ZNSBP: Zonisamide for Heavy Drinkers With Bipolar Disorder

• Sponsor: Yale University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01566370
• Collaborator: National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH)
• Enrollment: 3
• Location: 1
• Arms: 2
• Duration (Months): 14
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a randomized, double blind, placebo controlled trial of the medication zonisamide for the purpose of reducing heavy drinking and drinking, as well as reducing mood symptoms, in bipolar subjects that drink excessively and heavily.

Hypotheses: (Primary aims); Add-on zonisamide compared to placebo will result in:

1. significant reduction in heavy drinking days, drinks per week and per drinking day, and significantly greater increase in abstinent days, ii) greater rates of abstinence and abstinence to heavy drinking, greater reduction in biomarkers of heavy alcohol use such as gamma-glutamyl transferase (GGT), and greater reduction in alcohol urge or "craving",

2. Significant reduction in prevalent mood symptoms on the BRMS and BRMeS, CARS, HAMD, or no worsening of euthymic mood, and significant improvement on the Clinical Global Impressions Scale-Severity.

3. (Secondary aims) Add-on zonisamide compared to placebo will result in significant reduction in weight (kilograms) and other secondary weight-related metabolic factors such as fasting glucose, lipid profile, and blood pressure.

4. (Secondary aims) Add-on zonisamide compared to placebo will result in improved clinical global impression, overall functioning, quality of life, and reduced medical symptoms.

5.) (Exploratory Aims) To will examine interactions between genotype and medication on treatment response for allelic variation in genetic loci related to the major neurotransmitter and neurophysiologic pathways that are relevant to bipolar disorder, alcoholism, and zonisamide mechanism of action.

Condition or Disease	Intervention/Treatment	Phase
Alcohol Use Disorders; Bipolar Disorder	Drug: Zonisamide; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Zonisamide for Heavy Drinkers With Bipolar Disorder
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zonisamide Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind	Drug: Zonisamide; titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose; Other Names: Zonegran
Placebo Comparator: Placebo Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group	Drug: Placebo; placebo

Outcome Measures

Primary Outcome Measures

1. Percentage of Total Heavy Drinking Days [from week 11 through 14 (over 4 weeks)]

   The percentage of total heavy drinking days compared between groups (zonisamide and placebo) during the time spent on the target dose of the medication (i.e., not including the titration or taper periods), totaled between the time-points of weeks 11 and 14 (4 weeks time frame).

2. Change on Hamilton Depression Rating Scale [14 weeks]

   Change from baseline to endpoint in Hamilton scores compared between medication and placebo, using repeated measures

3. Change in Clinician Assisted Rating Scale for Mania (CARS-M) Scores [14 weeks]

   Comparison between groups on change in scores on the CARS-M over 14 weeks from baseline to endpoint, measured weekly and analyzed with repeated measures

Secondary Outcome Measures

1. Percentage of Abstinent Days [over four weeks, from week 11 through 14]

   The difference in total percentage of abstinent compared between groups (zonisamide and placebo) during the time spent on the target dose of the medication (i.e., not including the titration or taper periods), which includes week 11, 12, 13, and 14.

2. Change in Alcohol Urge Questionnaire Score [from baseline to endpoint, 14 weeks]

   This is the change in AUQ scores (urge to drink) measured weekly compared between groups using repeated measures

3. Change in Gamma Glutamyl Transferase (GGT) [14 weeks]

   Difference between groups on change in levels of GGT over time, measured at baseline, week 5, week 9, week 13, and endpoint, using repeated measures

4. Change in Beck Depression Inventory (BDI) Scores [14 weeks]

   Comparison between groups on change in BDI scores over the 14 weeks of the study, measured weekly, using repeated measures

5. Percentage of Total Drinking Days [4 weeks]

   The percentage of total drinking days compared between groups (zonisamide and placebo) during the time spent on the target dose of the medication (i.e., not including the titration or taper periods), which includes week 11, 12, 13, and 14.

6. Change in Number of Heavy Drinking Days Per Week by Time [14 weeks (baseline to endpoint)]

   A comparison between medication and placebo on the measure of number heavy drinking days per week over the course of the study (baseline to endpoint) via interaction with time using repeated measures

7. Change in Number of Drinks Per Week by Time [14 weeks (baseline to endpoint)]

   Comparison between medication and placebo groups on the change in number of drinks per week via interaction with time (from baseline to endpoint) using repeated measures

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female/male aged 18-65 years

• Ability to provide informed consent to participate

• Presence of Axis I diagnosis of BD (either type I, Type II, or NOS), in manic, hypomanic, depressive, mixed, or euthymic states plus presence of Axis I diagnosis of a current AUD and/or "at risk" regular heavy drinking (must average >2 heavy drinking days per week) with the goal of reducing or stopping drinking

