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Ibudilast and Withdrawal-Related Dysphoria

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ClinicalTrials.gov Identifier: NCT03489850
Recruitment Status : Completed
First Posted : April 6, 2018
Results First Posted : October 7, 2021
Last Update Posted : October 7, 2021
Sponsor:
Information provided by (Responsible Party):
Lara Ray, PhD, University of California, Los Angeles

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Alcohol Use Disorder
Interventions Drug: Ibudilast
Other: Placebo
Enrollment 52
Recruitment Details This study was conducted at an outpatient research clinic in a medical center. Participants were recruited through social media and mass transit advertisements. Initial screening was conducted through telephone interview, with eligible participants invited for an in-person assessment.
Pre-assignment Details  
Arm/Group Title Ibudilast Placebo
Hide Arm/Group Description

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

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

Matched to active

Placebo: Placebo is matched to ibudilast active medication.

Period Title: Overall Study
Started 24 28
Completed 23 27
Not Completed 1 1
Arm/Group Title Ibudilast Placebo Total
Hide Arm/Group Description

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

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

Matched to active

Placebo: Placebo is matched to ibudilast active medication.

Total of all reporting groups
Overall Number of Baseline Participants 24 28 52
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 24 participants 28 participants 52 participants
34.46  (9.24) 31.07  (7.81) 32.63  (8.58)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 28 participants 52 participants
Female
8
  33.3%
10
  35.7%
18
  34.6%
Male
16
  66.7%
18
  64.3%
34
  65.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 28 participants 52 participants
Hispanic or Latino
5
  20.8%
7
  25.0%
12
  23.1%
Not Hispanic or Latino
19
  79.2%
21
  75.0%
40
  76.9%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 28 participants 52 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
5
  17.9%
5
   9.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   3.6%
1
   1.9%
Black or African American
5
  20.8%
2
   7.1%
7
  13.5%
White
17
  70.8%
12
  42.9%
29
  55.8%
More than one race
1
   4.2%
5
  17.9%
6
  11.5%
Unknown or Not Reported
1
   4.2%
3
  10.7%
4
   7.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 24 participants 28 participants 52 participants
24 28 52
Education  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 24 participants 28 participants 52 participants
15.25  (2.64) 15.21  (1.75) 15.23  (2.18)
Withdrawal Related Dysphoria  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 28 participants 52 participants
9
  37.5%
11
  39.3%
20
  38.5%
Alcohol Use Disorder Symptom Count  
Mean (Standard Deviation)
Unit of measure:  Symptoms
Number Analyzed 24 participants 28 participants 52 participants
5.29  (2.37) 4.86  (2.27) 5.06  (2.30)
Alcohol Use Disorder Identification Test Total Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Score on scale
Number Analyzed 24 participants 28 participants 52 participants
16.38  (5.90) 16.71  (6.42) 16.56  (6.12)
[1]
Measure Description: The AUDIT has 10 questions and the possible responses to each question are scored 0, 1, 2, 3 or 4, with the exception of questions 9 and 10 which have possible responses of 0, 2 and 4. The range of possible scores is from 0 to 40 where 0 indicates an abstainer who has never had any problems from alcohol. A score of 1 to 7 suggests low-risk consumption according to World Health Organization (WHO) guidelines. Scores from 8 to 14 suggest hazardous or harmful alcohol consumption and a score of 15 or more indicates the likelihood of alcohol dependence (moderate-severe alcohol use disorder).
Alcohol Dependence Scale Total Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Score on scale
Number Analyzed 24 participants 28 participants 52 participants
13.00  (6.10) 12.07  (7.01) 12.50  (6.56)
[1]
Measure Description: Total scores can range from 0-47. A score of 0 indicates no symptoms. Scores from 1-13 indicate low level of dependence. Scores from 14-21 indicate intermediate levels of dependence. Scores from 22-30 indicate a substantial level of dependence. Scores above 30 indicate a severe level of dependence.
Penn Alcohol Craving Scale Total Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 24 participants 28 participants 52 participants
12.79  (5.14) 12.11  (7.04) 12.43  (6.18)
[1]
Measure Description: 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. Scores can range from 0-30. A score of 0 indicates no craving for alcohol. Higher scores indicate higher craving for alcohol.
Obsessive Compulsive Drinking Scale Total Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 24 participants 28 participants 52 participants
14.54  (6.05) 13.93  (8.07) 14.21  (7.15)
[1]
Measure Description: The Obsessive Compulsive Drinking Scale (OCDS) is a 14-item self-rating instrument that provides a total score that measures some cognitive aspects of alcohol craving. The total score range is from 0-40, with higher scores indicating greater severity of AUD. An OCDS total score of 7 and above discriminates between social drinkers and alcohol dependent drinkers, with a sensitivity of 93% and a specificity of 98%.
Reasons for Heavy Drinking Questionnaire - Reinforcing   [1] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 24 participants 28 participants 52 participants
23.29  (3.51) 22.82  (4.88) 23.04  (4.27)
[1]
