Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
Condition: Tourette Syndrome
MeSH terms: Tourette Syndrome; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      A joint NIH -Tourette Syndrome Association Conference has emphasized the critical need for
      the testing and development of new pharmacotherapy for tic suppression in Tourette syndrome
      (TS). This submission is a safety, tolerability and efficacy pilot study using two
      medications that modulate glutamate neurotransmission, riluzole, a glutamate antagonist, and
      D-serine, a glutamate agonist. Glutamate is the primary excitatory neurotransmitter in the
      central nervous system, an essential component of pathways implicated in TS and an extensive
      modulator of dopamine, the major neurotransmitter associated with tics.

      This is a single site, short-term, proof of concept study of riluzole and D-serine for the
      treatment of tics. Each medication will be evaluated and compared to placebo as part of a
      double-blind, randomized, parallel, flexible dose, three-arm, 8-week, treatment protocol
      (D-serine, riluzole, or placebo). A total of sixty patients (age 8-17 years) with TS and
      moderate to moderately-severe tics will receive study medication according to a 2:1 (dopamine
      modulating drug: placebo), randomized schedule, i.e., riluzole (n=24), D-serine (n=24),
      placebo (n=12). The primary outcome measure is tic suppression as determined by changes in
      the Total Tic Subscore of the Yale Global Tic Severity Scale (YGTSS). Secondary tic outcome
      measures include changes in the YGTSS Total Score and two Global Impression Scales. Further,
      since both riluzole and D-serine have been proposed as treatments for obsessive-compulsive
      behaviors, a TS co-morbidity, these symptoms will be followed. Safety measures include serial
      physical examinations, vital signs, laboratory studies (comprehensive metabolic panel,
      complete blood count, plasma amino acids, and urine analyses), documentation of side effects
      and adverse events, and measurement of changes in ADHD, depression and anxiety.

      This pilot investigation will provide important proof-of-concept data on glutamate therapies
      for TS and, in turn, evidence for large-scale, multi-center clinical trials.
    

Detailed description: 
      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.
    

Intervention name(s): D-serine; Riluzole; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): The dosage schedule will be flexible with a maximum dose for each subject being 30 mg/kg/day. 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 or 500 mg tablets of D-serine or placebo; capsule content to be determined by patient's weight. No changes in dosage will be made during the final week of treatment.; 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 capsules. No changes in dosage will be made during the final week of treatment.; 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 capsules.
Other intervention name(s): Rilutek
Intervention MeSH terms: Riluzole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Tourette syndrome; glutamatergic therapy; D-serine; riluzole; glutamate; glutamate agonist; glutamate antagonist; Tourette syndrome treatment study; OCD; tics