Multisite Controlled Trial of Cocaine Vaccine

This 18-week, placebo-controlled randomized clinical trial among 300 cocaine dependent
patients is designed to test the efficacy of a newly developed active vaccine against
cocaine (TA-CD). TA-CD vaccine consists of succinylnorcocaine (SNC) coupled to a recombinant
cholera toxin B subunit (rCTB) and is designed to raise anti-cocaine antibodies in the
circulation to bind to cocaine entering the bloodstream, following administration by
intravenous or intranasal routes or by smoking. The antigen-antibody complexes will be too
large to cross the blood-brain barrier, preventing high concentrations of cocaine reaching
the brain's nucleus accumbens thereby blocking the pleasurable response to cocaine and
reducing rates of drug use. The effectiveness of the vaccine is dependent on inducing
sufficient levels of anti-cocaine antibodies to match the challenge from a subsequent dose
of cocaine.

Because TA-CD takes several weeks to generate an antibody response, we plan to use
contingency management in this interval to sustain treatment engagement. Furthermore, since
TA-CD may prove most effective in patients where the antibodies can prevent a cocaine slip
from turning into a binge (or return to regular use) by attenuating the priming effect, we
are complementing the vaccine by using cognitive behavioral therapy (CBT) to teach patients
how to cope with this priming effect and prevent a full relapse.

Inclusion Criteria:

- (1) Age 18 to 55 years (inclusive); (2) Male or female. Females either must be of
non-child bearing potential (i.e., surgically sterilized or postmenopausal) or must
be using adequate contraception, have a negative pregnancy test, and must agree to
continue to use such precautions for 3 months after the last vaccination; (3) Meets
DSM-IV-TR criteria for a principal diagnosis of cocaine dependence as confirmed by
the SCID-CV. (Per DSM-IV-TR, principal diagnosis is the condition that is the primary
target of treatment at the time of presentation); (4) Motivated to discontinue or
reduce cocaine use during the period of the study as evidenced both by the judgment
of the Investigator or designee and by the subject providing at least 2 urine samples
in each of the 2 baseline weeks; (5) In good general health as determined by medical
history, general clinical examination, laboratory tests, and a World Health
Organization (WHO) performance status of 0 or 1; (6) Has provided written informed
consent. Subjects should be cooperative, willing and able to participate and adhere
to the Protocol requirements.

Exclusion Criteria:

- (1) Subject is cocaine-free (i.e., a negative urine result [BE level]) during the
2-week screening period. The subject may be rescreened at a later date; (2) Subject
has known immunodeficiency or has a history of autoimmune disease or hypersensitivity
to other vaccines. A human immunodeficiency virus (HIV) test must be performed at
Screening and reported as negative for HIV-1 and HIV-2; (3) Subject is currently
taking medication known to have significant immunosuppressive effects such as
systemic glucocorticoids (topical and inhaled formulations are permitted) or oral
systemic corticosteroids, within 30 days prior to randomization; (4) Subject is
currently taking a dopaminergic, dopamine-blocking, dopamine-modulating, or other
central dopamine-altering drug (e.g., antipsychotic drugs); a monoamine oxidase
inhibitor (MAOI); or an opiate antagonist; (5) Subject has an unstable medical,
neurologic, or psychiatric illness that would interfere with the subject's safety,
ability to participate in the study, or the interpretability of data. Subjects who
meet the DSM-IV-TR criteria for psychosis, schizophrenia, bipolar disorder or
clinically significant suicidal ideation. Subjects who have been taking stable doses
of antidepressants for at least 3 months will be allowed onto the study; (6) Subject
had dependence on benzodiazepines, barbiturates, opiates or amphetamines according to
DSM-IV-TR during the year prior to Screening. Opioid dependence includes methadone or
buprenorphine maintenance treatment; (7) Subject in alcohol withdrawal. Alcohol
withdrawal must be assessed in the context of a negative breathalyzer result. If it
is positive, alcohol withdrawal must be assessed as appropriate for 3 consecutive
days; (8) Subject has a history of sensitivity to aluminium hydroxide gel; (9)
Subject has a history of severe adverse reaction to cholera vaccine; (10) Subject had
previous vaccination with TA-CD; (11) Subject received other vaccines, including flu
vaccine, within 30 days prior to randomization; (12) Subject has participated in
another clinical trial or received any other investigational compound within 30 days
prior to randomization; (13) Subject has received blood or blood products within the
3 months prior to randomization; (14) Subject has liver function tests (including
alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline
phosphatase) greater than 3 times the upper limit of normal (ULN) at Screening; (15)
Subject has systolic blood pressure higher than 140 mmHg and/or diastolic blood
pressure >90 mmHg. Note: Blood pressure will be taken at least 10 minutes after entry
to the clinic and after the subject has been supine for at least 5 minutes; (16)
Female subjects with a positive pregnancy test, lactating mothers, women refusing to
agree to adequate contraception and pregnancy tests during the study, or women who
are planning to become pregnant during the period of the trial. Acceptable
contraceptive methods are oral or parenteral hormonal contraceptives, intrauterine
device (IUD), or barrier and spermicide, but not abstinence; (17) Male subjects
refusing to agree to adequate contraception during the study, or males who are part
of a couple planning to become pregnant during the period of the trial; (18) People
who are involuntarily detained in a penal institution (e.g. prisoners); (19) People
who become involuntarily detained in a penal institution during the study - Please
see vulnerable population statement in Section E2; (20) Any other factor that in the
opinion of the Investigator or designee would make the subject unsafe or unsuitable
for the study.