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

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.

Conditions

• Tourette Syndrome

Interventions

DRUG

D-serine

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.

DRUG

Riluzole

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.

DRUG

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 capsules.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH)

  collaborator NIH

• Johns Hopkins University

  lead OTHER

Principal Investigators

• Harvey S Singer, MD · Johns Hopkins University

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

8 Years

Max Age

17 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2009-11-30

Primary Completion

2013-09-30

Completion

2013-09-30

Countries

• United States

Study Locations