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Efficacy of Levetiracetam in Cocaine-Abusing Methadone Maintained Patients (Keppra-DB)

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ClinicalTrials.gov Identifier: NCT00577005
Recruitment Status : Completed
First Posted : December 19, 2007
Results First Posted : April 24, 2017
Last Update Posted : January 17, 2018
Sponsor:
Collaborator:
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
Yale University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Conditions Cocaine Dependence
Opioid Dependency
Interventions Drug: levetiracetam
Drug: Placebo
Enrollment 28
Recruitment Details Thirty three cocaine and opioid dependent treatment seeking individuals were recruited by newspaper advertising, word-of -mouth and referrals from community-based substance abuse clinics. Research staff obtained informed consent and subjects were evaluated for study eligibility.
Pre-assignment Details Twenty eight subjects were assigned to treatment groups while concurrently receiving treatment with methadone. Randomization was balanced with urn procedure on gender and severity of cocaine use score.
Arm/Group Title Levetiracetam 3000mg + Methadone Levetiracetam 0mg + Methadone
Hide Arm/Group Description

Participants were inducted onto methadone during the first week of study participation and then started on Levetiracetam 500mg in the mornings of the first day of week 2. The dose was titrated every third day on a twice day schedule, until the target dose of 3000mg/day was achieved or to the subject's maximum tolerated dose (MTD) by week 4.

Levetiracetam: 3000mg orally everyday for 12 weeks

Participants were inducted onto methadone during the first week of study participation. Matching placebo capsules were started on week 2. The placebo capsules were given on a twice a day schedule until week 13.

Placebo: Placebo orally everyday for 13 weeks

Period Title: Overall Study
Started 16 12
Completed 11 9
Not Completed 5 3
Reason Not Completed
Lost to Follow-up             3             2
Withdrawal by Subject             2             1
Arm/Group Title Levetiracetam Placebo Total
Hide Arm/Group Description

Levetiracetam tablets

levetiracetam: The participants will start receiving Levetiracetam 500mg in the mornings of the first day on week 2. The dose will be titrated every third day, until the target dose of 3000mg/day is achieved by week 4. The study medication must be titrated to 3000 mg/day or to the subject's maximum tolerated dose (MTD). The physician overseeing this titration as well as all study staff will be blind to the subject's medication administration. The medication will be discontinued over a two-week period.

matching placebo

Placebo

Total of all reporting groups
Overall Number of Baseline Participants 16 12 28
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 16 participants 12 participants 28 participants
35.1  (10.7) 33.6  (9.6) 34.4  (10.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 12 participants 28 participants
Female
7
  43.8%
5
  41.7%
12
  42.9%
Male
9
  56.3%
7
  58.3%
16
  57.1%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 16 participants 12 participants 28 participants
Caucasian 15 11 26
African American 0 1 1
Hispanic 1 0 1
1.Primary Outcome
Title Change of Thrice Weekly Cocaine Free Urine Toxicology From Week 1 to 13
Hide Description The primary outcome variable was the change from baseline to week 13 of the thrice weekly cocaine-free urine scores. In this repeated ordinal variable, 0 represented all 3 urine samples submitted by the subject as positives, 1 represented some urine samples submitted by the subject were negative, and 2 represented all 3 urine samples submitted by the subjects were negative for cocaine. Balancing the distribution between these categories improved the models for the analysis of repeated ordinal data. Data is summarized as number of participant that were cocaine free urine (score 2) per week by group.
Time Frame Weekly from baseline to week 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) sample were the 28 subjects were randomized and received one dose of study medication.
Arm/Group Title Levetiracetam 3000mg + Methadone Levetiracetam 0mg + Methadone
Hide Arm/Group Description:

Participants were inducted onto methadone during the first week of study participation and then started on Levetiracetam 500mg in the mornings of the first day of week 2. The dose was titrated every third day on a twice day schedule, until the target dose of 3000mg/day was achieved or to the subject's maximum tolerated dose (MTD) by week 4.

Levetiracetam: 3000mg orally everyday for 12 weeks

Participants were inducted onto methadone during the first week of study participation. Matching placebo capsules were started on week 2. The placebo capsules were given on a twice a day schedule until week 13.

