Effect of Zonisamide on Cocaine Reinforcement, Craving, and Relapse

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01137890
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 19
• Location: 1
• Arms: 2
• Duration (Months): 38
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Cocaine Dependence	Drug: Zonisamide; Drug: Placebo; Drug: Cocaine Hydrochloride; Behavioral: Neurocognitive and Performance Battery; Behavioral: Smoking Assessments	Phase 1/Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Effect of Zonisamide on Cocaine Reinforcement, Craving, and Relapse
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zonisamide Participants administered blind capsules containing either placebo or zonisamide.	Drug: Zonisamide; Eight capsules administered daily in split doses at 22:00 and 09:00.; Other Names: Zonegran, CAS 68291-97-4, ; Drug: 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.; Other Names: CAS 50-36-2 methylbenzoylecgonine benzoylmethylecgonine C17H21NO4 ; Behavioral: 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.; Behavioral: Smoking Assessments; Participants answer questions about smoking and smoking behaviors are monitored.
Placebo Comparator: Placebo Participants administered only placebo capsules containing lactose.	Drug: Placebo; capsules administered in split doses at 22:00 and 09:00.; Drug: 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.; Other Names: CAS 50-36-2 methylbenzoylecgonine benzoylmethylecgonine C17H21NO4 ; Behavioral: 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.; Behavioral: Smoking Assessments; Participants answer questions about smoking and smoking behaviors are monitored.

Outcome Measures

Primary Outcome Measures

1. Change in Visual Analog Questionnaire (VAQ) Score [Weeks 1-5; mean of weeks 1, 3 and 5 reported]

   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

2. Behavioral Choice Measures [Weeks 1-5, mean of weeks 1, 3 and 5 reported]

   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

3. Cocaine Craving [Day 1-39]

   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.

Secondary Outcome Measures

1. Drug Value Questionnaire [Weeks 1-5; mean of weeks 1, 3 and 5 reported]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age at least 21 years old, not older than 45 years.

• Evidence of cocaine dependence.

• Not seeking treatment for cocaine abuse.

• Able and willing to be restricted to our unit for 6-7 weeks.

• Able to answer frequent questionnaires reliably and consistently.

• Smoker.

Exclusion Criteria:

• Allergy to Sulfonamide drugs (e.g. topiramate, zonisamide, sulfamethoxazole/trimethoprim).

• Diabetes, respiratory insufficiency, renal tubular acidosis or renal insufficiency, heart failure, liver insufficiency, chronic diarrhea, other chronic diseases predisposing to acidosis.

• Renal insufficiency defined as serum creatine > 1.30 mg/DL for males or > 1.03 mg/DL for females.

• History of nephrolithiasis, unexplained hematuria on screening urinalysis.

• History of head injury (with loss of consciousness longer than a few minutes).

• History of seizure, or use of antiepileptic medications.

• HIV positive individuals who meet AIDS by Centers for Disease Control (CDC) criteria or are on antiretroviral medications.

• BMI < 19 or BMI > 34.

• Total cholesterol > 240mg%.

• Serous psychiatric illness with psychosis, dementia.

• Glaucoma, family history of glaucoma, one-sided blindness.

• For female participants: being pregnant, lactating or not using an effective method of contraception.

• Physical dependence on any drug other than cocaine, nicotine, or caffeine.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Behavioral Pharmacology Research Unit	Baltimore	Maryland	United States	21224

Sponsors and Collaborators

• Johns Hopkins University
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Annie Umbricht, M.D., Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01137890
• Other Study ID Numbers: R01DA027065; R01DA027065
• First Posted: Jun 7, 2010
• Last Update Posted: Sep 5, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by Johns Hopkins University: cocaine; addiction; drug dependence; anticonvulsant; zonisamide; drug self-administration; nicotine withdrawal; neurocognition
• Additional relevant MeSH terms: Cocaine-Related Disorders; Zonisamide; Cocaine

