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

• Status: Completed
• Trial end date: 2013-09-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Johns Hopkins University
• Collaborator: National Institute of Mental Health (NIMH)
• Treatments: Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Riluzole

Criteria

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