Placebo: Placebo orally everyday for 13 weeks

Overall Number of Participants Analyzed 16 12
Measure Type: Number
Unit of Measure: participants that were cocaine free
Baseline 6 0
week 1 3 2
week 2 6 3
week 3 5 4
week 4 5 4
week 5 5 2
week 6 3 4
week 7 3 3
week 8 4 3
week 9 4 4
week 10 5 4
week 11 5 5
week 12 5 5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levetiracetam 3000mg + Methadone, Levetiracetam 0mg + Methadone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.09
Comments p-value <0.05 considered statistically significant
Method Mixed Models Analysis
Comments We modeled the the change in thrice weekly cocaine urines using a mixed-effect ordinal regression approach with MIXOR.
Method of Estimation Estimation Parameter Slope
Estimated Value -0.05425
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.03211
Estimation Comments Group x time interaction: Z=-1.68950 p = 0.09112
2.Secondary Outcome
Title Change of Thrice Weekly Opioid Free Urine Toxicology From Week 1 to 13
Hide Description The secondary outcome variable was the change from baseline to week 13 of the thrice weekly opioid-free urine scores. In this repeated ordinal variable, 0 represented all 3 urines samples submitted by the subject as positives, 1 represented some urine samples submitted by the subject were negative, and 2 represented all 3 urines samples submitted by the subjects were negative for opioids excluding methadone. Balancing the distribution between these categories improved the models for the analysis of repeated ordinal data. Data summarized by number of participants who were had opioid free urine samples (score 2) per week by group.
Time Frame Weekly from baseline to week 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) sample were the 28 subjects were randomized and received one dose of study medication.
Arm/Group Title Levetiracetam 3000mg + Methadone Levetiracetam 0mg + Methadone
Hide Arm/Group Description:

Participants were inducted onto methadone during the first week of study participation and then started on Levetiracetam 500mg in the mornings of the first day of week 2. The dose was titrated every third day on a twice day schedule, until the target dose of 3000mg/day was achieved or to the subject's maximum tolerated dose (MTD) by week 4.

Levetiracetam: 3000mg orally everyday for 12 weeks

.

Participants were inducted onto methadone during the first week of study participation. Matching placebo capsules were started on week 2. The placebo capsules were given on a twice a day schedule until week 13.

Placebo: Placebo orally everyday for 13 weeks

Overall Number of Participants Analyzed 16 12
Measure Type: Number
Unit of Measure: participants with opioid free urine
Baseline 4 4
week 1 5 3
week 2 7 4
week 3 5 6
week 4 6 3
week 5 8 4
week 6 7 4
week 7 5 6
week 8 5 4
week 9 6 4
week 10 6 5
week 11 8 5
week 12 5 5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levetiracetam 3000mg + Methadone, Levetiracetam 0mg + Methadone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.55
Comments p-value <0.05 considered statistically significant
Method Mixed Models Analysis
Comments We modeled the the change in thrice weekly opioid urines using a mixed-effect ordinal regression approach with MIXOR.
Method of Estimation Estimation Parameter Slope
Estimated Value 0.02570
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.04369
Estimation Comments Group x time interaction: Z= 0.58823 p = 0.55638
3.Secondary Outcome
Title Treatment Retention
Hide Description Weekly from week 1 to 13
Time Frame Week 13
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-treat-sample (ITT) that was inducted onto methadone and received one dose of study medication on week 2.
Arm/Group Title Levetiracetam 3000mg + Methadone Levetiracetam 0mg + Methadone
Hide Arm/Group Description:

Participants were inducted onto methadone during the first week of study participation and then started on Levetiracetam 500mg in the mornings of the first day of week 2. The dose was titrated every third day on a twice day schedule, until the target dose of 3000mg/day was achieved or to the subject's maximum tolerated dose (MTD) by week 4.

Levetiracetam: 3000mg orally everyday for 12 weeks

Participants were inducted onto methadone during the first week of study participation. Matching placebo capsules were started on week 2. The placebo capsules were given on a twice a day schedule until week 13.

