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| ID | Type | Description | Link |
|---|---|---|---|
| R01DA027065 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Drug Abuse (NIDA) | NIH |
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This is a residential pilot trial to evaluate the pharmacodynamic interaction between zonisamide and cocaine, with the goal of evaluating zonisamide's potential for the treatment of cocaine dependence.
This is a residential pilot trial to evaluate the effect of zonisamide (ZNS) on cocaine reinforcement, craving and relapse. Cocaine addiction remains a major social and medical problem that imposes a significant burden on our society, as more than a half million cocaine dependent individuals are seeking treatment every year. Medications that act to antagonize the glutamate system and/or increase the GABA-system are new targets in the search towards effective cocaine treatment. ZNS is part of a new line of antiepileptic agents that act both as glutamate antagonists and to enhance the Gamma-AminoButyric acid (GABA) system. Topiramate, a similar agent, showed a positive signal in a pilot trial for cocaine dependence. ZNS has the advantages of a longer half-life requiring only once a day dosing and, being better tolerated, it requires a shorter induction phase and can be administered at higher doses. We hypothesize that ZNS in moderate to high doses will attenuate the central effect of cocaine and improve the neural perturbations resulting from cocaine use, thus decreasing cocaine craving. Healthy, adult cocaine dependent volunteers will be enrolled on our residential unit for 44 days for this double-blind within subject study. The pharmacodynamic interactions between ZNS and cocaine will be measured in cocaine self-administration procedure offering alternative reinforcers with monetary values. Cocaine reinforcing effect will be evaluated over a range of doses, and subjective and objective outcomes on mood and behavior will be collected. In addition, the effect of ZNS on ad-lib smoking will be studied on the days when no other procedure interferes with smoking behaviors. Neurocognitive and psychomotor effects of ZNS treatment will also be studied with an extensive test battery on the day of the week when no cocaine is administered. This study will explore the potential therapeutic effect of ZNS for the treatment of cocaine dependence while providing necessary safety assessments required for possible future outpatient clinical trials.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Zonisamide | Experimental | Participants administered blind capsules containing either placebo or zonisamide. |
|
| Placebo | Placebo Comparator | Participants administered only placebo capsules containing lactose. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Zonisamide | Drug | Eight capsules administered daily in split doses at 22:00 and 09:00. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Visual Analog Questionnaire (VAQ) Score | VAQ measures the change in effect after dose administration. Participants rate 6 items ("Any Drug Effect", "Rush", "Good Effects", "Bad Effects", "Liking", & "Desire for Cocaine") by pointing an arrow along a 100-point line anchored at either end with "none" (0) & "extremely" (100). Each participant's score is equal to the sum of all 6 ratings, & the mean of all participant's scores is reported across each condition. The VAQ is only administered to subjects in the zonisamide (Zon) condition (n=8). Repeated within-subject measures ANOVA performed to observe the main effects of Zon dose (0, 300, & 600mg) & cocaine dose (1, 20, & 40mg), & their interaction. All 8 subjects who received Zon completed both 300mg & 600mg doses. Assessments obtained on Week 1 (0mg Zon), Week 3 (300mg Zon), & Week 5 (600mg Zon), in which all 3 cocaine were co-administered at these times. Cocaine not administered (only Zon) during Weeks 2 & 4, thus no measures taken at these times | Weeks 1-5; mean of weeks 1, 3 and 5 reported |
| Behavioral Choice Measures | In each condition of cocaine-zonisamide dose, participants were asked to choose whether they would rather have a repeated cocaine dose (same dose as most recent administration) or cash of varying monetary value. The mean number of cocaine choices across each drug condition are reported. This measure only included participants in the zonisamide (Zon) condition (n=8), with each arm representing variation in co-administration of cocaine-Zon. Repeated within-subject measures ANOVA performed to observe the main effects of zonisamide dose (0, 300, and 600mg) and cocaine dose (1, 20, and 40mg), and their interaction. Only participants who received the active zonisamide medication (n=8) were included in this portion of the analysis. During self-administration sessions are every 15 min over 1hr45min period. Assessment on Weeks 1 (0mg Zon), 3 (300mg Zon), 5 (600mg Zon), in which varying cocaine doses co-administered. Cocaine not administered (only Zon) during Weeks 2 & 4 | Weeks 1-5, mean of weeks 1, 3 and 5 reported |
