Disulfiram for Cocaine Abuse

• Sponsor: University of Arkansas (Other)
• Overall Status: Completed
• CT.gov ID: NCT00395850
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 118
• Location: 1
• Arms: 4
• Duration (Months): 56
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

This study examines the influence of dopamine beta-hydroxylase enzyme activity on the clinical efficacy of the novel pharmacotherapy, disulfiram, for treating cocaine dependence in cocaine-dependent patients, some of whom are opioid dependent and maintained on an FDA-approved opioid agonist. Cocaine dependence as well as co-morbid cocaine and opioid-dependence is associated with more public health issues and poorer treatment prognosis when admitted to methadone maintenance. Yet no effective pharmacotherapies have been developed to treat cocaine dependence to date. One novel pharmacotherapy, disulfiram, has shown some promise as a treatment for this disorder in several clinical trials at a dose of 250 mg/day or more (e.g., Carroll et al., 1998, 2004). This 14-week, randomized, double blind clinical trial will provide treatment for up to160 cocaine-dependent individuals, aged 18-65 years. Participants who are opioid dependent will be stabilized on methadone maintenance during the first 2 weeks and baseline cocaine use will be assessed; participants will be stratified by DBH genotype and randomly assigned to receive disulfiram at either 0, 250, 375 or 500 mg/day. During induction onto methadone for opioid dependent individuals, participants are administered increasing doses of methadone on a daily basis until maintenance doses are attained. At the beginning of week 3, participants receive methadone, if relevant, plus disulfiram or placebo disulfiram according to their randomized assignments, and are maintained on study medication(s) through week 14. At the end of the study, participants will undergo detoxification from the opioid agonist, if relevant, and active/placebo medication over a 4- to 6-week period. All participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment) with experienced clinicians specifically trained to deliver the therapy and who will receive ongoing supervision. Participants undergo a delay discounting session during week 1. The primary outcomes will be retention, reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses, and disulfiram side-effects profile. Secondary outcomes will include reductions in other illicit drug and alcohol use, and improvements in psychosocial functioning. The prognostic relevance of genotype at the DBH locus, DβH activity, etc., on response to disulfiram will be examined.

Condition or Disease	Intervention/Treatment	Phase
Cocaine Dependence	Drug: Disulfiram	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 118 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Disulfiram for Cocaine Abuse
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 1 microcrystalline cellulose	Drug: Disulfiram; Disulfiram at 0, 250, 375, or 500 mg/day for 12 weeks
Experimental: 2 disulfiram at 250 mg/day	Drug: Disulfiram; Disulfiram at 0, 250, 375, or 500 mg/day for 12 weeks
Experimental: 3 Disulfiram at 375 mg/day	Drug: Disulfiram; Disulfiram at 0, 250, 375, or 500 mg/day for 12 weeks
Experimental: 4 Disulfiram at 500 mg/day	Drug: Disulfiram; Disulfiram at 0, 250, 375, or 500 mg/day for 12 weeks

Outcome Measures

Primary Outcome Measures

1. Cocaine Use Over Time [thrice weekly for 12 weeks]

   Urine toxicology results (dichotomous: positive or negative) for the presence of cocaine/cocaine metabolite during the disulfiram phase of the study. The change in the probability of a cocaine positive urine sample per day was assessed for each dose compared with placebo and slopes for each dose condition were calculated from Repeated Measures Genearlized Linear Models on a Binomial distribution (thus a Repeated Measures Logistic Regression)

Secondary Outcome Measures

1. Retention [14 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• current users of cocaine, including having a cocaine-positive urine

• self-reported use of > 7 gm during the preceding 6 months and > 1 time/week in at least one month preceding study entry

• meet DSM-IV criteria for cocaine dependence

Exclusion Criteria:

• current diagnosis of alcohol dependence

• significant medical conditions such as abnormal liver function

• active hepatitis

• hypertension

• a current cardiac condition or high risk of cardiovascular disease

• seizure disorders

• any another significant underlying medical condition which would contraindicate disulfiram or methadone treatment

• meeting DSM-IV psychiatric classifications for schizophrenia, bipolar disorder, or other psychotic disorders

