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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Harvey S. Singer, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01018056
First received: November 20, 2009
Last updated: May 29, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Tourette Syndrome
Drug: D-serine
Drug: Riluzole
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • The Change From Baseline to 6-week Scores for The Total Tic Subscale (TTS) [ Time Frame: Baseline and 6-weeks ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • The Change From Baseline to 6-week Scores for the Yale Global Tic Severity Scale (YGTSS) Total Score. [ Time Frame: Baseline and 6-weeks ] [ Designated as safety issue: No ]

    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), total maximum score is 100. This scale has established validity, as assessed by Dr. Walkup and colleagues and is considered the best currently available scale to rate the severity of tics. This scale ranges from 0 (the best possible outcome) to 100 (the worst possible outcome).

    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. Please note that summary data (mean and standard deviation per group) were intended to be reported, and not participant level data (i.e. each individual data point of every subject per group).


  • The Change From Baseline to 6-week Score for the Clinical Global Impression -Improvement (CGI-I). [ Time Frame: Baseline and 6-weeks ] [ Designated as safety issue: No ]

    Clinical Global Impression-Improvement (CGI-I): The CGI-I is used to compare current severity to baseline. A score of 1 corresponds to "very much improved"; 2 equals "much improved;" 3 denotes "minimal change"; and 4 represents "no change." Scores above 4 are used to indicate deterioration, i.e., 5 equals "minimally worse;" 6 is "much worse;" and 7 is "very much worse."

    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. Please note that summary data (mean and standard deviation per group) were intended to be reported, and not participant level data (i.e. each individual data point of every subject per group).


  • The Change From Baseline to 6-week Score for the Patient Global Impression of Improvement (PGI-I). [ Time Frame: Baseline and 6 weeks ] [ Designated as safety issue: No ]

    Patient Global Impression of Improvement (PGI-I) is a single seven point scale in which the patient/parent is asked to assess the change in overall condition ranging from "very much" improved to "very much worse."

    A score of 1 corresponds to "very much better"; 2 equals "much better;" 3 denotes "a little better"; and 4 represents "no change." Scores above 4 are used to indicate deterioration, i.e., 5 equals "a little worse;" 6 is "much worse;" and 7 is "very much worse."

    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. Please note that only summary data (mean and standard deviation per group) were intended to be reported, and not participant level data (i.e. each individual data point of every subject per group)--this applies to all outcome measures reported in the results.


  • Changes in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) From Baseline to 6-weeks. [ Time Frame: Baseline and 6-weeks ] [ Designated as safety issue: No ]

    Secondary outcome for obsessive-compulsive behaviors will be measured by changes in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) from baseline to 6-weeks.

    The severity of OCD was evaluated using either the Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS) or Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The (C)Y-BOCS is the most widely used instrument to assess the severity of obsessive-compulsive symptoms in research studies involving children. The (C)Y-BOCS has well established psychometric properties. The scale ranges from 0 (the best possible outcome) to 10 (the worst possible outcome).

    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.


  • The Use of an Expanded Pittsburgh Side Effect Scale Modified to Include Side Effects of Riluzole and D-serine. [ Time Frame: Baseline, and at 2, 4, 6, and 8 weeks. ] [ Designated as safety issue: Yes ]
  • Measurement of Vital Signs (BP, Pulse). [ Time Frame: Screen visit, Baseline, and at 2, 4, 6, and 8 weeks ] [ Designated as safety issue: Yes ]
  • Body Weight and Physical Examination. [ Time Frame: Screen, at Baseline, and at 2, 4, 6, and 8 weeks ] [ Designated as safety issue: Yes ]
  • Comprehensive Metabolic Panel (CMP). [ Time Frame: Screen and at 2, 4, and 6 weeks ] [ Designated as safety issue: Yes ]
  • Complete Blood Count (CBC) [ Time Frame: Screen and at 2, 4, and 6 weeks ] [ Designated as safety issue: Yes ]
  • The Change From Baseline to 6-week in Plasma Amino Acid Levels [ Time Frame: Baseline and 6 weeks. ] [ Designated as safety issue: Yes ]
    Blood testing was performed at baseline and at each clinic visit. Data shown below reflects baseline Glutamic Acid minus Week 6 Glutamic Acid, and baseline Serine minus Week 6 Serine levels; as acquired from the blood tests during these respective clinic visits.

  • Urine Analysis [ Time Frame: Baseline, and at 2, 4, and 6 weeks ] [ Designated as safety issue: Yes ]
  • The Change From Baseline to 6-week in Scores of the DuPaul Attention Deficit Hyperactivity Disorder Rating Scale. [ Time Frame: Baseline and 6 weeks ] [ Designated as safety issue: Yes ]

    DuPaul ADHD Rating Scale: The presence of ADHD symptoms will be assessed using the DSM-IV version of the ADHD rating scale developed by DuPaul. This scale has been normed in large clinical and community samples and has excellent psychometric properties including a test-retest reliability over a 2-week period of 0.93 and significant correlations with direct observations of classroom behavior. The scale has a maximum possible score of 72, and a minimum of 0. The scale ranges from 0 (the best possible outcome) to 70 (the worst possible outcome).

    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.


  • The Change From Baseline to 6-week in Scores of the Child Depression Inventory - Short Version (CDI-S) Scale [ Time Frame: Baseline and 6-weeks ] [ Designated as safety issue: Yes ]

    Depression Inventory-Short Version (DI-S): Depression severity will be rated by using the Depression Inventory-Short Version (DI-S). This 10 item scale takes about 5 minutes to complete. It has excellent psychometric properties and is designed for repeated administrations over time. The maximum possible score of 20, and a minimum score of 0. Higher score on this scale indicates greater severity of depression in children.

    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 = 3). For consistency, all values weather positive or negative represent baseline minus week 6.


  • The Change From Baseline to 6-week in Scores of the Multi-Dimensional Anxiety Scale for Children (MASC) [ Time Frame: Baseline and 6-weeks ] [ Designated as safety issue: Yes ]

    Multidimensional Anxiety Scale (MAS): Anxiety will be followed using the Multidimensional Anxiety Scale for Children (MASC), which has been developed by Dr. John March at Duke University and is now considered the preferred instrument for rating anxiety. The MASC asks the patient how they have been thinking and acting recently. It has a maximum possible score of 117 and a minimum score of 0. Higher score on this scale indicates greater severity of anxiety in children.

    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.



Enrollment: 39
Study Start Date: November 2009
Study Completion Date: September 2013
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: D-serine (glutamate agonist)
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
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.
Experimental: Riluzole (glutamate antagonist)
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
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.
Other Name: Rilutek
Placebo Comparator: Placebo
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
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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   8 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01018056

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Johns Hopkins University
Investigators
Principal Investigator: Harvey S Singer, MD Johns Hopkins University
  More Information

No publications provided

Responsible Party: Harvey S. Singer, Haller Professor of Pediatric Neurology, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01018056     History of Changes
Other Study ID Numbers: 1R34MH085844-01A109, R34MH085844
Study First Received: November 20, 2009
Results First Received: March 24, 2014
Last Updated: May 29, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Johns Hopkins University:
Tourette syndrome
glutamatergic therapy
D-serine
riluzole
glutamate
glutamate agonist
glutamate antagonist
Tourette syndrome treatment study
OCD
tics

Additional relevant MeSH terms:
Tourette Syndrome
Syndrome
Disease
Pathologic Processes
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
Mental Disorders Diagnosed in Childhood
Mental Disorders
Riluzole
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agonists
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Neuroprotective Agents
Protective Agents

ClinicalTrials.gov processed this record on September 18, 2014