Ibudilast and Withdrawal-Related Dysphoria

NCT03489850 | Completed Phase 2 Results FDA Drug

• 1 other identifier: IRB#17-001741
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

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.

Conditions

Alcohol Use Disorder

Outcome Measures

Primary Outcomes (1)

• Negative Affect

  Negative affect as measured by self-reported ratings of "Downhearted", "Discouraged", "Uneasy", and "Anxious". Each item was rated on a scale from 0 (not at all) to 4 (extremely). The 4 items were summed for the total negative affect score for each day, ranging from 0 - 16. Higher scores indicate more negative mood.

  Assessed through daily prompts throughout the 2-week study period.

Secondary Outcomes (3)

• Heavy Drinking

  14 days

• Any Drinking

  14 days

• Ventral Striatum Activation

  Day 8

Study Arms (2)

Ibudilast

ACTIVE COMPARATOR

20mg BID Days 1-2 50mg BID Days 3-14

Drug: Ibudilast

Placebo

PLACEBO COMPARATOR

Matched to active

Other: Placebo

Interventions

Ibudilast DRUG

Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.

Ibudilast

Placebo OTHER

Placebo is matched to ibudilast active medication.

Placebo

Eligibility Criteria

• Age: 21 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age between 21 and 45
• Meet DSM-5 criteria for current Moderate-to-Severe AUD
• 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
• Have reliable internet access

You may not qualify if:

• Currently receiving or seeking treatment for AUD\*
• Past year DSM-5 diagnosis of any substance use disorder other than alcohol or nicotine
• A lifetime diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder
• Current use of drugs, other than marijuana, verified by a urine toxicology screen\*
• Pregnant, nursing, or refusal to use reliable birth control (if female)\*
• 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)
• Self-reported recent (i.e. past 30 day) use of medications that are contraindicated with ibudilast\*
• Non-removable ferromagnetic objects in body
• Claustrophobia
• 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.

Sponsors & Collaborators

• University of California, Los Angeles: lead

Study Sites (1)

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

Related Publications (2)

• 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.

  PMID: 28091532 BACKGROUND

• 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.

  PMID: 34585396 DERIVED

MeSH Terms

Conditions

Alcoholism

Interventions

ibudilast

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Results Point of Contact

• Title: Dr. Lara Ray
• Organization: University of California Los Angeles

lararay@psych.ucla.edu

310-794-5383

Study Officials

• Lara A Ray, PhD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 8, 2018
• First Posted: April 6, 2018
• Study Start: July 16, 2018
• Primary Completion: March 31, 2020
• Study Completion: March 31, 2020
• Last Updated: October 7, 2021
• Results First Posted: October 7, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)