| Cocaine Craving | Cocaine craving measured by Cocaine Selectivity Severity Assessment (CSSA). The CSSA is a reliable and valid tool to measure cocaine withdrawal severity within a 24 hr period, and has been shown to predict treatment response in a treatment setting. Participants are asked to rate 18-items on a Likert scale 0-7, with composite scores ranging 0-126 and higher numbers indicative of more severe withdrawal. Mean scores on CSSA across 39-day time period are reported. |
| Measure | Description | Time Frame |
|---|---|---|
| Drug Value Questionnaire | Street Value of Sampled Dose. After co-administration of cocaine-zonisamide, participants were asked to hypothetically estimate the value of the drug they received, if they were to purchase it on the street. The mean value (dollars) across all drug conditions is reported here. Repeated within-subject measures ANOVA performed to observe the main effects of zonisamide dose (0, 300, and 600mg) and cocaine dose (0, 20, and 40mg), and their interaction. Only participants who received the active zonisamide medication (n=8) were included in this portion of the analysis. Additionally, all 8 subjects who received zonisamide completed both 300mg and 600mg doses. Within-subject repeated interval during self-administration sessions. Cocaine not administered (only Zon) during Weeks 2 & 4, thus no measures taken at these times |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Annie Umbricht, M.D. | Johns Hopkins University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Behavioral Pharmacology Research Unit | Baltimore | Maryland | 21224 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Zonisamide | Participants administered blind capsules containing either placebo or zonisamide. Zonisamide: Eight capsules administered daily in split doses at 22:00 and 09:00. Cocaine Hydrochloride: Cocaine Challenge Sessions: Human laboratory sessions with administration of moderate doses of cocaine by the intravenous route under controlled conditions and cardiovascular monitoring. Neurocognitive and Performance Battery: Participants will complete tests to assess their abilities and performances on a number of tasks given by a computer or other type of equipment. Smoking Assessments: Participants answer questions about smoking and smoking behaviors are monitored. |
| FG001 | Placebo | Participants administered only placebo capsules containing lactose. Placebo: capsules administered in split doses at 22:00 and 09:00. Cocaine Hydrochloride: Cocaine Challenge Sessions: Human laboratory sessions with administration of moderate doses of cocaine by the intravenous route under controlled conditions and cardiovascular monitoring. Neurocognitive and Performance Battery: Participants will complete tests to assess their abilities and performances on a number of tasks given by a computer or other type of equipment. Smoking Assessments: Participants answer questions about smoking and smoking behaviors are monitored. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Zonisamide | |
| BG001 | Placebo | |
| BG002 | Total |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Visual Analog Questionnaire (VAQ) Score | VAQ measures the change in effect after dose administration. Participants rate 6 items ("Any Drug Effect", "Rush", "Good Effects", "Bad Effects", "Liking", & "Desire for Cocaine") by pointing an arrow along a 100-point line anchored at either end with "none" (0) & "extremely" (100). Each participant's score is equal to the sum of all 6 ratings, & the mean of all participant's scores is reported across each condition. The VAQ is only administered to subjects in the zonisamide (Zon) condition (n=8). Repeated within-subject measures ANOVA performed to observe the main effects of Zon dose (0, 300, & 600mg) & cocaine dose (1, 20, & 40mg), & their interaction. All 8 subjects who received Zon completed both 300mg & 600mg doses. Assessments obtained on Week 1 (0mg Zon), Week 3 (300mg Zon), & Week 5 (600mg Zon), in which all 3 cocaine were co-administered at these times. Cocaine not administered (only Zon) during Weeks 2 & 4, thus no measures taken at these times | Because we are interested in how co-administered of cocaine-Zon affects this measure, only Zon participants are included (n=8). Each participant receives varying doses of Zon (0, 300, 600mg) at weeks 1, 2-3, 4-5, respectively. After getting used to each Zon dose, they are co-administered all 3 cocaine doses (1, 20, 40mg) during Weeks 1, 3, and 5 | Posted | Mean | Standard Deviation | units on a scale | Weeks 1-5; mean of weeks 1, 3 and 5 reported |
39 days
Reported adverse events (AEs) include participants who were randomized into the study's conditions (zonisamide/placebo), and of which were rated as being either possibly, probably, or definitely related to the study.