Measure Description: The Reasons for Heavy Drinking Questionnaire is a brief assessment of motivations for heavy alcohol use. The Reinforcing sub-scale measures the tendency to drink for hedonic (positive reinforcement) and stress relief (negative reinforcement) motivations. Items 1-3 make up the reinforcement sub-scale. Scores range from 0-30. Higher scores indicate more endorsement of drinking motivation for reinforcement.
Reasons for Heavy Drinking Questionnaire - Normalizing   [1] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 24 participants 28 participants 52 participants
9.67  (7.10) 8.29  (7.34) 8.92  (7.20)
[1]
Measure Description: The Reasons for Heavy Drinking Questionnaire is a brief assessment of motivations for heavy alcohol use. The Normalizing sub-scale measures the tendency to drink to feel normal ore avoid withdrawal symptoms. Items 4-6 make up the reinforcement sub-scale. Scores range from 0-30. Higher scores indicate more endorsement of drinking motivation to feel normal.
Total Drinks   [1] 
Mean (Standard Deviation)
Unit of measure:  Drinks over prior 30 days
Number Analyzed 24 participants 28 participants 52 participants
122.89  (64.58) 114.9  (108.72) 118.20  (90.32)
[1]
Measure Description: Total drinks measures the number of total standard alcoholic drinks consumed as reported on the 30-day Timeline Followback Interview (TLFB).
Drinking Days   [1] 
Mean (Standard Deviation)
Unit of measure:  Number of days in the prior 30 days
Number Analyzed 24 participants 28 participants 52 participants
22.21  (6.87) 20.25  (6.51) 21.15  (6.68)
[1]
Measure Description: Drinking days measures the number of days an alcohol drink was consumed as reported on the 30-day Timeline Followback Interview (TLFB).
Drinks Per Day   [1] 
Mean (Standard Deviation)
Unit of measure:  Average drinks over prior 30 days
Number Analyzed 24 participants 28 participants 52 participants
4.10  (2.15) 3.81  (3.62) 3.94  (3.01)
[1]
Measure Description: Drinks per day measures the number of total standard alcoholic drinks consumed divided by 30 days (average number of drinks per day over 30 days) as reported on the 30-day Timeline Followback Interview (TLFB).
Drinks Per Drinking Day  
Mean (Standard Deviation)
Unit of measure:  Drinks
Number Analyzed 24 participants 28 participants 52 participants
5.70  (2.58) 5.34  (3.57) 5.51  (3.13)
Heavy Drinking Days   [1] 
Mean (Standard Deviation)
Unit of measure:  Number of heavy drinking days
Number Analyzed 24 participants 28 participants 52 participants
10.79  (8.29) 8.68  (8.04) 9.65  (8.15)
[1]
Measure Description: Heavy drinking days measures the number of days an individual met heavy drinking standards as reported on the 30-day Timeline Followback Interview (TLFB). Heavy drinking is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as ≥5 drinks/day for men and ≥4 drinks/day for women.
Cigarette Smokers  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 28 participants 52 participants
11
  45.8%
14
  50.0%
25
  48.1%
Fagerstrom Test for Nicotine Dependence Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Score on scale
Number Analyzed 24 participants 28 participants 52 participants
2.82  (2.82) 1.07  (1.54) 1.96  (2.27)
[1]
Measure Description: The Fagerstrom Test for Nicotine Dependence is summed to yield a total score of 0-10. The higher the total Fagerström score, the more intense is the patient's physical dependence on nicotine.
Total Cigarettes   [1] 
Mean (Standard Deviation)
Unit of measure:  Number of cigarettes smoked prior 30 day
Number Analyzed 24 participants 28 participants 52 participants
52.28  (79.85) 133.07  (205.78) 102.44  (197.18)
[1]
Measure Description: Total cigarettes measures the number of total cigarettes smoked as reported on the 30-day Timeline Followback Interview (TLFB).
Cigarettes Per Day  
Mean (Standard Deviation)
Unit of measure:  Cigarettes
Number Analyzed 24 participants 28 participants 52 participants
7.39  (8.70) 5.06  (6.76) 6.14  (7.73)
THC+ Urine  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 28 participants 52 participants
7
  29.2%
8
  28.6%
15
  28.8%
Cannabis Days   [1] 
Mean (Standard Deviation)
Unit of measure:  Number of days used in prior 30 days
Number Analyzed 24 participants 28 participants 52 participants
11.38  (9.99) 8.15  (8.24) 9.64  (9.14)
[1]
Measure Description: Cannabis days measures the number of days cannabis was used as reported on the 30-day Timeline Followback Interview (TLFB). Cannabis use was assessed by a binary yes or no for each day.
Beck Depression Inventory-II Total Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 24 participants 28 participants 52 participants
12.42  (8.47) 8.64  (7.2) 10.38  (8.27)
[1]
Measure Description: The Beck Depression Inventory-II is a 21-item self-administered survey which is scored on a scale of 0-3 in a list of four statements arranged in increasing severity about a particular symptom of depression. The scores are summed to give a total score. Scores of 0-13 indicate minimal symptoms of depression; scores of 14-19 indicate mild symptoms of depression; scores of 20-28 indicate moderate symptoms of depression; and scores of 29-63 indicate severe symptoms of depression;
1.Primary Outcome
Title Negative Affect
Hide Description Negative affect as measured by self-reported ratings of "Downhearted", "Discouraged", "Uneasy", and "Anxious". Each item was rated on a scale from 0 (not at all) to 4 (extremely). The 4 items were summed for the total negative affect score for each day, ranging from 0 - 16. Higher scores indicate more negative mood.
Time Frame Assessed through daily prompts throughout the 2-week study period.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ibudilast Placebo
Hide Arm/Group Description:

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

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

Matched to active

Placebo: Placebo is matched to ibudilast active medication.

Overall Number of Participants Analyzed 24 28
Least Squares Mean (Standard Error)
Unit of Measure: units
2.91  (0.55) 2.47  (0.41)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ibudilast, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .62
Comments [Not Specified]
Method Generalized Estimating Equation
Comments [Not Specified]
Method of Estimation Estimation Parameter Parameter Estimate
Estimated Value 0.34
Confidence Interval (2-Sided) 95%
-1.01 to 1.69
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.69
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Heavy Drinking
Hide Description Medication effects on number of heavy drinking days. Heavy drinking is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as ≥5 drinks/day for men and ≥4 drinks/day for women. Values indicate estimated probability of a heavy drinking day across time for each group.
Time Frame 14 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ibudilast Placebo
Hide Arm/Group Description:

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

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

Matched to active

Placebo: Placebo is matched to ibudilast active medication.

Overall Number of Participants Analyzed 24 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: predicted probability in percent
24.16
(17.12 to 32.94)
36.80
(28.43 to 46.05)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ibudilast, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Generalized Estimating Equation
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.55
Confidence Interval (2-Sided) 95%
.30 to .98
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Any Drinking
Hide Description Medication effects on number of days where any drinking was reported. . Values indicate estimated probability of a drinking day across time for each group.
Time Frame 14 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ibudilast Placebo
Hide Arm/Group Description:

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

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

Matched to active

Placebo: Placebo is matched to ibudilast active medication.