• exhibiting current suicidality or homicidality

• pregnancy

• current use of a prescribed psychotropic medication (e.g., antidepressants, anxiolytics, antipsychotics, anticonvulsants, etc.) which cannot be discontinued current use of medications such as anticoagulants, isoniazid, metronidazole, clotrimazole, and paraldehyde.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205

Sponsors and Collaborators

• University of Arkansas
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Alison Oliveto, Ph.D., University of Arkansas

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Arkansas
• ClinicalTrials.gov Identifier: NCT00395850
• Other Study ID Numbers: NIDA-13441; 5R01DA013441-02; 5R01DA013441-03; 5R01DA013441-04; 5R01DA013441-06; 1R01DA013441-01A1; 7R01DA013441-05; 5R01DA013441-09; 5R01DA013441-10; 5R01DA013441-08; R01DA013441; DPMC
• First Posted: Nov 3, 2006
• Last Update Posted: Nov 13, 2013
• Last Verified: Sep 1, 2013

• Keywords provided by University of Arkansas: cocaine dependence; disulfiram; clinical trial; methadone maintenance; pharmacogenetics; dopamine beta-hydroxylase
• Additional relevant MeSH terms: Cocaine-Related Disorders; Disulfiram

Study Results

Participant Flow

Recruitment Details	Recruitment occurred between April 2006 and September 2011. Opioid- or nonopioid dependent treatment seekers recruited via newspaper ads, radio ads, flyer, word-of-mouth and referrals and attended the Treatment Research Unit, initially located in an off-campus facility and then relocated to the the Psychiatric Research Institute (12/08).
Pre-assignment Detail	Participants underwent either a two-week induction onto methadone (if opioid dependent) or a two-week baseline period prior to randomization to the treatment arms and receiving medication starting in week 3. Those receiving at >1 dose of medication and completing assessments at at least 2 time points during week 3 were include in the analyses.

Arm/Group Title	Placebo	Disulfiram 250	Disulfiram 375	Disulfiram 500
Arm/Group Description	microcrystalline cellulose	disulfiram at 250 mg/day	Disulfiram at 375 mg/day	Disulfiram at 500 mg/day
Period Title: Pre-randomization Baseline/Induction
STARTED	118	0	0	0
COMPLETED	107	0	0	0
NOT COMPLETED	11	0	0	0
Period Title: Pre-randomization Baseline/Induction
STARTED	27	25	30	25
COMPLETED	22	23	24	21
NOT COMPLETED	5	2	6	4
Period Title: Pre-randomization Baseline/Induction
STARTED	20	23	24	21
COMPLETED	11	9	5	8
NOT COMPLETED	9	14	19	13

Baseline Characteristics

Arm/Group Title	Placebo	Disulfiram 250	Disulfiram 375	Disulfiram 500	Total
Arm/Group Description	microcrystalline cellulose	disulfiram at 250 mg/day	Disulfiram at 375 mg/day	Disulfiram at 500 mg/day	Total of all reporting groups
Overall Participants	27	25	30	25	107
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	27 100%	25 100%	30 100%	25 100%	107 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.0 (12.4)	39.8 (11.3)	39.4 (10.1)	40.4 (10.1)	40.6 (11.0)
Sex: Female, Male (Count of Participants)
Female	10 37%	10 40%	13 43.3%	8 32%	41 38.3%
Male	17 63%	15 60%	17 56.7%	17 68%	66 61.7%
Region of Enrollment (participants) [Number]
United States	27 100%	25 100%	30 100%	25 100%	107 100%

Outcome Measures

1. Primary Outcome

Title	Cocaine Use Over Time
Description	Urine toxicology results (dichotomous: positive or negative) for the presence of cocaine/cocaine metabolite during the disulfiram phase of the study. The change in the probability of a cocaine positive urine sample per day was assessed for each dose compared with placebo and slopes for each dose condition were calculated from Repeated Measures Genearlized Linear Models on a Binomial distribution (thus a Repeated Measures Logistic Regression)
Time Frame	thrice weekly for 12 weeks

Outcome Measure Data

Analysis Population Description

number is based on those who participated long enough to have assessments completed at two time points during the disulfiram phase

Arm/Group Title	Placebo	Disulfiram 250	Disulfiram 375	Disulfiram 500
Arm/Group Description	microcrystalline cellulose	disulfiram at 250 mg/day	Disulfiram at 375 mg/day	Disulfiram at 500 mg/day
Measure Participants	27	25	30	25
Number [slope (change in prob of coc-pos utox/d)]	0.01	0.007	-0.01	0.007

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Disulfiram 250, Disulfiram 375, Disulfiram 500
	Comments	Used placebo group as contrast to determine whether slopes of disulfiram groups differed from slope of placebo group data
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Repeated Measures Logistic Regression
	Comments	Repeated Measures Generalized Linear Models on a Binomial distribution, thus a Repeated Measures Logistic Regression
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-1.02
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Retention
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

those who were entered the disulfiram phase,e tc.

