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High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers

Phase 2/Phase 3
18 Years
Open (Enrolling)
Alcohol Dependence, Nicotine Dependence

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Trial Information

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers

We propose a novel pharmacological strategy for treating alcohol and nicotine dependence

The reinforcing effects of both alcohol and nicotine are mediated through the
cortico-mesolimbic dopamine (CMDA) system, and the concomitant use of both drugs enhances
their pharmacological effects. We propose a better approach to control dopamine (DA) effects
by contemporaneous indirect modulation of DA release and its functional expression. Both DA
release from its cell bodies in the ventral tegmental area and the expression of its
reinforcing effects through the cortico-mesolimbic system are modulated by GABA efferents
under the tonic control of glutamate-mediated excitatory amino acid pathways. Thus, it is
reasonable to hypothesize that a medication that facilitates cortico-mesolimbic GABAergic
function and inhibits glutamate action should diminish both nicotine's and alcohol's
reinforcing effects by inhibiting the release of midbrain DA and its functional expression
through pathways projecting from the nucleus accumbens to the cortex. The promise of this
novel approach is exemplified by our recent proof-of-concept demonstration that topiramate
compared with placebo significantly improved smoking abstinence rates and decreased serum
cotinine levels among alcoholdependent smokers. An important clinical effect of topiramate
in alcohol-dependent individuals appears to be that its anti-withdrawal effects promote the
gradual tapering of drinking. Hence, due to this unique antiwithdrawal effect of topiramate,
we propose to adopt the same methodology for treating alcohol-dependent individuals, as is
common practice with smokers, of setting a target quit date (TQD) after which relapse to
either drug can be measured. We propose an 18-week, double-blind clinical trial with
follow-up visits at 1 month and 3 months, in which alcohol-dependent smokers will receive
brief behavioral compliance enhancement treatment (BBCET) plus a smoking self-help manual as
their psychosocial treatment, and will be randomized to receive placebo,high-dose topiramate
(up to 250 mg/day), or low-dose topiramate (up to 125 mg/day) to prevent relapse to heavy
drinking and smoking. Each of the 3 treatment arms shall contain 98 individuals, with a
total N of 294.

The TQD will occur at the beginning of the 6th week of treatment. Our primary objective is
to determine whether both low- and high-dose topiramate will be more efficacious than
placebo at reducing the percentage of heavy drinking days and increasing the continuous
abstinence rate for smoking determined by a combination of self-report and CO monitoring
after the TQD and in the last 4 weeks of treatment. We also will be able to determine
whether a lower dose of topiramate is as efficacious as the higher dose and, therefore, is
associated with a lower adverse profile. Our secondary objectives are to test whether
topiramate will be more efficacious than placebo at improving quality of life and reducing
craving after the TQD and in the last 4 weeks of treatment and whether this improvement will
be sustained in the follow-up phase.

Inclusion Criteria:

- Males and females who have given written informed consent

- Subjects must be above the age of 18

- Good physical health

- DSM-IV diagnosis of alcohol dependence. Subjects who abuse other substances will be
included as long as their use patterns would not preclude safe participation or
adequate compliance with the protocol.

- Score of ≥3 on the Fagerstrom Test for Nicotine Dependence

- Smoking ≥10 cigarettes/day Subjects must provide evidence of stable residence

- The pregnancy test for females of child-bearing potential at screen and prior to
randomization must be negative. Additionally, women of child-bearing potential must
be using an acceptable form of contraception.

- Literate in English and able to read, understand, and complete the rating scales and
questionnaires accurately, follow instructions, and make use of the behavioral

- Willing to participate in a treatment program for alcohol and nicotine dependence

Exclusion Criteria:

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Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

percent heavy drinking days, continuous abstinence rate for smoking

Outcome Description:

The timeline follow-back (TLFB) method of measuring alcohol consumption will be used for PHDD.Continuous abstinence in smoking is determined by a combination of self-report and CO monitoring after the quit date

Outcome Time Frame:

In the last 4 weeks of treatment

Safety Issue:


Principal Investigator

Nassima Ait-Daoud Tiouririne, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Virginia


United States: Food and Drug Administration

Study ID:




Start Date:

September 2011

Completion Date:

September 2015

Related Keywords:

  • Alcohol Dependence
  • Nicotine Dependence
  • alcohol
  • alcoholism
  • nicotine
  • cigarette
  • Alcoholism
  • Tobacco Use Disorder



University of Texas MD Anderson Cancer Center Houston, Texas  77030
University of California, San Diego La Jolla, California  92037-1709
University of Virginia Center for Addiction Research & Education Charlottesville, Virginia  22911