Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission

Study Design Overview: The goal of this study is to perform a short-term, proof of concept
study to examine the safety, tolerability and efficacy of riluzole and D-serine in the
treatment of tics. Each medication will be evaluated and compared to placebo as part of a
randomized, double-blind, flexible dose, parallel, eight-week protocol, containing six weeks
of active treatment (D-serine, riluzole, or placebo). A total of sixty patients (age 8-17
years) with Tourette syndrome or chronic motor tics (Tourette Syndrome Study Group criteria)
having moderate to moderately-severe tics will participate; riluzole (n=24), D-serine (n=24),
placebo (n=12).

This study contains six weeks of active treatment with D-serine, riluzole or placebo. The
decision to implement a 6-week treatment protocol was based on the following: a) the ability
to gradual increase doses of medication on a weekly basis over the first five weeks to
dosages beneficial in other conditions; b) a treatment duration similar to that used in other
glutamate modulatory treatment studies; and c) a time period necessary to identify a
treatment effect in milder non-neuroleptic tic-suppressing medications such as clonidine. We
emphasize that this is a short term, proof of concept study for riluzole and D-serine in the
treatment of tics. Specific questions such as long term durability of beneficial effects,
potential long-term side-effects, and comparisons to non-drug interventions are important,
but not a focus of this pilot study.

The study will begin with a screening evaluation to ensure that each subject satisfies all
eligibility criteria and to allow subjects to become familiar with our assessment procedures.
Randomization of medications contained in look-alike capsules will occur at the baseline
visit and is performed by a member of the Research Pharmacy staff. Patients will be evaluated
at baseline, have direct formal scheduled evaluations at the end of treatment week's 2, 4,
and 6 (+ 2 days), have telephone evaluations at the end of treatment week's 1, 3, and 5 (+ 2
days), and a final visit at 8 weeks. The primary outcome measure is effective tic suppression
as determined by the difference in the Total Tic subscale (TTS) scores of the Yale Global Tic
Severity Scale (YGTSS) at baseline and 6 weeks. Secondary outcome measures will include the
change from baseline and 6 week scores for the YGTSS total score, the Clinical Global
Impression -Improvement (CGI-I), and Patient Global Impression of Improvement (PGI-I).
Secondary outcome for obsessive-compulsive behaviors will be measured by changes in the
Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Safety measures will include the
use of an expanded Pittsburgh Side Effect Scale modified to include side effects of riluzole
and D-serine, incidence of adverse events, measurement of vital signs (BP, pulse) and body
weight, physical examination, laboratory studies (comprehensive metabolic panel (CMP),
complete blood count (CBC), plasma amino acids, and urine analysis), the DuPaul ADHD Rating
Scale, Child Depression Inventory-short version (CDI-S), and Multi-Dimensional Anxiety Scale
for Children (MASC). A Drug Safety Monitoring Board containing three clinician-scientists
with experience in pharmacological trials will meet quarterly to review this study.

1. Study Population:

a) Recruitment: Subjects with TS/CMT (ages 8-17 years) will be recruited from the Tourette
Syndrome Clinic at the Johns Hopkins Hospital and child psychiatry practice.

Patients with TS/CMT will be candidates for this study if: 1) they are tic-suppressing drug
naive; 2) are not currently on treatment for TS (off medications for at least three weeks);
or 3) if, in the judgment of the Investigators (Dr Singer and Grados), they are not
adequately managed using current therapy (prescribed for greater than one month) and are
willing to maintain a constant dose throughout the protocol. We believe that limiting the
study to include only "drug-free" subjects would have a negative impact on recruitment. Many
individuals with moderately severe to severe tics (TTS > 22) are receiving medications and in
our opinion requiring prolonged tapers and extended drug free intervals are not in the best
interest of the patient.

