IBUD ph II: Trial of Ibudilast for Methamphetamine Dependence

• Sponsor: University of California, Los Angeles (Other)
• Overall Status: Completed
• CT.gov ID: NCT01860807
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 125
• Location: 1
• Arms: 2
• Duration (Months): 54
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

The objective of this study is to test the safety and potential efficacy of ibudilast to treat methamphetamine dependence. The study hypotheses are that ibudilast will reduce methamphetamine use and increase treatment retention more than placebo among patients seeking treatment for methamphetamine dependence. As HIV infection is a common complication of methamphetamine dependence, half of the participants will be HIV positive and the study will assess whether ibudilast also improves HIV related outcomes (e.g. medication adherence, CD4 count, risk behaviors).

Condition or Disease	Intervention/Treatment	Phase
Methamphetamine Dependence; HIV Infection	Drug: Ibudilast; Drug: Placebo	Phase 2

Detailed Description

Ibudilast (IBUD) is a macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE)-4 and -10 inhibitor at peak clinical exposures (Rolan, Hutchinson et al. 2009) that increases glial cell line-derived neurotrophic factor (GDNF) expression (Mizuno, Kurotani et al. 2004) and reduces microglial activation (Suzumura, Ito et al. 1999; Suzumura, Ito et al. 2003), including HIV-induced glial activation (Kiebala and Maggirwar 2011). IBUD significantly reduces methamphetamine (MA) prime- and stress-induced reinstatement of MA seeking in rats (Beardsley, Shelton et al. 2010) and has multiple effects that may make it an effective treatment for MA dependence including amelioration of dopaminergic and neuroinflammatory dysfunction. Multiple studies implicate glial cells in a variety of neurodegenerative diseases (Hirsch and Hunot 2009; Sidoryk-Wegrzynowicz, Wegrzynowicz et al. 2011) including MA dependence and HIV infection (Nath 2010). Activated glial cells secrete pro-inflammatory mediators (Minghetti, Ajmone-Cat et al. 2005) that may exacerbate MA-induced dopaminergic dysfunction. Glial cells also produce neurotrophic factors, including GDNF, which may ameliorate dopaminergic dysfunction (Pascual, Hidalgo-Figueroa et al. 2008). Thus, IBUD may be an effective medication for MA dependence due to its modulation of glial cell activation resulting in amelioration of dopaminergic and neurocognitive dysfunction and improved treatment outcomes in MA dependence. IBUD may also have unique effects in HIV positive MA users as it may additionally block the degradation of neuronal integrity seen in HIV infection (Chana, Everall et al. 2006; Dash, Gorantla et al. 2011).

Study Design

• Study Type: Interventional
• Actual Enrollment: 125 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Trial of Ibudilast for Methamphetamine Dependence
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Dec 31, 2017
• Actual Study Completion Date: Dec 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ibudilast Ibudilast 50 mg twice daily	Drug: Ibudilast
Placebo Comparator: Placebo matching placebo twice daily	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Methamphetamine Use [12 weeks]

   End of treatment methamphetamine abstinence

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 18 years of age or older;

2. meet DSM-IV-TR criteria for MA dependence (SCID verified);

3. a MA-positive urine drug screen at one or more visit during the two week lead-in period;

4. seeking treatment for MA problems;

5. willing and able to comply with study procedures;

6. provide written informed consent;

7. English speaking

8. reside within 35 miles of the clinical research site; and

9. if female of childbearing potential, not pregnant or lactating and willing to use a medically reliable method of birth control during the trial (e.g., birth control pills, Depo-Provera, and/or condoms with spermicide).

Exclusion Criteria:

1. a medical condition that, in the study physician's judgment, may interfere with safe study participation (e.g., active TB; unstable cardiac, renal, or liver disease; uncontrolled hypertension; unstable diabetes);

2. CD4 count < 50 cells/mm3 (suggestive of advanced HIV infection)

3. AST, ALT, or GGT > 3 times upper normal limit;

4. A corrected QT of > 450 msecs in men or > 460 msec in women on at least two ECGs during the baseline period, or clinical risk factors for Torsades de Pointes (e.g. (e.g., heart failure, hypokalemia, family history of Long QT Syndrome), or requiring ongoing treatment with concomitant medication(s) with established risk of Torsades de Pointes (e.g. Amiodarone, Arsenic trioxide, Astemizole, Bepridil, Chloroquine, Chlorpromazine, Cisapride, Citalopram, Clarithromycin, Disopyramide, Dofetilide, Domperidone, Droperidol, Erythromycin, Flecainide, Halofantrine, Haloperidol, Ibutilide, Levomethadyl, Mesoridazine, Methadone, Moxifloxacin, Pentamidine, Pimozide, Probucol, Procainamide, Quinidine, Sotalol, Sparfloxacin, Terfenadine, Thioridazine, Vandetanib);

