Official Title: “Lab Trials to Develop Medication for Cocaine Dependence”

Cocaine addiction is a serious health problem with no available medical treatment for preventing relapse. Topiramate, a medication which lowers dopamine levels, may have the ability to diminish cocaine cravings in addicts. The purpose of this study is to determine the effectiveness of topiramate in reducing cocaine's rewarding effects in individuals addicted to cocaine.

Study Type: Interventional

Study Design: Basic Science, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Crossover Assignment, Safety/Efficacy Study

Study Primary Completion Date: January 2009

GABA is an inhibitory neurotransmitter that is found primarily in the brain. High GABA levels result in low levels of dopamine, another neurotransmitter that is the brain's "feel good" chemical and which plays a primary role in cocaine drug addiction. Cravings for cocaine can be reduced by lowering dopamine levels. This makes topiramate, a GABA-altering medication, a potential treatment for cocaine addiction. This study will involve two sequential experiments and will evaluate the subjective, behavioral, and physiological effects of topiramate in individuals addicted to cocaine. The purpose of the first experiment is to evaluate the effectiveness of various doses of topiramate at reducing cocaine-mediated mood changes. The purpose of the second experiment is to evaluate whether the most effective topiramate dose from the first experiment reduces cocaine-induced mood changes over a period of several days.

In turn, these findings may guide future cocaine pharmacotherapy trials.

Potential participants will initially attend a 4- to 6-hour screening session. This will include review of medical and drug histories, standardized psychological questionnaires, a physical exam, and blood collection. Eligible participants will then be admitted to the inpatient clinic. During the first day of both experiments, participants will receive instructions and information about the study procedures. They will also undergo a physical exam, an electrocardiogram, standardized psychological questionnaires, and blood and urine collection. A single test dose of cocaine will be administered intravenously to all participants to ensure safety with continuation in the study. Vital signs will be monitored hourly throughout the day.

The first experiment will last 29 days and will enroll 18 individuals addicted to cocaine.

Participants will take part in nine testing sessions, each separated by 2 to 4 days.

Participants will receive varying combinations of topiramate, cocaine, and placebo during the testing sessions. They will be monitored by the study physician throughout the sessions.

Blood will be drawn frequently to assess levels of cocaine and topiramate. Participants will complete standardized questionnaires to evaluate mood changes and cognitive function.

The second experiment will last 25 days and will enroll 24 individuals addicted to cocaine.

In this three-part experiment, participants will be admitted to the inpatient clinic for an 8-day study session. Following this session, they will be discharged from the clinic for a 1-week washout phase. Participants will then return to the inpatient clinic for another 8-day study session. The two study sessions will be identical. During both sessions, participants will first receive topiramate or placebo for 4 consecutive days. While continuing to receive topiramate or placebo, participants will then also receive intravenous cocaine or placebo for 3 consecutive days. Topiramate doses will be determined by the results of the first experiment. Participants will be monitored by the study physician. Electrocardiograms will be used to monitor heart activity, and blood will be drawn frequently to monitor levels of cocaine and topiramate. Participants will complete standardized questionnaires several times each day to assess mood changes and cognitive function.

Intervention(s) in this Clinical Trial

• Drug: Topiramate
  • the maximum topiramate test dose is 200 mg/d.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Topiramate
• Placebo Comparator: Placebo

Primary Measures

• Cocaine-induced mood changes
  • Time Frame: measured throughout cocaine and topiramate testing sessions
    Safety Issue?: No
• Effects of topiramate on cognitive function
  • Time Frame: measured throughout cocaine and topiramate testing sessions
    Safety Issue?: No
• Drug safety
  • Time Frame: measured throughout cocaine and topiramate testing sessions
    Safety Issue?: Yes
• Cardiovascular response to cocaine (measured throughout cocaine and topiramate testing sessions)
  • Time Frame: measured throughout cocaine and topiramate testing sessions
    Safety Issue?: Yes

Secondary Measures

• Physiological response (measured throughout cocaine and topiramate testing sessions)
  • Time Frame: measured throughout cocaine and topiramate testing sessions
    Safety Issue?: No

Inclusion Criteria:

• Meets DSM-IV-TRTM diagnostic criteria for cocaine dependence
• Subjects must be non-treatment seeking, cocaine-dependent or cocaine-abusing individuals who report taking cocaine at least once a month
• In generally good health as confirmed by medical history, physical examination, electrocardiogram, laboratory screening tests, and vital signs
• Must be able to take oral medication, adhere to the medication regimens, and be willing to return to the clinic for regular study visits
• Must be able to read and understand all instructions, rating scales, and questionnaires in English
• Must be willing to stay overnight at the University Clinical Psychopharmacology
• Laboratory (UCPL)
• Must comply with the alcohol, tobacco, and drug-free environment regulations at the

UCPL

• If female, must be postmenopausal for at least 1 year, surgically sterile, or willing to use contraception throughout the study

Exclusion Criteria:

• History of mental illness, other than cocaine or nicotine dependence
• History of mental retardation or neuropsychological functioning greater than 1.5 standard deviation below expected rang.
• Clinically significant abnormalities found on the electrocardiogram
• History of hypertension (blood pressure greater than 140/90 mm Hg) or systolic hypotension (blood pressure less than 90/75 mm Hg)
• Resting pulse rate of greater than 90 beats per minute
• Cerebrovascular accident or transient ischemic attack
• Ischemic heart disease or heart attack
• Symptomatic coronary artery disease or peripheral vascular disease
• Cancer or history of cancer within the 5 years of study entry (other than basal cell carcinoma)
• Kidney disease and/or impaired kidney function, as defined by an estimated creatinine clearance of 60 mL per minute
• Gastrointestinal system disease, including active liver disease or current active hepatitis; subjects with AST and/or ALT levels greater than four times the upper limit of the normal range and/or an increased total serum bilirubin level greater than two times the upper limit of normal at screening
• Endocrinological disorders, including thyroid disorders
• Glaucoma
• Gross neurological disorders, including seizure disorders and progressive or degenerative neurological disorders (e.g., multiple sclerosis)
• History of nephrolithiasis
• Clinically significant laboratory screening test results on hematology, chemistry, or urine analysis; up to four times above the normal range of the following will be allowed unless there is evidence of hepatocellular disease or failure: liver enzymes (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), lactate dehydrogenase (LDH)
• Any disease or condition that compromises the function of body systems that may result in altered absorption, excess accumulation, or impaired metabolism or excretion of topiramate
• Current use of psychoactive drugs, including sympathomimetics, caffeinated drinks in excess of 500 mg per day, and tobacco consumption of greater than 0.75 grams per day (approximately 25 cigarettes per day); non-pathological levels of alcohol consumption is permitted
• Suicide attempt or suicidal thoughts within 30 days of study entry
• Evidence of behavioral toxicity, including seizures, severe agitation, or psychosis
• Be taking a medication that could interact adversely with topiramate, unless the medication is discontinued.
• History of any severe or life-threatening medication interactions
• Currently taking any prescribed medications for heart or cerebrovascular disease
• Currently taking any medication with potential interactions with cocaine or topiramate, including glutamate antagonists (e.g., acamprosate), serotonin re-uptake inhibitors (e.g., fluoxetine), serotonin antagonists (e.g., ritanserin or buspirone), other antidepressants (e.g., tricyclic antidepressants or monoamine oxidase inhibitors), dopamine antagonists (e.g., haloperidol), calcium channel antagonists (e.g., isradipine), compounds with actions similar to disulfiram (Antabuse), or any carbonic anhydrase medication or medication containing triamterene
• Previously treated with topiramate for any reason and discontinued treatment due to an adverse event or a hypersensitivity reaction to topiramate
• Participation deemed unsafe because of precautions, warnings, or contraindications outlined in the topiramate investigator brochure and/or package insert, as determined by study investigator
• Expected to stay in a restricted environment or awaiting imprisonment
• Currently living in the same household as another study participant
• Received an investigational drug or device or participated in a clinical trial in the 30 days prior to study entry
• Employee of the investigator or study center
• Pregnant or breastfeeding

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 45 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Virginia

Overall Clinical Trial Officials and Contacts

Bankole A. Johnson, DSc,MD.PhD Principal Investigator University of Virginia  

Overall Contact: Mindy Borszich, BA 1-888-882-2345 uvacare@virginia.edu

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00223626

Study ID Number: R01DA012191

ClinicalTrials.gov Identifier: NCT00223626

Health Authority: United States: Food and Drug Administration

UVA CARE website