Aripiprazole and Topiramate on Free-Choice Alcohol Use (AT)

October 5, 2015 updated by: Robert Swift, National Institute on Alcohol Abuse and Alcoholism (NIAAA)

The current study investigates the effects of two potential alcohol treatment medications on drinking in a laboratory setting. Aripiprazole (APZ), effects dopamine and serotonin receptors with fewer limiting side effects seen with other atypical antipsychotics. Topiramate (TPMT), an antiepileptic, affects glutamate and GABA-A receptors and shows promise in reducing heavy drinking. Few studies have used two medications with such a diverse combination of actions to examine a potential synergistic effect on reducing alcohol consumption.

The primary aims are to:

  1. determine if APZ and TPMT are each more effective than placebo, and the combination of APZ and TPMT is more effective than either drug alone or placebo, in reducing alcohol use in non-treatment seeking alcohol dependent subjects in a laboratory based alcohol self-administration experiment (ASAE)
  2. examine a hypothesized dose-response for three doses of APZ (0, 7.5 mg/d and 15 mg/d) along with three doses of TPMT (0, 100mg/d and 200mg/d)
  3. examine the putative mechanisms of action of APZ, TPMT alone and together on craving, subjective stimulation, candidate gene influences and other behavioral effects associated with alcohol consumption
  4. establish the safety of giving APZ and TPMT together. Non-treatment seeking, alcohol dependent Participants (N=216) will be recruited from the community and randomly assigned to one of the 9 cells. Subjects drinking and safety is monitored over a 5-week titration to their target dose, leading to an in-laboratory alcohol self administration session, during which clinical and behavioral effects are assessed during access to alcohol. A 1 month follow-up assesses adverse events and drinking.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Due to the modest effect of current pharmacotherapies, more effective treatments must be developed to optimally treat alcohol dependent patients. Treatments combining pharmacotherapies with different mechanisms of action may better address the diverse neurobiology of alcohol and the heterogeneity of alcoholics. However, little is known about how medication may affect behavior to reduce drinking. Aripiprazole (APZ), a partial dopamine agonist, affects dopamine and serotonin receptors without the limiting side effects seen with other atypical antipsychotics. Dopamine mediates reward based drinking and craving. Topiramate (TPMT), an antiepileptic, affects glutamate and GABA-A receptors and shows promise in reducing heavy drinking. Glutamate and GABA may mediate relief-based drinking and protracted withdrawal. Despite strong evidence that multiple neurotransmitters contribute to alcoholism, few studies have used two medications with such a diverse combination of actions to examine a potential synergistic effect on reducing alcohol consumption.

The present study will recruit 216 healthy, alcohol-dependent volunteers who are not currently seeking treatment for their alcohol dependence to learn more about how these medications may work.

The primary aims are to: (1) determine if APZ and TPMT are each more effective than placebo, and the combination of APZ and TPMT is more effective than either drug alone or placebo, in reducing alcohol use in non-treatment seeking alcohol dependent subjects in an alcohol self administration experiment (ASAE); (2) examine a hypothesized dose-response for three doses of APZ (0, 7.5mg/d and 15 mg/d) and three doses of TPMT (0, 100mg/d, 200mg/d); (3) examine the putative mechanisms of action of APZ, TPMT alone and together on craving, subjective stimulation, candidate gene influences and other behavioral effects associated with alcohol consumption; and (4) establish the safety of giving APZ and TPMT together. We will use of a 3 X 3 drug (7.5mg, 15mg APZ vs. placebo) by drug (100mg, 200mg TPMT vs. placebo) between-subjects factorial design. Participants are randomly assigned to one of 9 cells. Subjects drinking and safety is monitored over a 5-week titration to their target dose, leading to an in-laboratory alcohol self administration session, during which clinical and behavioral effects are assessed during access to alcohol. A 1 month follow-up assesses adverse events and drinking. The long term objectives of this research are to improve medications available for alcoholism treatment and inform research and theory on the mechanisms of action of such medications.

Study Type

Interventional

Enrollment (Actual)

90

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Rhode Island
      • Providence, Rhode Island, United States, 02903
        • Brown University Center for Addiction Studies

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • must be non-treatment seeking for alcohol dependence
  • a current DSM-IV-TR diagnosis of alcohol dependence supported by the Structured Clinical Interview for DSM-IV-TR Axis I Disorders Patient Edition (SCID-I/P a minimum of ≥ 35drinks a week for men or ≥ 28 or more drinks a week for women
  • must be suitable for outpatient treatment
  • able to read English at an eighth grade level, understand their rights as provided by the informed consent, and be willing to sign an informed consent to participate in the study
  • be between 21 and 65 years on age (inclusive)
  • provide evidence of stable residence in the two months prior to enrollment and no plans to move for the next four months
  • provide a verifiable contact person prior to randomization
  • be in generally good health as determined by the physical exam, medical history, ECG and laboratory tests
  • have a Body Mass Index >18kg/m2 and < 33 kg/m2
  • if female, must be postmenopausal practicing an effective method of birth control, have negative pregnancy tests at randomization and before the ASAE;
  • be willing to be adherent to medication dosing.