Overall Number of Participants Analyzed 24 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: predicted probability in percent
59.25
(47.62 to 69.92)
63.63
(54.65 to 71.75)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ibudilast, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Generalized Estimating Equation
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.47 to 1.48
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Ventral Striatum Activation
Hide Description Medication effect on alcohol cue-induced ventral striatal activation. Participants completed an fMRI alcohol cue-reactivity paradigm where they viewed pictures of alcoholic beverages, non-alcoholic beverages, blurred images, and a plus sign. The mean percent signal change between the ALC and BEV blocks was extracted from an a priori defined region of interest: bilateral ventral striatum (VS), 6 mm-radius sphere centered at ±12 6 9 in MNI space.
Time Frame Day 8
Hide Outcome Measure Data
Hide Analysis Population Description
Participants were excluded from neuroimaging analyses for the following reasons: participant missed mid-point study visit (n=1, placebo); participant could not be scanned due to COVID-19 safety restrictions (n=1, placebo); participant began scan but ended early due to claustrophobia (n=1, ibudilast); scanner issues prevented the collection of alcohol cue reactivity data (n=1, ibudilast); and participant was found to be not safe for MRI scanning on the day-of the study visit (n=1, ibudilast).
Arm/Group Title Ibudilast Placebo
Hide Arm/Group Description:

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

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

Matched to active

Placebo: Placebo is matched to ibudilast active medication.

Overall Number of Participants Analyzed 20 25
Mean (Standard Deviation)
Unit of Measure: percent signal change
-0.08  (0.20) 0.14  (0.32)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ibudilast, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter F
Estimated Value 7.36
Estimation Comments [Not Specified]
Time Frame 2 weeks
Adverse Event Reporting Description Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
 
Arm/Group Title Ibudilast Placebo
Hide Arm/Group Description

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

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

Matched to active

Placebo: Placebo is matched to ibudilast active medication.

All-Cause Mortality
Ibudilast Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/24 (0.00%)      0/28 (0.00%)    
Hide Serious Adverse Events
Ibudilast Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/24 (0.00%)      0/28 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Ibudilast Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   14/24 (58.33%)      18/28 (64.29%)    
Gastrointestinal disorders     
Nausea  1  6/24 (25.00%)  6 3/28 (10.71%)  3
Vomiting  1  1/24 (4.17%)  1 1/28 (3.57%)  1
Diarrhea  1  1/24 (4.17%)  1 0/28 (0.00%)  0
Dyspepsia  1  1/24 (4.17%)  1 2/28 (7.14%)  2
Frequent Bowel Movements  1  1/24 (4.17%)  1 0/28 (0.00%)  0
General disorders     
Gut pain  1  0/24 (0.00%)  0 1/28 (3.57%)  1
Cold Sweat  1  1/24 (4.17%)  1 0/28 (0.00%)  0
Lethargy  1  1/24 (4.17%)  1 1/28 (3.57%)  1
Nervous system disorders     
Dizziness  1  0/24 (0.00%)  0 1/28 (3.57%)  1
Headache  1  1/24 (4.17%)  1 1/28 (3.57%)  1
Disorientation  1  1/24 (4.17%)  1 0/28 (0.00%)  0
Blurred Vision  1  1/24 (4.17%)  1 0/28 (0.00%)  0
Somnolence  1  0/24 (0.00%)  0 1/28 (3.57%)  1
Insomnia  1  2/24 (8.33%)  2 1/28 (3.57%)  1
Psychiatric disorders     
Libido Increased  1  0/24 (0.00%)  0 1/28 (3.57%)  1
Depression  1  0/24 (0.00%)  0 3/28 (10.71%)  3
Anxiety  1  2/24 (8.33%)  2 1/28 (3.57%)  1
Grief Reaction  1  0/24 (0.00%)  0 1/28 (3.57%)  1
Irritability  1  1/24 (4.17%)  1 1/28 (3.57%)  1
Respiratory, thoracic and mediastinal disorders     
Cold (Influenza)  1  2/24 (8.33%)  2 2/28 (7.14%)  2
Asthmatic Crisis  1  1/24 (4.17%)  1 0/28 (0.00%)  0
1
Term from vocabulary, MedDRA v22.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Lara Ray
Organization: University of California Los Angeles
Phone: 310-794-5383
EMail: lararay@psych.ucla.edu
Layout table for additonal information
Responsible Party: Lara Ray, PhD, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT03489850    
Other Study ID Numbers: IRB#17-001741
First Submitted: March 8, 2018
First Posted: April 6, 2018
Results First Submitted: April 9, 2021
Results First Posted: October 7, 2021
Last Update Posted: October 7, 2021