Study Results

Participant Flow

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	14	5
COMPLETED	8	2
NOT COMPLETED	6	3

Baseline Characteristics

Arm/Group Title	Zonisamide	Placebo	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	8	4	12
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 100%	4 100%	12 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.9 (5.6)	38.2 (4.1)	38.7 (5)
Sex: Female, Male (Count of Participants)
Female	0 0%	1 25%	1 8.3%
Male	8 100%	3 75%	11 91.7%
Region of Enrollment (participants) [Number]
United States	8 100%	4 100%	12 100%

Outcome Measures

1. Primary Outcome

Title	Change in Visual Analog Questionnaire (VAQ) Score
Description	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
Time Frame	Weeks 1-5; mean of weeks 1, 3 and 5 reported

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	1mg-0mg	1mg-300mg	1mg-600mg	20mg-0mg	20mg-300mg	20mg-600mg	40mg-0mg	40mg-300mg	40mg-600mg
Arm/Group Description	1mg cocaine - 0mg zonisamide Both doses are expected to be inactive, thus this arm is viewed as Placebo	1mg cocaine - 300mg zonisamide	1mg cocaine - 600mg zonisamide	20mg cocaine - 0mg zonisamide	20mg cocaine - 300mg zonisamide	20mg cocaine - 600mg zonisamide	40mg cocaine - 0mg zonisamide	40mg cocaine - 300mg zonisamide	40mg cocaine - 600mg zonisamide
Measure Participants	8	8	8	8	8	8	8	8	8
Mean (Standard Deviation) [units on a scale]	0.38 (0.74)	3.75 (6.41)	0.38 (0.74)	40.63 (24.37)	32.63 (14.78)	30.00 (27.88)	37.38 (21.84)	29.75 (16.52)	37.25 (25.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	p-value was calculated as less than 0.01. Note: this is not an attempt to indicate a threshold
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	F-value for main effect of Coc dose
	Estimated Value	24.9
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	F-value for main effect of Cocaine dose on VAQ score

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.72
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	F-value for main effect of Zon dose
	Estimated Value	0.34
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	F-value for main effect of Zonisamide dose on VAQ score

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	F-value for main effect of Coc x Zon
	Estimated Value	0.66
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	F-value for main effect of Cocaine x Zonisamide interaction on VAQ scores

2. Primary Outcome

Title	Behavioral Choice Measures
Description	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
Time Frame	Weeks 1-5, mean of weeks 1, 3 and 5 reported

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	1mg-0mg	1mg-300mg	1mg-600mg	20mg-0mg	20mg-300mg	20mg-600mg	40mg-0mg	40mg-300mg	40mg-600mg
Arm/Group Description	1mg cocaine - 0mg zonisamide Both doses are expected to be inactive, thus this arm is viewed as Placebo	1mg cocaine - 300mg zonisamide	1mg cocaine - 600mg zonisamide	20mg cocaine - 0mg zonisamide	20mg cocaine - 300mg zonisamide	20mg cocaine - 600mg zonisamide	40mg cocaine - 0mg zonisamide	40mg cocaine - 300mg zonisamide	40mg cocaine - 600mg zonisamide
Measure Participants	8	8	8	8	8	8	8	8	8
Mean (Standard Deviation) [number of cocaine choices]	0 (0)	0 (0)	0.25 (0.71)	2 (2.67)	2.38 (2.33)	2.25 (2.05)	3.5 (2.93)	3 (2.2)	3.38 (2.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	p-value was calculated as less than 0.01. Note: this is not an attempt to indicate a threshold
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	F-value for main effect of Coc dose
	Estimated Value	9.91
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	F-value for main effect of Cocaine dose on Behavioral Choice measure

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	F-value for main effect of Zon dose
	Estimated Value	0.07
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	F-value for main effect of Zonisamide dose on Behavioral Choice measure