• treatment with a standard mood stabilizer medication and or other medications with known psychotropic effects on mood state but not alcohol use; Lithium, and/or atypical antipsychotic medications will be the preferred medications,

• Subjects not on any primary acceptable mood stabilizer as described above must be willing to begin treatment with Lithium in open label fashion,

• English speaking, Able to read at the eighth grade or higher level and show no evidence of significant cognitive impairment;

• Women of child-bearing potential (i.e., no hysterectomy, bilateral oophorectomy, or tubal ligation or <2 years postmenopausal), must be non-lactating, practicing a reliable method of birth control, and have a negative serum pregnancy test prior to initiation of treatment;

• Must continue to have at least 2 heavy drinking days per week (averaged per month, with heavy drinking defined as having >4 standard drinks per day for males, and >3 standard drinks per day for females) up to the screening appointment

Exclusion Criteria:

• Presence of another major Axis I disorder such as Schizophrenia or Schizoaffective disorder, Delusional disorder, or other severe psychiatric disorder. A history of suicidal or violent behavior which, in the opinion of the study physician, puts the patient at significant risk of suicide or homicide during the study.

• Past history of drug abuse or dependence will be allowed, but active drug dependence (with the exception of nicotine dependence) in the last 30 days will be disqualifying.

• Serious neurological, or endocrine disorder,

• Evidence of potentially serious or as yet undiagnosed medical problems,

• Neurocognitive cognitive or language limitations, or other incapacity with providing informed consent;

• Known adverse reaction to zonisamide, sulfa-drug allergy, penicillin allergy, other severe adverse drug reaction or allergy, or any serious systemic autoimmune illness,

• Patients currently undergoing ECT treatment.

• Also patients with a history of seizures (other than febrile seizures), renal calculi, or currently taking medications that could either significantly increase the risk of seizures (e.g., tricyclic antidepressant agents, Bupropion, clozaril), or that could potentially theoretically significantly influence drinking behavior such as benzodiazepines, stimulants, opioid painkillers, sedative-hypnotics, etc.).

• Subjects on the following anticonvulsant medications will also be excluded as they may increase the risk of similar side-effects (similar to zonisamide) such as rash, cognitive impairment, or potentially could confound the study of drinking behavior; topiramate, tiagabine, oxcarbazepine, carbamezapine, valproic acid, lamotrigine

• Patients who, on clinical examination by a physician, are deemed to be too severely alcohol dependent to permit them to participate in an outpatient level of care medication trial. We have, over the years, developed methods for reliably and safely assessing patients for alcohol treatment and dual diagnosis studies.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Connecticut Healthcare System	West Haven	Connecticut	United States	06516

Sponsors and Collaborators

• Yale University
• National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

• Principal Investigator: Albert J Arias, MD, Yale University, VA CT Health System

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT01566370
• Other Study ID Numbers: ZNS-BP; VACT MIRECC; K23AA017689
• First Posted: Mar 29, 2012
• Last Update Posted: Jan 13, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by Yale University: alcoholism; alcohol use disorder; alcohol dependence; alcohol abuse; bipolar; anticonvulsant; zonisamide
• Additional relevant MeSH terms: Disease; Alcoholism; Alcoholic Intoxication; Bipolar Disorder; Alcohol Drinking; Zonisamide

Study Results

Participant Flow

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Period Title: Overall Study
STARTED	2	1
COMPLETED	0	0
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Zonisamide	Placebo	Total
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo	Total of all reporting groups
Overall Participants	2	1	3
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	2 100%	1 100%	3 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	58.5	45	51.75
Gender (Count of Participants)
Female	0 0%	1 100%	1 33.3%
Male	2 100%	0 0%	2 66.7%
Region of Enrollment (participants) [Number]
United States	2 100%	1 100%	3 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Total Heavy Drinking Days
Description	The percentage of total heavy drinking days compared between groups (zonisamide and placebo) during the time spent on the target dose of the medication (i.e., not including the titration or taper periods), totaled between the time-points of weeks 11 and 14 (4 weeks time frame).
Time Frame	from week 11 through 14 (over 4 weeks)

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

2. Primary Outcome

Title	Change on Hamilton Depression Rating Scale
Description	Change from baseline to endpoint in Hamilton scores compared between medication and placebo, using repeated measures
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

3. Primary Outcome

Title	Change in Clinician Assisted Rating Scale for Mania (CARS-M) Scores
Description	Comparison between groups on change in scores on the CARS-M over 14 weeks from baseline to endpoint, measured weekly and analyzed with repeated measures
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

