintained at the study site. 
 
11.2.5. Financial Disclosure 
 
Clinical investigators are required to provide financial disclosure information for the submission 
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR 
§54.2, a clinical investigator is a listed or identified investigator or sub-investigator who is 
directly involved in the treatment or evaluation of research subjects. The term also includes the 
spouse and each dependent child of the investigator. In addition, investigators must promptly 
update financial disclosure information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the study. 
 
12. DATA HANDLING AND RECORD KEEPING 
 
Source documents include but are not limited to original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, laboratory results, 
data recorded in automated instruments, and pharmacy records, etc. This study will use an 
electronic data capture (EDC) eCRF system (Qualtrics) and paper source documents. Data will 
be transcribed from source documentation directly into a statistical program such as SPSS. 
Only questionnaire data will be entered directly into eCRF (i.e., without prior written or electronic 
record of data). 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.  
The EDC system maintains a full audit trail of data entry, data corrections, and data queries. 
 
 
12.1. 
Subject Identification and Confidentiality  
 
Subjects will be identified on eCRFs and paper source documents by a unique subject number. 
No personal identifier will be used in any publication or communication used to support this 
research study. 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, FDA, and IRB, 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. 
 
12.2. 
Retention of Records 
 
The investigator is responsible for creating and/or maintaining all study documentation required 
by Title 21 Code of Federal Regulations (21CFR) Parts 50, 54, 56, and 312, ICH E6 section 8, 
as well as any other documentation defined in the protocol. The investigator must provide key 
documents to the Sponsor prior to start of the study. Federal and local regulations require that 
the investigator retain a copy of all regulatory documents and records that support the data for 
this study for whichever of the following is the longest period of time: 
 
• 
A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study drug for the purposes that were the subject of the investigation; or 
• 
A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an 


IBUD for AUD 
Protocol V10, March 1, 2022 
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29 
 
application for a research or marketing permit for the study drug for the purposes that 
were the subject of the investigation. 
 
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Study records should not be destroyed without consultation with the Sponsor. 
 
 
12.3. 
Trial Registration 
 
The PI will register the trial on the National Library of Medicine’s Clinical Trials Registry at 
http://www.clinicaltrials.gov. 
 
 


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