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

NCT01018056 | Completed Phase 4 Results DMC

• 2 other identifiers: NA_00023969R34MH085844
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

Tourette syndrome; glutamatergic therapy; D-serine; riluzole; glutamate; glutamate agonist; glutamate antagonist; Tourette syndrome treatment study; OCD; tics

Outcome Measures

Primary Outcomes (1)

• The Change From Baseline to 6-week Scores for The Total Tic Subscale (TTS)

  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. i) Yale Global Tic Severity Scale (YGTSS): The YGTSS is a semi-structured clinical interview designed to measure current tic severity. It is comprised of two parts, a tic score (0-50) and a total impairment score (0-50). The Total Tic Score (TTS: 0-50) has been selected as the primary outcome measure. The scale ranges from 0 (the best possible outcome) to 50 (the worst possible outcome). This scale is considered the best currently available scale to rate the severity of tics. The data provided below represents the mean change (baseline minus six week) for the D-serine group (n = 9), Riluzole (n = 10), and Placebo group (n = 5). For consistency, all values weather positive or negative represent baseline minus week 6.

  Baseline and 6-weeks

Secondary Outcomes (13)

• The Change From Baseline to 6-week Scores for the Yale Global Tic Severity Scale (YGTSS) Total Score.

  Baseline and 6-weeks

• The Change From Baseline to 6-week Score for the Clinical Global Impression -Improvement (CGI-I).

  Baseline and 6-weeks

• The Change From Baseline to 6-week Score for the Patient Global Impression of Improvement (PGI-I).

  Baseline and 6 weeks

• Changes in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) From Baseline to 6-weeks.

  Baseline and 6-weeks

• The Change From Baseline to 6-week in Plasma Amino Acid Levels

  Baseline and 6 weeks.

Study Arms (3)

D-serine (glutamate agonist)

EXPERIMENTAL

24 subjects age 8-17 years with moderate to severe TS (TTS \> 22) will be enrolled in this treatment arm. They will receive D-serine for 6-weeks of the study, during which time drug dose may gradually be increased as needed. At 6-weeks participants will taper off drug.

Drug: D-serine

Riluzole (glutamate antagonist)

EXPERIMENTAL

24 subjects age 8-17 years with moderate to severe TS (TTS \> 22) will be enrolled in this treatment arm. They will receive riluzole for 6-weeks of the study, during which time drug dose may gradually be increased as needed. At 6-weeks participants will taper off drug.

Drug: Riluzole

Placebo

PLACEBO COMPARATOR

12 subjects age 8-17 years with moderate to severe TS (TTS \> 22) will be enrolled in this treatment arm. They will receive placebo for 6-weeks of the study, during which time drug dose may gradually be increased as needed. At 6-weeks participants will taper off drug.

Drug: Placebo

Interventions

D-serine DRUG

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.

D-serine (glutamate agonist)

Riluzole DRUG

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.

Also known as: Rilutek

Riluzole (glutamate antagonist)

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 8 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

MeSH Terms

Conditions

Tourette Syndrome; Tics

Interventions

Riluzole

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tic Disorders; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neurodevelopmental Disorders; Mental Disorders; Dyskinesias; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Benzothiazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

Study was limited by its small sample size as well as a small placebo group.

Results Point of Contact

• Title: Dr. Harvey S. Singer
• Organization: Johns Hopkins University

hsinger@jhmi.edu

410-955-7212

Study Officials

• Harvey S Singer, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2009
• First Posted: November 23, 2009
• Study Start: November 1, 2009
• Primary Completion: September 1, 2013
• Study Completion: September 1, 2013
• Last Updated: January 30, 2018
• Results First Posted: July 1, 2014

Record last verified: 2018-01

Locations

US (1)