4. Secondary Outcome

Title	Percentage of Abstinent Days
Description	The difference in total percentage of abstinent compared between groups (zonisamide and placebo) during the time spent on the target dose of the medication (i.e., not including the titration or taper periods), which includes week 11, 12, 13, and 14.
Time Frame	over four weeks, from week 11 through 14

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

5. Secondary Outcome

Title	Change in Alcohol Urge Questionnaire Score
Description	This is the change in AUQ scores (urge to drink) measured weekly compared between groups using repeated measures
Time Frame	from baseline to endpoint, 14 weeks

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

6. Secondary Outcome

Title	Change in Gamma Glutamyl Transferase (GGT)
Description	Difference between groups on change in levels of GGT over time, measured at baseline, week 5, week 9, week 13, and endpoint, using repeated measures
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

7. Secondary Outcome

Title	Change in Beck Depression Inventory (BDI) Scores
Description	Comparison between groups on change in BDI scores over the 14 weeks of the study, measured weekly, using repeated measures
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

8. Secondary Outcome

Title	Percentage of Total Drinking Days
Description	The percentage of total drinking days compared between groups (zonisamide and placebo) during the time spent on the target dose of the medication (i.e., not including the titration or taper periods), which includes week 11, 12, 13, and 14.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

9. Secondary Outcome

Title	Change in Number of Heavy Drinking Days Per Week by Time
Description	A comparison between medication and placebo on the measure of number heavy drinking days per week over the course of the study (baseline to endpoint) via interaction with time using repeated measures
Time Frame	14 weeks (baseline to endpoint)

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

10. Secondary Outcome

Title	Change in Number of Drinks Per Week by Time
Description	Comparison between medication and placebo groups on the change in number of drinks per week via interaction with time (from baseline to endpoint) using repeated measures
Time Frame	14 weeks (baseline to endpoint)

Outcome Measure Data

Analysis Population Description

None of the subjects completed the study or made it to the 12 week endpoint.

Arm/Group Title	Zonisamide	Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose	Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
Measure Participants	0	0

Adverse Events

Time Frame	baseline, week 1, week 2
Adverse Event Reporting Description	Adverse events reported on the SAFTEE form.
Arm/Group Title	Zonisamide		Placebo
Arm/Group Description	Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind Zonisamide: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose		Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group Placebo: placebo
All Cause Mortality
	Zonisamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zonisamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Zonisamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		1/1 (100%)
Gastrointestinal disorders
Diarrhea	1/2 (50%)		1/1 (100%)
Gas	0/2 (0%)		1/1 (100%)
General disorders
Nervousness	1/2 (50%)		1/1 (100%)
Feeling Drowsy	1/2 (50%)		1/1 (100%)
Fatigue	1/2 (50%)		1/1 (100%)
Irritability	2/2 (100%)		0/1 (0%)
Slowed Movements	1/2 (50%)		0/1 (0%)
Swelling feet/ankles	0/2 (0%)		1/1 (100%)
Gait Disturbance	0/2 (0%)		1/1 (100%)
Extreme Thirst	1/2 (50%)		0/1 (0%)
Metabolism and nutrition disorders
Loss of Appette	1/2 (50%)		0/1 (0%)
Musculoskeletal and connective tissue disorders
Leg Cramps	1/2 (50%)		1/1 (100%)
Back pain	0/2 (0%)		1/1 (100%)
Nervous system disorders
Headache	1/2 (50%)		1/1 (100%)
Memory Problems	1/2 (50%)		0/1 (0%)
Difficulty Paying attention	1/2 (50%)		0/1 (0%)
Extreme Tiredness	1/2 (50%)		1/1 (100%)
Psychiatric disorders
Depressed Mood	2/2 (100%)		0/1 (0%)
Mood swings	2/2 (100%)		0/1 (0%)
Restlessness	1/2 (50%)		0/1 (0%)
Confusion	2/2 (100%)		0/1 (0%)
Aggressive Behavior	1/2 (50%)		0/1 (0%)
Difficulty Sleeping	1/2 (50%)		0/1 (0%)
Reproductive system and breast disorders
Decreased Sex Drive	2/2 (100%)		0/1 (0%)
Breast Pain	0/2 (0%)		1/1 (100%)
Impotence	1/2 (50%)		0/1 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal Congestion	0/2 (0%)		1/1 (100%)
Rapid Breathing	0/2 (0%)		1/1 (100%)
Chest pain	0/2 (0%)		1/1 (100%)
Shortness of breath	0/2 (0%)		1/1 (100%)
Skin and subcutaneous tissue disorders
Rash	1/2 (50%)		0/1 (0%)
Itching	1/2 (50%)		0/1 (0%)
Decreased Sweating	1/2 (50%)		0/1 (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.