Clinical trial NCT03489850: Ibudilast and Withdrawal-Related Dysphoria
Official title: Withdrawal-Related Dysphoria as a Moderator of Ibudilast for Alcohol Use Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alcohol Use Disorder
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
First posted: 2018-04-06
Enrollment: 52
Sex: ALL
Minimum age (years): 21
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Alcohol use disorder (AUD) is a prevalent and disabling psychiatric disorder with few, and only moderately efficacious, treatment options. Consequently, the identification of novel treatment targets and the development of rigorous laboratory paradigms to screen and optimize novel therapeutics represents a research priority. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor. Recently in an AUD sample, IBUD was shown to decrease reactivity to a psychological stressor. Furthermore, IBUD was effective in blunting alcohol reward among participants with greater depressive symptoms, a hallmark symptom of protracted withdrawal. Recently, preclinical research in opiates has demonstrated that drug withdrawal is necessary for microglia activation and neuroinflammation in reward networks, suggesting that IBUD may be most effective among patients who experience withdrawal-related dysphoria. Therefore, this proposed study aims to examine withdrawal-related dysphoria as a moderator of IBUD efficacy in the natural environment measured using Daily Diary Assessment (DDA) approaches. To accomplish this aim, participants meeting criteria for AUD and balanced on the presence of withdrawal-related dysphoria will be enrolled in a double-blinded IBUD trial including consisting of two weeks randomized to medication and DDA assessment. The proposed research aims are:

Aim 1: Test whether IBUD reduces basal negative affect in abstinence, and blunts alcohol-related negative reinforcement. It is hypothesized that IBUD will reduce basal levels of negative affect during alcohol abstinence, and in so doing will interfere with alcohol-induced blunting of negative affectivity as captured during naturalistic drinking episodes.

Aim 2: Test whether IBUD attenuates neural alcohol cue-reactivity. It is hypothesized that IBUD will reduce BOLD activation to alcohol cues in mesocorticolimbic reward circuitry.

Aim 3: Test whether withdrawal-related dysphoria moderates the effects of IBUD. It is hypothesized that IBUD will alleviate basal negative affect, interfere with alcohol-induced negative reinforcement and attenuate BOLD activation to alcohol cues only among participants who experience dysphoria in withdrawal.

Aim 4: Test whether neural activation to alcohol cues is predictive of drinking outcomes. It is hypothesized that individuals with higher mesocorticolimbic activation to alcohol cues will report more drinking in the week following the neuroimaging session.


Eligibility criteria: Inclusion Criteria:

1. Age between 21 and 45
2. Meet DSM-5 criteria for current Moderate-to-Severe AUD
3. Current Heavy Drinking (\> 14 drinks per week for men; \> 7 drinks per week for women), as indicated by self-reported drinking for the 30 days prior to screening
4. Have reliable internet access

Exclusion Criteria:

1. Currently receiving or seeking treatment for AUD\*
2. Past year DSM-5 diagnosis of any substance use disorder other than alcohol or nicotine
3. A lifetime diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder
4. Current use of drugs, other than marijuana, verified by a urine toxicology screen\*
5. Pregnant, nursing, or refusal to use reliable birth control (if female)\*
6. A medical condition that may interfere with safe participation (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension, diabetes, or AST, ALT, or GGT ≥ 3 times upper normal limit)
7. Self-reported recent (i.e. past 30 day) use of medications that are contraindicated with ibudilast\*
8. Non-removable ferromagnetic objects in body
9. Claustrophobia
10. Serious head injury or prolonged period of unconsciousness (\>30 minutes)

    * Participants who meet these criteria at any point during the course of the study (i.e. after randomization) will be withdrawn from the study for safety purposes.

Primary outcomes:
measure: Negative Affect
timeFrame: Assessed through daily prompts throughout the 2-week study period.
Secondary outcomes:
measure: Heavy Drinking
timeFrame: 14 days
measure: Any Drinking
timeFrame: 14 days
measure: Ventral Striatum Activation
timeFrame: Day 8
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
Study officials:
affiliation: University of California, Los Angeles
name: Lara A Ray, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ray LA, Bujarski S, Shoptaw S, Roche DJ, Heinzerling K, Miotto K. Development of the Neuroimmune Modulator Ibudilast for the Treatment of Alcoholism: A Randomized, Placebo-Controlled, Human Laboratory Trial. Neuropsychopharmacology. 2017 Aug;42(9):1776-1788. doi: 10.1038/npp.2017.10. Epub 2017 Jan 16.
citation: Burnette EM, Ray LA, Irwin MR, Grodin EN. Ibudilast attenuates alcohol cue-elicited frontostriatal functional connectivity in alcohol use disorder. Alcohol Clin Exp Res. 2021 Oct;45(10):2017-2028. doi: 10.1111/acer.14696. Epub 2021 Sep 29.