5. current ongoing treatment with psychotropic medications (e.g., antidepressants, antipsychotics, antiepileptics, sedative/hypnotics, narcotic analgesics);

6. a neurological disorder (e.g., organic brain disease, dementia) or a medical condition which would make study agent compliance difficult or which would compromise informed consent;

7. a major psychiatric disorder not due to substance abuse (e.g., schizophrenia, bipolar disorder) as assessed by the SCID;

8. attempted suicide in the past 3 years and/or serious suicidal intention or plan in the past year as assessed by the C-SSRS;

9. currently on prescription medication that is contraindicated for use with IBUD including alpha or beta agonists, theophylline, or other sympathomimetics;

10. current dependence on cocaine, opiates, alcohol, or benzodiazepines as defined by DSM-IV-TR;

11. alcohol dependence within the past year;

12. greater than one urine specimens during the lead-in with a riboflavin concentration of < 900 ng/ml as assessed via UV fluorescence;

13. a history of sensitivity to IBUD; or

14. any other circumstances that, in the opinion of the investigators, would compromise participant safety;

15. current participation in another clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Vine Street Clinic	Los Angeles	California	United States	90038

Sponsors and Collaborators

• University of California, Los Angeles
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Keith Heinzerling, MD, University of California, Los Angeles

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 11, 2016

More Information

Publications

None provided.

• Responsible Party: Keith Heinzerling, Associate Professor in Residence, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT01860807
• Other Study ID Numbers: 1R01DA035054-01; R01DA035054
• First Posted: May 23, 2013
• Last Update Posted: Jan 30, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Keith Heinzerling, Associate Professor in Residence, University of California, Los Angeles: methamphetamine; ibudilast; HIV
• Additional relevant MeSH terms: HIV Infections; Ibudilast

Study Results

Participant Flow

Arm/Group Title	Ibudilast	Placebo
Arm/Group Description	Ibudilast 50 mg twice daily Ibudilast	matching placebo twice daily Placebo
Period Title: Overall Study
STARTED	64	61
COMPLETED	34	32
NOT COMPLETED	30	29

Baseline Characteristics

Arm/Group Title	Ibudilast	Placebo	Total
Arm/Group Description	Ibudilast 50 mg twice daily Ibudilast	matching placebo twice daily Placebo	Total of all reporting groups
Overall Participants	64	61	125
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.9 (9.0)	42.8 (10.5)	41.9 (10.0)
Sex: Female, Male (Count of Participants)
Female	15 23.4%	18 29.5%	33 26.4%
Male	49 76.6%	43 70.5%	92 73.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	30 46.9%	30 49.2%	60 48%
Not Hispanic or Latino	34 53.1%	31 50.8%	65 52%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 3.1%	2 3.3%	4 3.2%
Asian	4 6.3%	2 3.3%	6 4.8%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.6%	1 0.8%
Black or African American	7 10.9%	7 11.5%	14 11.2%
White	29 45.3%	30 49.2%	59 47.2%
More than one race	1 1.6%	0 0%	1 0.8%
Unknown or Not Reported	21 32.8%	19 31.1%	40 32%
Baseline methamphetamine use on 26 or more days per month (Count of Participants)
Count of Participants [Participants]	33 51.6%	33 54.1%	66 52.8%

Outcome Measures

1. Primary Outcome

Title	Methamphetamine Use
Description	End of treatment methamphetamine abstinence
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ibudilast	Placebo
Arm/Group Description	Ibudilast 50 mg twice daily Ibudilast	matching placebo twice daily Placebo
Measure Participants	64	61
Count of Participants [Participants]	9 14.1%	10 16.4%

Adverse Events

Time Frame	12 week medication treatment period and 4 week post-treatment follow-up period
Arm/Group Title	Ibudilast		Placebo
Arm/Group Description	Ibudilast 50 mg twice daily Ibudilast		matching placebo twice daily Placebo
All Cause Mortality
	Ibudilast		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/61 (0%)
Serious Adverse Events
	Ibudilast		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/64 (3.1%)		1/61 (1.6%)
Cardiac disorders
Chest Pain	0/64 (0%)	0	1/61 (1.6%)	1
Nervous system disorders
Convulsion	1/64 (1.6%)	1	0/61 (0%)	0
Psychiatric disorders
Suicide Attempt	1/64 (1.6%)	1	0/61 (0%)	0
Other (Not Including Serious) Adverse Events
	Ibudilast		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	57/64 (89.1%)		32/61 (52.5%)
Gastrointestinal disorders
Nausea	11/64 (17.2%)		9/61 (14.8%)
Diarrhea	8/64 (12.5%)		7/61 (11.5%)
Nervous system disorders
Headache	32/64 (50%)		11/61 (18%)
Psychiatric disorders
Insomnia	10/64 (15.6%)		5/61 (8.2%)

Limitations/Caveats

Study did not determine if ibudilast may help patients who have stopped methamphetamine use prior to starting medication

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.