4. Procedures: i) Screening visit ( - 3 to -1 weeks): Determination of diagnostic eligibility
criteria: medical history, complete physical examination (weight, heart rate, blood pressure,
respiratory rate); familiarization with assessment procedures, rating scales for: tics, the
Yale Global Tic Severity Scale (YGTSS), Clinical Global Impression-Severity Scale (CGI-S),
obsessive-compulsive problems, Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS);
attention deficit hyperactivity disorder, DuPaul ADHD Rating Scale, depression, Child
Depression Inventory- Short Version (CDI-S); and anxiety, the Multidimensional Anxiety Scale
for Children (MASC). Informed consent and child assent will be obtained. Urine (urine
analysis) and blood (comprehensive metabolic panel, complete blood count, and plasma amino
acids) will be obtained. Females who have begun to menstruate will be screened with a blood
pregnancy test. Parents will be told the results of these tests. If the patient is
uncomfortable with our telling the results of the pregnancy test to her parent(s), then they
may decide not to take part in this study.

ii) Baseline Visit (Day 0): Determination of diagnostic eligibility criteria and the results
of blood and urine analysis studies will be reviewed. Evaluation will include weight, heart
rate, blood pressure, and respiratory rate, physical examination, rating scales for tics,
obsessive-compulsive problems, ADHD, depression, and anxiety. As part of the baseline visit,
the PI and Study Coordinator will meet with the parent to explain the procedures for dose
titration, review in detail the outcome measures, and review approaches to administering
medication (e.g., providing the pill with water or other beverage, observing the child
swallow the medication without biting or chewing). Following confirmation of study
eligibility, Dr Singer will forward a request for medication to the Johns Hopkins Research
Pharmacy.

iii) Randomization (Day 0): A computer generated unequal randomized scheme will be used by a
research pharmacist in the Johns Hopkins Research Pharmacy to assign patients to riluzole,
D-serine, or placebo. The pharmacist making the treatment assignment will be proved with all
essential data including patient name and study number, age, weight, and a list of concurrent
medications. Subjects already on medications will be equally distributed among treatment
groups. Twenty-four subjects each will be randomized to riluzole and D-serine and twelve to
placebo. Medications, packaged in look-alike capsules, will be distributed by The Johns
Hopkins Research Pharmacy. All medication codes will be retained by the research pharmacist
until the completion of the study. All study medication will be double-blind: the
Investigators, Study Coordinator and patient/parent will not be aware of the treatment
assignment.

iv) Treatment groups (weeks 1 through 6): All treatments will be packaged in look-alike
capsules. Patients will receive a 16 day supply of medication at the Baseline visit, and at
the 2 and 4 week visits. Medications will be administered for the first week on a qday basis
(morning) and thereafter on a twice a day schedule (morning and bedtime).

Each subject will be contacted at the end of weeks 1, 3, and 5 by telephone and evaluated in
person end the end of weeks 2, 4, 6, and 8.

The maximum number of capsules per day in each treatment group is five. In order to achieve
this fixed number, if necessary, Research Pharmacy will provide an additional vial of
capsules containing the appropriate medication (see drug descriptions).

Riluzole (Rilutek):

Selection of dosage: For reference, in adults with ALS, riluzole was safe and effective in
dosages of 100 and 200 mg twice daily. In a treatment study of infants with spinal muscular
atrophy the maximum dosage was 10 mg higher than a 107 mg/m2 dose, e.g., for a 5 kg child
whose surface area was 0.33 m2 , the dose was 35 mg/day. No child had any change in
laboratory studies or had adverse effects.

Selection and timing of doses for subjects: The starting dose of riluzole will be 50 mg for
one week; administered as one capsule (50) every morning. Dosage schedules will be flexible.
If needed for tic suppression, the dose will be increased weekly by 50 mg and given in BID
doses. The maximum dose will be 200 mg/day (administered as 2 capsules BID). In any
individual subject, dose escalation may proceed more slowly, or the dose may be reduced if
necessary. At the 4 week visit, if an additional dosage increase is prescribed by Dr Singer,
the pharmacy will provide an additional vial of 14 capsules labeled as study drug, but
containing placebo (P) capsules. No changes in dosage will be made during the final week of
treatment.