Placebo: Placebo orally everyday for 13 weeks

Overall Number of Participants Analyzed 16 12
Measure Type: Number
Unit of Measure: participants
13 9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levetiracetam 3000mg + Methadone, Levetiracetam 0mg + Methadone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.67
Comments p-value <0.05 considered statistically significant
Method Log Rank
Comments Chi-Square 0.175. df = 1, p=0.676
4.Secondary Outcome
Title Cocaine Craving
Hide Description Weekly cocaine craving was measure at intake and weekly after with the Visual Analog Scale (VAS) of the Cocaine Selective Severity Assessment. The VAS measures the intensity of cocaine craving with a scale from 0 (No desire at all) to 7 (Unable to resist), and frequency of cocaine craving in the previous 24 hours with a scale from 0 ( never) to 7 ( all the time). The scale is totaled for a maximum number of 14, the minimum is 0. (Kampman et al., 1998; Mulvaney et al., 1999).
Time Frame Weekly from baseline to week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat sample
Arm/Group Title Levetiracetam Placebo
Hide Arm/Group Description:

Levetiracetam tablets

levetiracetam: The participants will start receiving Levetiracetam 500mg in the mornings of the first day on week 2. The dose will be titrated every third day, until the target dose of 3000mg/day is achieved by week 4. The study medication must be titrated to 3000 mg/day or to the subject's maximum tolerated dose (MTD). The physician overseeing this titration as well as all study staff will be blind to the subject's medication administration. The medication will be discontinued over a two-week period.

matching placebo

Placebo

Overall Number of Participants Analyzed 16 12
Mean (Standard Error)
Unit of Measure: units on a scale
Baseline 7.19  (1.512) 6.50  (1.617)
week 1 4.13  (1.373) 5.75  (1.488)
week 2 2.64  (1.097) 2.83  (1.192)
week 3 2.13  (1.041) 3.42  (1.417)
week 4 2.13  (0.985) 3.17  (1.140)
week 5 2.53  (0.904) 3.27  (1.556)
week 6 3.00  (1.144) 2.18  (1.278)
week 7 2.67  (1.484) 3.18  (1.470)
week 8 2.80  (1.340) 3.60  (1.454)
week 9 2.33  (1.124) 3.09  (1.486)
week 10 2.18  (1.306) 3.55  (1.603)
week 11 2.09  (1.031) 4.20  (1.800)
week 12 3.27  (1.579) 4.22  (1.985)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levetiracetam, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.11
Comments Significant p-value < 0.05
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Slope
Estimated Value -0.1557
Estimation Comments Interaction of time x group: Z = -1.5671, p = 0.11708
Time Frame Adverse events were collected from week 1 to week 13
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Levetiracetam 3000mg + Methadone Levetiracetam 0mg + Methadone
Hide Arm/Group Description

Participants were inducted onto methadone during the first week of study participation and then started on Levetiracetam 500mg in the mornings of the first day of week 2. The dose was titrated every third day on a twice day schedule, until the target dose of 3000mg/day was achieved or to the subject's maximum tolerated dose (MTD) by week 4.

Levetiracetam: 3000mg orally everyday for 12 weeks

Participants were inducted onto methadone during the first week of study participation. Matching placebo capsules were started on week 2. The placebo capsules were given on a twice a day schedule until week 13.

Placebo: Placebo orally everyday for 13 weeks

All-Cause Mortality
Levetiracetam 3000mg + Methadone Levetiracetam 0mg + Methadone
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Levetiracetam 3000mg + Methadone Levetiracetam 0mg + Methadone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/16 (0.00%)      0/12 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Levetiracetam 3000mg + Methadone Levetiracetam 0mg + Methadone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/16 (6.25%)      3/12 (25.00%)    
Hepatobiliary disorders     
Hepatitis *  1/16 (6.25%)  1 0/12 (0.00%)  0
Infections and infestations     
Infection *  1/16 (6.25%)  1 2/12 (16.67%)  2
Musculoskeletal and connective tissue disorders     
Cut finger-accident *  0/16 (0.00%)  0 1/12 (8.33%)  1
*
Indicates events were collected by non-systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Gerardo Gonzalez, MD
Organization: University of Massachusetts Medical School
Phone: 508 856 6480
EMail: gerardo.gonzalez@umassmed.edu
Layout table for additonal information
Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT00577005     History of Changes
Other Study ID Numbers: 0707002832
5R01DA017782-04 ( U.S. NIH Grant/Contract )
NIDA-5R01DA017782-04
Yale-0508000534
VA-gg0006
First Submitted: December 17, 2007
First Posted: December 19, 2007
Results First Submitted: September 8, 2016
Results First Posted: April 24, 2017
Last Update Posted: January 17, 2018