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.92
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	F-value for main effect of Coc x Zon
	Estimated Value	0.24
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	F-value for main effect of Cocaine dose x Zonisamide dose interaction on Behavioral Choice measure

3. Primary Outcome

Title	Cocaine Craving
Description	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.
Time Frame	Day 1-39

Outcome Measure Data

Analysis Population Description

Includes all participants analyzed (n=12; 8 zonisamide, 4 placebo)

Arm/Group Title	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Day 8	Day 9	Day 10	Day 11	Day 12	Day 13	Day 14	Day 15	Day 16	Day 17	Day 18	Day 19	Day 20	Day 21	Day 22	Day 23	Day 24	Day 25	Day 26	Day 27	Day 28	Day 29	Day 30	Day 31	Day 32	Day 33	Day 34	Day 35	Day 36	Day 37	Day 38	Day 39
Arm/Group Description
Measure Participants	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12
Zonisamide	27.88 (10.25)	27.25 (15.29)	25 (14.32)	19.13 (8.63)	17.88 (11.51)	13.5 (8)	12.75 (11.21)	12.13 (9.85)	13.75 (10.93)	9.63 (8.99)	11.75 (9.18)	14.25 (11.41)	12.38 (10.86)	23.63 (31.01)	26.75 (39.46)	24.88 (39.41)	25.38 (38.93)	24.13 (39.47)	25.13 (39.67)	12.75 (12.74)	25.5 (29.82)	15.25 (14.27)	16.88 (12.05)	13.88 (13.07)	8.25 (9.41)	10.25 (11)	10.75 (10.17)	7.63 (9.78)	7.63 (10.82)	6.57 (10.13)	9.50 (9.09)	11.25 (12.90)	8.5 (10.43)	13.5 (11.49)	21.38 (17.74)	8.13 (11.76)	23.25 (35.25)	8.25 (11.99)	19.25 (27.22)
Placebo	42.75 (11)	41 (20.54)	30.25 (23.49)	28.25 (15.73)	28.25 (14.57)	26.5 (9.32)	29.5 (6.35)	27.25 (11.87)	28.5 (13.82)	19 (9.93)	25.33 (5.85)	25.25 (15.6)	22.75 (5.12)	22.75 (9.74)	24.75 (14.5)	19.25 (5.25)	24.00 (11.53)	22.5 (12.36)	24.5 (15.86)	26 (15.490)	25.5 (18.21)	23 (15.09)	18 (9.17)	19 (0)	15.5 (0.70)	16. (2.83)	14.5 (2.12)	16.5 (3.53)	24 (0)	16.5 (0.71)	16.5 (0.71)	19.5 (4.95)	18. (2.83)	17. (1.41)	19. (7.07)	16 (0)	19 (4.24)	20 (4.24)	16.5 (2.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28, Day 29, Day 30, Day 31, Day 32, Day 33, Day 34, Day 35, Day 36, Day 37, Day 38, Day 39
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments	Group (Zonisamide vs Placebo)
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	t-value for main effect of Group
	Estimated Value	1.51
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28, Day 29, Day 30, Day 31, Day 32, Day 33, Day 34, Day 35, Day 36, Day 37, Day 38, Day 39
	Comments
	Type of Statistical Test	Superiority
	Comments	Day (Day 1-39)
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	t-value for main effect of Day
	Estimated Value	-3.2
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28, Day 29, Day 30, Day 31, Day 32, Day 33, Day 34, Day 35, Day 36, Day 37, Day 38, Day 39
	Comments
	Type of Statistical Test	Superiority
	Comments	Group*Day interaction
Statistical Test of Hypothesis	p-Value	0.10
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	t value for Group x Day interaction
	Estimated Value	-1.63
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Drug Value Questionnaire
Description	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
Time Frame	Weeks 1-5; mean of weeks 1, 3 and 5 reported