Although 19 participants were randomized, 9 did not complete. However, 2 of these provided sufficient data to be included in analyses. Thus, the possibility of study related AEs could only occur in 12 subjects (8 zonisamide, 4 placebo). This is the case for serious AEs, too.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Zonisamide | Participants administered blind capsules containing either placebo or zonisamide. Zonisamide: Eight capsules administered daily in split doses at 22:00 and 09:00. Cocaine Hydrochloride: Cocaine Challenge Sessions: Human laboratory sessions with administration of moderate doses of cocaine by the intravenous route under controlled conditions and cardiovascular monitoring. Neurocognitive and Performance Battery: Participants will complete tests to assess their abilities and performances on a number of tasks given by a computer or other type of equipment. Smoking Assessments: Participants answer questions about smoking and smoking behaviors are monitored. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Allergic Rhinitis | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Annie Umbricht | Johns Hopkins University | 410-550-1917 | annieumbricht@jhu.edu |
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| ID | Term |
|---|---|
| D019970 | Cocaine-Related Disorders |
| D016739 | Behavior, Addictive |
| D019966 | Substance-Related Disorders |
| ID | Term |
|---|---|
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
| D003192 | Compulsive Behavior |
| D007175 | Impulsive Behavior |
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| ID | Term |
|---|---|
| D000078305 | Zonisamide |
| D003042 | Cocaine |
| ID | Term |
|---|---|
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013450 | Sulfones |
| D013457 |
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| Placebo | Drug | capsules administered in split doses at 22:00 and 09:00. |
|
| Cocaine Hydrochloride | Drug | Cocaine Challenge Sessions: Human laboratory sessions with administration of moderate doses of cocaine by the intravenous route under controlled conditions and cardiovascular monitoring. |
|
|
| Neurocognitive and Performance Battery | Behavioral | Participants will complete tests to assess their abilities and performances on a number of tasks given by a computer or other type of equipment. |
|
| Smoking Assessments | Behavioral | Participants answer questions about smoking and smoking behaviors are monitored. |
|
| Day 1-39 |
| Weeks 1-5; mean of weeks 1, 3 and 5 reported |
Total of all reporting groups
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
|
|
| Primary | Behavioral Choice Measures | In each condition of cocaine-zonisamide dose, participants were asked to choose whether they would rather have a repeated cocaine dose (same dose as most recent administration) or cash of varying monetary value. The mean number of cocaine choices across each drug condition are reported. This measure only included participants in the zonisamide (Zon) condition (n=8), with each arm representing variation in co-administration of cocaine-Zon. Repeated within-subject measures ANOVA performed to observe the main effects of zonisamide dose (0, 300, and 600mg) and cocaine dose (1, 20, and 40mg), and their interaction. Only participants who received the active zonisamide medication (n=8) were included in this portion of the analysis. During self-administration sessions are every 15 min over 1hr45min period. Assessment on Weeks 1 (0mg Zon), 3 (300mg Zon), 5 (600mg Zon), in which varying cocaine doses co-administered. Cocaine not administered (only Zon) during Weeks 2 & 4 | Because we are interested in how co-administered of cocaine-Zon affects this measure, only Zon participants are included (n=8). Each participant receives varying doses of Zon (0, 300, 600mg) at weeks 1, 2-3, 4-5, respectively. After getting used to each Zon dose, they are co-administered all 3 cocaine doses (1, 20, 40mg) during Weeks 1, 3, and 5 | Posted | Mean | Standard Deviation | number of cocaine choices | Weeks 1-5, mean of weeks 1, 3 and 5 reported |
|
|
|
|
| Primary | Cocaine Craving | Cocaine craving measured by Cocaine Selectivity Severity Assessment (CSSA). The CSSA is a reliable and valid tool to measure cocaine withdrawal severity within a 24 hr period, and has been shown to predict treatment response in a treatment setting. Participants are asked to rate 18-items on a Likert scale 0-7, with composite scores ranging 0-126 and higher numbers indicative of more severe withdrawal. Mean scores on CSSA across 39-day time period are reported. | Includes all participants analyzed (n=12; 8 zonisamide, 4 placebo) | Posted | Mean | Standard Deviation | units on a scale | Day 1-39 |
|
|
|
|