Arm/Group Title	Placebo	Disulfiram 250	Disulfiram 375	Disulfiram 500
Arm/Group Description	microcrystalline cellulose	disulfiram at 250 mg/day	Disulfiram at 375 mg/day	Disulfiram at 500 mg/day
Measure Participants	27	25	30	25
Mean (Standard Deviation) [Weeks]	8.3 (5.4)	9.0 (4.9)	6.4 (4.7)	8.3 (4.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Disulfiram 250, Disulfiram 375, Disulfiram 500
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.5
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	12 weeks (during disulfiram phase) plus 2 wk washout
Adverse Event Reporting Description	although participants were out of the protocol at the end of week 14, because disulfiram could interact with alcohol for up to 2 weeks after stopping use, we continued to monitor participants during this time.
Arm/Group Title	Placebo		Disulfiram 250		Disulfiram 375		Disulfiram 500
Arm/Group Description	microcrystalline cellulose		disulfiram at 250 mg/day		Disulfiram at 375 mg/day		Disulfiram at 500 mg/day
All Cause Mortality
	Placebo		Disulfiram 250		Disulfiram 375		Disulfiram 500
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Disulfiram 250		Disulfiram 375		Disulfiram 500
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		1/23 (4.3%)		1/24 (4.2%)		0/21 (0%)
Cardiac disorders
Acute COPD exacerbation	0/20 (0%)	0	1/23 (4.3%)	1	0/24 (0%)	0	0/21 (0%)	0
Nervous system disorders
Spinal Abcess	0/20 (0%)	0	0/23 (0%)	0	1/24 (4.2%)	1	0/21 (0%)	0
Psychiatric disorders
Suicidal ideation	1/20 (5%)	1	0/23 (0%)	0	0/24 (0%)	0	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Disulfiram 250		Disulfiram 375		Disulfiram 500
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/20 (40%)		12/23 (52.2%)		10/24 (41.7%)		11/21 (52.4%)
Cardiac disorders
Increased Vital Signs (e.g., BP, HR)	1/20 (5%)	1	4/23 (17.4%)	5	2/24 (8.3%)	3	2/21 (9.5%)	2
Gastrointestinal disorders
GI Distress (e.g., nausea, vomiting, etc.)	2/20 (10%)	2	7/23 (30.4%)	9	6/24 (25%)	8	6/21 (28.6%)	6
Dry mouth/Excessive Thirst	1/20 (5%)	1	2/23 (8.7%)	2	0/24 (0%)	0	0/21 (0%)	0
Constipation	0/20 (0%)	0	1/23 (4.3%)	1	0/24 (0%)	0	1/21 (4.8%)	2
General disorders
Sweating	2/20 (10%)	2	3/23 (13%)	3	0/24 (0%)	0	1/21 (4.8%)	1
Metallic or Garlic Taste	2/20 (10%)	2	2/23 (8.7%)	2	2/24 (8.3%)	2	3/21 (14.3%)	3
Lethargy/Sedation	1/20 (5%)	1	1/23 (4.3%)	1	2/24 (8.3%)	2	3/21 (14.3%)	3
Musculoskeletal and connective tissue disorders
Slurred speech	0/20 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	2/21 (9.5%)	2
Nervous system disorders
Headache	1/20 (5%)	2	3/23 (13%)	3	1/24 (4.2%)	2	1/21 (4.8%)	1
Psychiatric disorders
Confusion	1/20 (5%)	1	0/23 (0%)	0	0/24 (0%)	0	2/21 (9.5%)	2
Anxiety/Nervousness	0/20 (0%)	0	2/23 (8.7%)	2	0/24 (0%)	0	0/21 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.