D-Serine for Cocaine Dependence Pilot

STUDY DESIGN. This is a 12 week, 2 group randomized controlled trial that will be completed
in an outpatient setting. Eligible participants will be randomized to D-serine or matching
placebo and will be scheduled to attend three research visits per week throughout the active
treatment phase which begins with randomization and ends on day 7 of study week 12. A single
visit will be scheduled in week 13 to complete retrospective data for week 12. Participants
will receive D-serine or placebo throughout the 12-week active treatment phase.
Randomization will be in a 1:1 ratio, stratified by cocaine use frequency (<10 days or ≥ 10
days in the 28 days prior to consent).

STUDY POPULATION. Approximately 80 participants recruited from a single site will be
randomized. The study population will include adults who meet Diagnostic and Statistical
Manual-IV-Text Revision (DSM-IV-TR) criteria for cocaine dependence who have used cocaine in
the 30 days prior to consent and who provide at least one benzoylecgonine (BE) positive
urine during screening/baseline.

TREATMENTS. Study participants will be randomly assigned to receive either D-serine (target
~60 mg/kg per day) or matching placebo. All participants will receive once weekly
manual-guided cognitive behavioral therapy during the 12 week treatment period. Medication
adherence will be assessed with the Medication Events Monitoring System (MEMS).

EFFICACY ASSESSMENTS. The primary outcome measure will be cocaine abstinence for three or
more consecutive weeks, with abstinence during a week defined as self-report of no cocaine
use during the week as well as negative urine BE (BE<300 ng/mL) results during the week
with at least two urine samples provided. Key secondary efficacy measures include the
proportion of urine BE negative results obtained and cocaine abstinence during study weeks
11 and 12 as measured by self-report and urine BE. Other efficacy measures include drug
attention bias, cocaine craving, drug compulsivity, cocaine withdrawal symptoms, and
treatment retention.

SAFETY ASSESSMENTS. Safety measures include urinalysis, adverse events (AEs), vitals,
electrocardiogram (ECG), and laboratory tests. Tolerability will be assessed by the
proportion of participants needing a dose reduction and being discontinued from study
medication.

ANALYSIS. Each outcome variable will be analyzed using appropriate statistical methods for
the intention-to-treat (ITT) population and the evaluable population. All participants who
have taken at least one study medication dose will be included in the safety analysis. Data
will be summarized by treatment group. Summary statistics will include the mean, sample
size, standard deviation, median, minimum and maximum values for continuous variables, and
frequencies and percentages for categorical variables.

Inclusion Criteria:

1. be 18 years of age or older

2. be able to understand the study, and having understood, provide written informed
consent in English

3. meet DSM-IV-TR diagnostic criteria for current (within the last 12 months) dependence
for cocaine,

4. have at least 1 positive urine BE specimen (> 300 ng/mL) during screening/baseline
with a minimum of 3 urine samples tested if screening/baseline is completed within 7
days or a minimum of 4 urine samples tested if screening/baseline is completed during
a period >7 days and ≤ 14 days

5. have a willingness to comply with all study procedures and medication instructions

6. be seeking treatment for cocaine dependence

7. weigh >101 and <340 pounds

8. if female and of child bearing potential, agree to use one of the following methods
of birth control:

- oral contraceptives

- contraceptive patch

- barrier (diaphragm or condom)

- intrauterine contraceptive system

- levonorgestrel implant

- medroxyprogesterone acetate contraceptive injection

- complete abstinence from sexual intercourse

- hormonal vaginal contraceptive ring

Exclusion Criteria:

1. have current dependence, defined by DSM-IV-TR criteria, on any psychoactive substance
other than cocaine, alcohol, nicotine, or marijuana or physiological dependence on
alcohol requiring medical detoxification.

2. have been enrolled in a medication assisted treatment program for opioid dependence
(e.g., methadone, buprenorphine) within 2 months of consent.

3. have a medical or psychiatric condition that, in the judgment of the study physician,
would make study participation unsafe or which would make treatment compliance
difficult. Medical conditions that may compromise participant safety or study conduct
include, but are not limited to:

- significant renal disease or estimated Glomerular Filtration Rate (GFR) ≤ 60

- AIDS according to the current Centers for Disease Control (CDC) criteria for
AIDS

- liver function tests greater than 3 times the upper limit of normal

- serum creatinine outside the normal range

4. have initiated or had a dose change in psychotropic medication in the 28 days prior
to randomization if currently taking psychotropic medication

5. have a known or suspected hypersensitivity to D-serine

6. be pregnant or breastfeeding or plan to become pregnant

7. plan to take any of the following agents during the treatment phase:

- nonsteroidal anti-inflammatory drugs (NSAIDs)

- angiotensin-converting enzyme (ACE) inhibitors

- aminoglycosides

- angiotensin receptor blockers (ARBs)

- calcineurin inhibitors

8. be anyone who, in the judgment of the investigator, would not be expected to complete
the study protocol (e.g., due to relocation from the clinic area, probable
incarceration, etc.)

9. be a significant suicidal/homicidal risk