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	1mg-0mg	1mg-300mg	1mg-600mg	20mg-0mg	20mg-300mg	20mg-600mg	40mg-0mg	40mg-300mg	40mg-600mg
Arm/Group Description	1mg cocaine - 0mg zonisamide Both doses are expected to be inactive, thus this arm is viewed as Placebo	1mg cocaine - 300mg zonisamide	1mg cocaine - 600mg zonisamide	20mg cocaine - 0mg zonisamide	20mg cocaine - 300mg zonisamide	20mg cocaine - 600mg zonisamide	40mg cocaine - 0mg zonisamide	40mg cocaine - 300mg zonisamide	40mg cocaine - 600mg zonisamide
Measure Participants	8	8	8	8	8	8	8	8	8
Mean (Standard Deviation) [dollars]	0 (0)	0 (0)	0 (0)	9.29 (7.32)	8.50 (5.81)	7.63 (3.54)	16 (14.96)	18.13 (18.31)	9.5 (8.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	p-value was calculated as less than 0.01. Note: this is not an attempt to indicate a threshold
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	F-value for main effect of Coc dose
	Estimated Value	21.1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	F-value for main effect of Cocaine dose

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	F-value for main effect of Zon dose
	Estimated Value	0.77
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	F-value for main effect of Zonisamide dose

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	1mg-0mg, 1mg-300mg, 1mg-600mg, 20mg-0mg, 20mg-300mg, 20mg-600mg, 40mg-0mg, 40mg-300mg, 40mg-600mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	F-value for the main effect of Zon x Coc
	Estimated Value	0.93
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	F-value for main effect of Zonisamide x Cocaine interaction on drug value (i.e., street value) measurement

Adverse Events

Time Frame	39 days
Adverse Event Reporting Description	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.
Arm/Group Title	Zonisamide		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Zonisamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/4 (0%)
Serious Adverse Events
	Zonisamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Zonisamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Anemia	1/8 (12.5%)	1	0/4 (0%)	0
Chemistry Abnormal	1/8 (12.5%)	1	0/4 (0%)	0
Cardiac disorders
Palpitations	1/8 (12.5%)	1	0/4 (0%)	0
Eye disorders
Tinnitus	1/8 (12.5%)	1	0/4 (0%)	0
Gastrointestinal disorders
Appetite Decreased	1/8 (12.5%)	1	0/4 (0%)	0
Constipation	1/8 (12.5%)	1	1/4 (25%)	1
Hepatitis	0/8 (0%)	0	2/4 (50%)	2
Indigestion	0/8 (0%)	0	1/4 (25%)	1
Liver function abnormal	1/8 (12.5%)	1	0/4 (0%)	0
Tooth Disease	4/8 (50%)	4	2/4 (50%)	2
General disorders
Allergic Rhinitis	1/8 (12.5%)	1	0/4 (0%)	0
Headache	6/8 (75%)	9	2/4 (50%)	4
Inguinal Hernia	1/8 (12.5%)	1	0/4 (0%)	0
Skin Rash	0/8 (0%)	0	1/4 (25%)	1
Creatinine Elevation	1/8 (12.5%)	1	0/4 (0%)	0
Asthma	1/8 (12.5%)	1	1/4 (25%)	1
Rhinitis	0/8 (0%)	0	1/4 (25%)	1
Athlete's foot	1/8 (12.5%)	1	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	1/8 (12.5%)	1	0/4 (0%)	0
Pain lower extremity	0/8 (0%)	0	1/4 (25%)	1
Nervous system disorders
Tingling sensation in extremity	1/8 (12.5%)	2	0/4 (0%)	0
Agitation	0/8 (0%)	0	2/4 (50%)	2
Dream abnormal	0/8 (0%)	0	2/4 (50%)	2
Insomnia	2/8 (25%)	2	0/4 (0%)	0
Jittery	1/8 (12.5%)	1	0/4 (0%)	0
Restlessness	1/8 (12.5%)	1	0/4 (0%)	0
Renal and urinary disorders
Urethritis	1/8 (12.5%)	1	0/4 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

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.