Exclusion Criteria:

  • clinically significant medical abnormalities (i.e. ECG, hematological assessment, bilirubin > 150% of the upper limit of normal or ALT or AST elevations >300% the upper limit of normal, biochemistry including urinalysis, electrolytes,). (Persons with medical conditions that are adequately controlled by their primary care physician will not be excluded.)
  • have significant alcohol withdrawal symptoms (clinical institute withdrawal assessment for alcohol revised (CIWA-Ar) >10
  • a history of suicide; history of renal impairment or nephrolithiasis; creatinine clearance of <60 dl/minute
  • pregnant or lactating or not using an adequate form of birth control
  • taking other medications that may have an effect on alcohol consumption or are carbonic anhydrase inhibitors
  • clinically significant diseases of the gastrointestinal system or active liver disease; subjects compelled to receive treatment to avoid imprisonment or loss of employment
  • previously with a history of adverse reaction or hypersensitivity to either Topiramate or aripiprazole
  • have a diagnosis of with schizophrenia or bipolar disorder and/or taking antipsychotics and other drugs that inhibit CYP3A4 or CYP2D6 isoenzymes
  • history of seizures (e.g. epilepsy)
  • patients currently diagnosed with a substance dependence diagnosis other than alcohol or tobacco
  • patients who have participated in any clinical trial with an investigational agent within the past 30 days
  • individuals with a reasonable expectation of being institutionalized during the course of the trial or pending legal charges
  • pregnant or nursing women.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Double Placebo
Placebo, Placebo
Drug: Double Placebo
1 capsule daily
Experimental: Aripiprazole 15, Placebo
15 mg Aripiprazole, Placebo
Drug: Aripiprazole 15, placebo
15 mg Aripiprazole daily plus placebo daily
Other Names:
  • Abilify, Topamax
Experimental: Aripiprazole 7.5, Placebo
Aripiprazole 7.5 mg daily plus Placebo daily
Drug: Aripiprazole 7.5, Placebo
Aripiprazole 7.5 mg daily plus Placebo daily
Experimental: Topiramate 100mg, Placebo
Topiramate 100 mg daily plus Placebo daily
Drug: Topiramate 100, Placebo
Topiramate 100 mg daily plus Placebo daily
Experimental: Topiramate 200, Placebo
Topiramate 200 mg daily plus Placebo daily
Drug: Topiramate 200, Placebo
Topiramate 200 mg daily plus Placebo daily
Experimental: Topiramate 100, Aripiprazole 5
Topiramate 100 daily plus, Aripiprazole 5mg daily
Drug: Topiramate 100, Aripiprazole 15
Topiramate 100 mg daily plus Aripiprazole 15mg daily
Other Names:
  • Abilify, Topamax
Drug: Topiramate 100, Aripiprazole 15mg
Topiramate 100 mg daily plus Aripiprazole 15mg daily
Other Names:
  • Abilify
  • Topamax
Experimental: Topiramate 200, Aripiprazole 15
Topiramate 200 mg daily plus Aripiprazole 15mg daily
Drug: Topiramate 200, Aripiprazole 15
Topiramate 200mg daily plus Aripiprazole 15mg daily
Other Names:
  • Abilify
  • Topamax
Experimental: Topiramate 100, Aripiprazole 7.5
Topiramate 100 mg daily, Aripiprazole 7.5 mg daily
Drug: Topiramate 100, Aripiprazole 7.5
Topiramate 100 mg daily plus Aripiprazole 7.5mg daily
Experimental: Topiramate 200, Aripiprazole 7.5mg
Topiramate 200 mg daily plus Aripiprazole 7.5mg daily
Drug: Topiramate 200, Aripiprazole 7.5mg
Topiramate 200 mg daily plus Aripiprazole 7.5mg daily
Other Names:
  • Abilify
  • Topamax

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of alcoholic drinks consumed in a laboratory setting
Time Frame: 90 minutes
90 minutes
Safety and tolerability of the medications singly and in combination, compared to placebo
Time Frame: 4 years
4 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Drinks consumed during the medication titration period
Time Frame: 4 weeks
4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborators

Brown University

Investigators

  • Principal Investigator: Robert M Swift, MD, PhD, Brown University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2007

Primary Completion (Actual)

October 1, 2015

Study Completion (Actual)

October 1, 2015

Study Registration Dates

First Submitted

April 20, 2009

First Submitted That Met QC Criteria

April 20, 2009

First Posted (Estimate)

April 21, 2009

Study Record Updates

Last Update Posted (Estimate)

October 7, 2015

Last Update Submitted That Met QC Criteria

October 5, 2015

Last Verified

October 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NIAAA-Swift-AA015753
  • NIH Grant 5RO1AA015753-02

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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