D-serine:

Selection of dosage: In man, D-serine is synthesized from L-serine via one enzymatic step
catalyzed by the enzyme serine racemase. Levels of D-serine are controlled by the activity of
serine racemase, the later having the highest expression in the forebrain. D-serine is
currently being used in IND# 71,369 (D Javitt, PI). This approved serine will purchased by
the Research Pharmacy at Johns Hopkins and encapsulated into capsules containing 250 and 500
mg of D-serine. The established treatment dose in the aforementioned IND is 30 mg/kg/day. In
adults with schizophrenia and OCD, D-serine was safe and effective in dosages of 2 grams per
day [Javitt Personal Communication].

Selection and timing of doses for subjects: The dosage schedule will be flexible with a
maximum dose for each subject being 30 mg/kg/day. The following Table provides examples of
subjects of different weights receiving increases of dosages. In any individual subject, dose
escalation may proceed more slowly, or the dose may be reduced if necessary. At the 4 week
visit, if an additional dosage increase is prescribed by Dr Singer, the pharmacy will provide
an additional vial of capsules labeled as study drug, but containing either 250 (A) or 500
(B) mg tablets of D-serine or placebo (P); capsule content to be determined by patient's
weight (see below). No changes in dosage will be made during the final week of treatment.

Placebo:

Placebo tablets will be formulated in look-alike capsules. At the 4 week visit, if an
additional dosage increase is prescribed by Dr Singer, the pharmacy will provide an
additional vial of 14 capsules labeled as study drug, but containing additional placebo (P)
capsules.

Compliance: To assess medication compliance, subjects and parents will be asked at each
evaluation point (telephone and visit) about their compliance. Subjects will be required to
return their medication vials at each visit and Dr Singer will verify whether the number of
tablets returned by the subject corresponds to the prescribed intake. Compliance is defined
as taking >80% to <120% of the prescribed doses.

vi) Concomitant medication: At each patient visit (baseline, 2, 4, and 6 weeks) the
patient/parent will be asked to provide the names of any prescribed medications, over-the
counter or herbal preparations used since the last visit.

vii) Medication taper: At the completion of the 6 week treatment phase, medication will be
tapered over a ten day period; reduction of one capsule every other day. The half life of
riluzole is 12 hours.

viii) Post-intervention (end of week 8) follow-up and management By the end of week 8, the
subject will be completely off the study medication. Since study medications cannot be
continued following completion of the protocol, this visit will, in part, be devoted to
establishing ongoing care and treatment. All subjects will be offered ongoing care,
treatment, and follow up with Dr Singer at Johns Hopkins. If the subject already has a
treating physician, Dr Singer will be available to provide consultative services. Neither the
Investigators nor subjects will receive information about the experimental drug assignment
until the entire study has been completed.

ix) Evaluations: This is an 8-week study (6 weeks treatment, 2 week taper). Telephone
evaluations will be performed by Dr Singer at the end of week's 1,3, and 5. At each telephone
contact, clinical response, possible side effects, drug compliance, and medication adjustment
will be discussed. Each subject will have direct evaluations by Dr Singer at baseline and the
end of week's 2, 4, 6.and 8. These evaluations will include a pill count (except baseline) to
assure compliance and safety measures including physical examination, vital signs (BP, heart
rate), weight, blood and urine studies, and assessment of side effects using the Pittsburgh
side effects scale. Dr Grados, a blinded outcome evaluator, will administer and score the
outcome measures at each of the subject's visits (baseline, end of weeks 2, 4, 6).

x) Early stopping rules: Subjects may be withdrawn from the study at any time at the
discretion of the subject, primary care physician, or Dr Singer.