| Secondary | Drug Value Questionnaire | Street Value of Sampled Dose. After co-administration of cocaine-zonisamide, participants were asked to hypothetically estimate the value of the drug they received, if they were to purchase it on the street. The mean value (dollars) across all drug conditions is reported here. Repeated within-subject measures ANOVA performed to observe the main effects of zonisamide dose (0, 300, and 600mg) and cocaine dose (0, 20, and 40mg), and their interaction. Only participants who received the active zonisamide medication (n=8) were included in this portion of the analysis. Additionally, all 8 subjects who received zonisamide completed both 300mg and 600mg doses. Within-subject repeated interval during self-administration sessions. Cocaine not administered (only Zon) during Weeks 2 & 4, thus no measures taken at these times | Because we are interested in how co-administration cocaine-zon affects this measure, only zon participants are included (n=8). Each participant receives varying doses of zon (0, 300, 600mg) at weeks 1, 2-3, 4-5, respectively. After getting used to each zon dose, they are co-administered all 3 cocaine doses (1, 20, 40mg) during Weeks 1, 3, and 5 | Posted | Mean | Standard Deviation | dollars | Weeks 1-5; mean of weeks 1, 3 and 5 reported |
|
|
|
|
| 0 |
| 8 |
| 0 |
| 8 |
| 8 |
| 8 |
| EG001 | Placebo | Participants administered only placebo capsules containing lactose. Placebo: capsules administered in split doses at 22:00 and 09:00. Cocaine Hydrochloride: Cocaine Challenge Sessions: Human laboratory sessions with administration of moderate doses of cocaine by the intravenous route under controlled conditions and cardiovascular monitoring. Neurocognitive and Performance Battery: Participants will complete tests to assess their abilities and performances on a number of tasks given by a computer or other type of equipment. Smoking Assessments: Participants answer questions about smoking and smoking behaviors are monitored. | 0 | 4 | 0 | 4 | 4 | 4 |
| Headache | General disorders | Non-systematic Assessment |
|
| Inguinal Hernia | General disorders | Non-systematic Assessment |
|
| Skin Rash | General disorders | Non-systematic Assessment |
|
| Creatinine Elevation | General disorders | Non-systematic Assessment |
|
| Palpitations | Cardiac disorders | Non-systematic Assessment |
|
| Appetite Decreased | Gastrointestinal disorders | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
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| Hepatitis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Indigestion | Gastrointestinal disorders | Non-systematic Assessment |
|
| Liver function abnormal | Gastrointestinal disorders | Non-systematic Assessment |
|
| Tooth Disease | Gastrointestinal disorders | Non-systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Chemistry Abnormal | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Pain lower extremity | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Tingling sensation in extremity | Nervous system disorders | Non-systematic Assessment |
|
| Agitation | Nervous system disorders | Non-systematic Assessment |
|
| Dream abnormal | Nervous system disorders | Non-systematic Assessment |
|
| Insomnia | Nervous system disorders | Non-systematic Assessment |
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| Jittery | Nervous system disorders | Non-systematic Assessment |
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| Restlessness | Nervous system disorders | Non-systematic Assessment |
|
| Asthma | General disorders | Non-systematic Assessment |
|
| Rhinitis | General disorders | Non-systematic Assessment |
|
| Athlete's foot | General disorders | Non-systematic Assessment |
|
| Tinnitus | Eye disorders | Non-systematic Assessment |
|
| Urethritis | Renal and urinary disorders | Non-systematic Assessment |
|
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| D001519 |
| Behavior |
| Sulfur Compounds |
| D007555 | Isoxazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D014326 | Tropanes |
| D053961 | Azabicyclo Compounds |
| D001372 | Aza Compounds |
| D000470 | Alkaloids |
| D019086 | Bridged Bicyclo Compounds, Heterocyclic |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
|
| ANOVA |
| 0.93 |
| F-value for main effect of Zon dose |
| 0.07 |
| 2-Sided |
F-value for main effect of Zonisamide dose on Behavioral Choice measure |
| Superiority |
| ANOVA | 0.92 | F-value for main effect of Coc x Zon | 0.24 | 2-Sided | F-value for main effect of Cocaine dose x Zonisamide dose interaction on Behavioral Choice measure | Superiority |
| Placebo |
|
| Superiority |
| t-test, 2 sided | 0.0015 | t-value for main effect of Day | -3.2 | 2-Sided | Superiority | Day (Day 1-39) |
| t-test, 2 sided | 0.10 | t value for Group x Day interaction | -1.63 | 2-Sided | Superiority | Group*Day interaction |
| ANOVA |
| 0.48 |
| F-value for main effect of Zon dose |
| 0.77 |
| 2-Sided |
F-value for main effect of Zonisamide dose |
| Superiority |
| ANOVA | 0.46 | F-value for the main effect of Zon x Coc | 0.93 | 2-Sided | F-value for main effect of Zonisamide x Cocaine interaction on drug value (i.e., street value) measurement | Superiority |