Pilot Trial of Acamprosate for the Treatment of Cocaine Dependence

The primary objective of the trial is to evaluate the safety, tolerability and efficacy of
acamprosate for the treatment of 60 treatment seeking cocaine dependent outpatients. The
study will be an exploratory, double-blind, placebo-controlled 9-week trial, with a 2-cell
design (30 subjects per cell) in which either 1998 mg/day of acamprosate (666 mg TID) or
placebo will be given. Study medications will be given by medical practitioners, trained to
provide NIAAA's COMBINE Medical Management. In addition, patients will receive weekly
individual psychosocial treatment sessions utilizing Cognitive Behavioral Therapy (CBT) at
the University of Pennsylvania Treatment Research Center (TRC).

Primary Hypotheses:

1. Efficacy: Acamprosate-treated subjects will demonstrate less cocaine use during the
medication/placebo treatment phase, compared to placebo-treated subjects. Cocaine use
will be measured by self-report from the TLFB confirmed with urine assay for
benzoylecgonine (BE)

2. Safety and Tolerability: Acamprosate-treated subjects and placebo-treated subjects will
report similar rates of adverse events, assessed by weekly evaluations, physical exams
and laboratory testing.

Secondary Hypotheses:

1. Acamprosate-treated subjects, compared to placebo-treated subjects, will report less
craving for cocaine, measured by lower scores on the Brief Substance Craving Scale
(BSCS) (Somoza et al, 1995) and Multiple Choice Procedure (MCP) (Griffiths et al., 1993)
during the medication treatment phase.

2. Acamprosate-treated subjects, compared to placebo-treated subjects, will report fewer
withdrawal symptoms, measured by the Cocaine Selective Severity Assessment (Kampman et
al., 1998).

3. Acamprosate-treated subjects, compared to placebo-treated subjects, will report fewer
mood and anxiety symptoms, measured by the Hamilton Depression Rating Scale (HAM-D)
(Hamilton, 1967), Hamilton Anxiety Rating Scale (HAM-A) (Hamilton, 1969), and Clinical
Global Impression Scale (CGI).

4. Subjects who are highly acamprosate-adherent (>80% pills taken, verified by combining
patient report with blister cards) will have more cocaine non-use days during the
medication treatment phase, compared to those who are less acamprosate-adherent (<80%
pills taken).

Inclusion Criteria

1. Male and females 18 years of age or older.

2. Subject meets DSM-IV criteria for current diagnose of cocaine dependence, determined
by The Structured Clinical Interview for DSM-IV (SCID-IV).

3. Subject used cocaine in the past 30 days totaling at least $200 worth of cocaine.
Cocaine use will be determined by utilizing the modified Timeline Followback,
crosschecked with the ASI, which inquires about dollar amounts spent on drug use.

4. Subject lives a commutable distance from the TRC and agrees to attend all research
visits, including follow-up visits.

5. Subject speaks, understands, and prints in English.

6. Written informed consent signed by the subject.

Exclusion Criteria

1. Subjects mandated to treatment based upon a legal decision or as a condition of
employment.

2. Subjects with evidence of current substance dependence other than cocaine, alcohol or
nicotine dependence, as determined by the SCID-IV.

3. Subjects who meets DSM-IV criteria for current alcohol dependence who require a
medical alcohol detoxification.

4. Requires treatment with any psychoactive medications, including any anti-seizure
medications (with the exception of Benadryl used sparingly, if necessary, for sleep).

5. Has a lifetime DSM-IV diagnosis of bipolar affective disorder, schizophrenia or any
psychotic disorder, or organic mental disorder. Has current DSM-IV diagnosis of any
other clinically significant psychiatric disorder that will interfere with study
participation, as determined by the study physician or PI (Drs. Kyle Kampman, Charles
Dackis and Helen Pettinati).

6. Female subjects who are pregnant or lactating, or female subjects of childbearing
potential who are not using acceptable methods of birth control. Acceptable methods of
birth control include: barrier (diaphragm or condom) with spermicide, intrauterine
progesterone contraceptive system, levonorgestrel implant, medroxyprogesterone acetate
contraceptive injection, and oral contraceptives.

7. Clinical laboratory tests (CBC, blood chemistries, urinalysis) outside normal limits
that are clinically unacceptable to the Principal Investigator. EKG-1st degree heart
block, sinus tachycardia, left axis deviation, and nonspecific ST or T wave changes
are allowed; liver function tests [LFTs] < 5 x ULN are acceptable. Eligibility will be
determined by most recent lab results collected prior to randomization.

8. Subjects with impaired renal function as indicated by corrected creatinine clearance
below 80 ml/min/70 kg as determined by the modified Cockcroft equation (Center for
Disease Control, 1986).

9. Subjects who have any disease of the gastrointestinal tract, liver or kidneys that
could result in a possibility of altered metabolism or excretion of the study drug. As
it is not possible to enumerate the many conditions which might impair absorption,
metabolism, or excretion, the investigators will be guided by evidence such as:
History of major gastrointestinal tract surgery (gastrectomy, gastrostomy, bowel
resection, etc) or a history of an active peptic ulcer or chronic disease of the GI
tract (ulcerative colitis, regional enteritis, or gastrointestinal bleeding).

10. History of significant heart disease (an arrhythmia which required medication, angina
pectoris, documented history of myocardial infarction, or heart failure).

11. Known hypersensitivity to acamprosate.

12. Subjects having participated in any investigational drug trial within 30 days prior to
randomizing into the study.

13. Subjects with any serious illnesses that may require hospitalization during the study,
as determined by the study physician or PI (Drs. Kyle Kampman, Charles Dackis and
Helen Pettinati).