1. Dr Singer can decide the subject should be withdrawn. This decision could be made
because of an adverse effect, abnormal laboratory values, or a failure to comply with
the study protocol.

2. The subject or his/her personal physician requests the subject be withdrawn.

3. The subject, for any reason, requires treatment with another therapeutic agent that
could conflict with the use of riluzole or D-serine or complains of unacceptable
side-effects.

4. A Drug Safety Monitoring Board (SMB). The duty of the SMB is to provide recommendations
to the PI regarding medication issues and premature termination of the study for safety
reasons. The SMB will be responsible for the quarterly review of data related to adverse
clinical experiences and to assure that safety standards are maintained throughout the
clinical trial. Three clinician-scientists, knowledgeable in the performance of clinical
trials, members of the full time faculty at the adjacent Kennedy Krieger Institute, and
not under the influence of the Johns Hopkins Director of Pediatric Neurology, will serve
on the Board: Pediatric neurologists Dr's Gerald Raymond and Sakku Naidu and Dr Bruce
Shapiro, a neurodevelopmental pediatrician.

The Research Coordinator, with assistance of the Statistician, will prepare data for the
quarterly review by the SMB from data stored on a secure computer. The SMB will act
independently to review the data. If there is any safety concern related to one or more of
these groups, then the Board may choose to identify the actual treatment groups by access to
the randomization codes maintained by the pharmacy. Significant adverse events will be
reported to the IRB, SMB and FDA within 24 hours.

Inclusion Criteria:

- Tourette syndrome (criteria based on the TS Classification Study Group), which
includes onset before 18 years, multiple involuntary motor tics, one or more vocal
tics, a waxing and waning course, the gradual replacement of old symptoms with new
ones, the presence of tics for more than one year, the absence of other medical
explanations (effects of a substance (e.g., stimulants) or a general medical condition
for tics, and observation of tics by a reliable examiner) or Chronic Motor Tic
disorder (criteria similar to Tourette syndrome except for the absence of vocal tics)

- Age 8-17 years, either gender

- Observable tics, achieving a minimum score of > 22 on the Total Tic score of Yale
Global Tic Severity Scale (YGTSS)

- Tic symptoms severe enough to warrant therapy (e.g., causing psycho-social or physical
difficulty)

- Written informed consent provided by the patient's parent (or legal guardian) and
assent provided by the patient consistent with Institutional Review Board requirements

- Ability and willingness to comply with study protocol requirements

- Women of childbearing potential must be using a medically acceptable contraceptive
method. Acceptable methods of birth control are limited to: Intra-Uterine Device
(IUD), oral, implantable, injectable contraceptives and estrogen patch, double barrier
method (spermicide+diaphragm), or abstinence

- Baseline weight of at least 33 kilograms

- Tic-suppressing drug naive, or currently not on treatment for TS (off medications for
at least three weeks), or if, in the judgment of the PI, they are not adequately
managed using current therapy (prescribed for greater than one month) and are willing
to maintain a constant dose throughout the protocol.

Exclusion Criteria:

- Secondary tics

- Significant medical illness (metabolic, endocrine, cardiac, hematological,
gastrointestinal, pulmonary, epilepsy)

- Current major depression

- generalized anxiety disorder

- separation anxiety disorder

- psychotic symptoms (based on clinical evaluation and the results of the CY-BOCS,
CDI-S, and MASC evaluations)

- pervasive developmental disorder

- autism

- mental retardation (I.Q. less than 70)

- anorexia/bulimia, or substance abuse

- Any other conditions that in the opinion of the Investigators would interfere with the
evaluation of the results or constitute a health hazard for the patient

- Pregnancy

- Hypersensitivity to D-serine or riluzole

- Abnormal laboratory values on screening laboratory testing if clinically significant
at the Principal Investigator's discretion.

Subjects with co-morbid ADHD, obsessive compulsive disorder (OCD), and conduct disorder
will not be excluded as long as these diagnoses are not the subject's primary problem