Asperger Disorder, Autism, Autism Spectrum Disorder, Developmental Disorder, Obsessive-Compulsive Disorder
Conditions
Keywords
Clinical Trial, Glutamate Antagonist, Pediatrics, Basal Ganglia, Neuropsychological, Obsessive Compulsive Disorder, OCD, Riluzole, Rilutek
Brief summary
This study will examine the effectiveness of riluzole for treating Obsessive-Compulsive Disorder in Youth, Including those with Autism Spectrum Disorders.
Detailed description
Obsessive-Compulsive Disorder (OCD) is a chronic psychiatric disorder characterized by the presence of intrusive and unwanted obsessional thoughts and images and of compulsive behaviors. Its presentation during childhood is similar to that seen in adulthood, except that children sometimes lack insight into the senselessness of the thoughts and behaviors. Although many patients benefit from treatment with selective serotonin reuptake inhibitors (SSRIs), a significant proportion have limited or no response to these medications. Cognitive behavioral therapy (CBT) may also be effective for OCD, alone or in combination with SSRIs, but there is a shortage of qualified therapists, and many patients and families cannot participate effectively in the therapy. There is a pressing need, then, for the development of alternative, novel treatments for pediatric OCD. Neuropsychological and neuroimaging data suggest that OCD may arise from dysfunction of orbitofronto-striato-thalamocortical circuitry. Glutamate plays a crucial role in the regulation of excitatory activity within this circuit and may be involved in the etiopathogenesis of OCD. If so, then agents which reduce glutamatergic neurotransmission may provide unique antiobsessional benefits. Riluzole is a medication that reduces glutamatergic activity. A small open-label trial suggested that it might reduce OCD severity among children and adolescents. The investigation will enroll up to 80 pediatric subjects with OCD including some who have both autistic spectrum disorder (ASD) and OCD. The subjects will participate in a double-blind, placebo-controlled 12-week trial of riluzole as a sole agent or as an augmentation to their currently inadequate therapy. Following the double-blind portion of the trial, subjects may receive three months of open-label treatment with riluzole, if it is clinically indicated. All subjects will be followed at regular intervals until one year from baseline.
Interventions
DRUGRiluzole
Active drug put into 10-mg capsules by NIH Clinical Center Pharmacy. Matched placebo capsules were also prepared by NIH Clinical Center Pharmacy. Dose up to 120 mg daily, divided into bid dosages.
DRUGPlacebo
Capsules matched active drug in appearance.
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Subjects may be included in the study only if they meet all of the following criteria: 1. Male or female subjects, 7 to 17 years of age. 2. Male and female subjects of childbearing potential must be using a medically accepted means of contraception or must remain abstinent. 3. Each legal guardian must have a level of understanding sufficient to agree to all required tests and examinations. Each legal guardian must understand the nature of the study. Each legal guardian must consent to study protocol. 4. Subjects must fulfill DSM-IV criteria for (OCD) and have a CY-BOCS score of greater than 20. In the double-blind phase, subjects enrolled in the combined OCD and ASD cohort must also meet DSM-IV criteria for Pervasive Developmental Disorder as well as OCD. 5. Each subject already taking medicine must be taking usually effective doses of a medicine demonstrated to be effective in childhood OCD, must have been stable on that dose for at least six weeks, and must have no newly recognized or intolerable adverse effects from that medicine. Subjects who are currently not taking such a medication must have had adequate trial in the past of at least one medicine that has been shown to be effective for the symptoms of childhood OCD, and must have failed to see improvement or must have had intolerable adverse effects from the medicine. 6. Subjects must be able to swallow capsules.
Exclusion criteria
Subjects will be excluded from the study for any of the following reasons: 1. Presence of psychotic symptoms or lifetime history of schizophrenia, bipolar disorder, other psychotic disorder, or other serious unstable psychiatric illness. Medically unstable due to binging, purging, or starvation. 2. Judged clinically to be at risk for suicide (suicidal ideation, severe depression, or other factors). Diagnosis of DSM-IV Major Depressive Disorder is not necessarily an exclusion criterion. 3. Disabling Tic Disorder requiring contraindicated medicines. 4. Male or female subjects who are unwilling to use effective contraception, or female subjects who are pregnant or nursing. 5. Serious unstable illnesses, including gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease. 6. Renal or hepatic dysfunction that would interfere with excretion or metabolism of riluzole as evidenced by increase above upper limits of normal for BUN/creatinine, or more than two-fold elevation above upper limits of normal of serum transaminases (ALT/SGPT, AST/SGOT), gamma glutamate (GGT), or bilirubin. 7. Documented history of hypersensitivity or intolerance to riluzole. 8. DSM-IV Substance Abuse Disorder within the past 90 days or Substance Dependence Disorder within the past 5 years, or any use of tobacco. 9. Taking contraindicated drugs. 10. Unable to swallow capsules. 11. In addition, patients will not receive cognitive-behavior therapy during the period of the study. 12. Abnormal EEG unless evaluated by a neurologist and approved by that specialist for this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Much/Very Much Improved on Clinical Global Impressions - Improvement Score (CGI-I) | 12 weeks | — |
| Children's Yale-Brown Obsessive-Compulsive Scale Scores (CY-BOCS) | 12 weeks | CY-BOCS is a 0-40 point scale of obsessive-compulsive symptom severity, higher number indicates more severe obsessive-compulsive symptoms. Comparison of 12 weeks scores for placebo and riluzole groups. |
Countries
United States
Participant flow
Pre-assignment details
Subjects had to be symptomatic for at least 6 weeks, with a score of at least 20 CY-BOCS; had to have had at least one standard-of-care treatment for childhood OCD for adequate periods of time; had to have been stable for at least 6 weeks on any medicine; had to meet entrance criteria at a screening and 2 weeks later.
Participants by arm
| Arm | Count |
|---|---|
| Riluzole In a 12-weeks long double-blind phase, the clinicians and subjects and their guardians were blind to active drug or placebo. There were approx. twice monthly in-person or telephone contacts.
Riluzole was titrated upward to at least 100 mg of active drug. If adverse effects are noted, dose titration was slowed, stopped, or reversed, or the drug was discontinued. Maximum permitted dose of riluzole was 120 mg/day. At the end of the 12 weeks study period, subjects and their families could elect to take open-label riluzole.Since neither subjects nor investigators knew whether subjects had been receiving active drug,the open-label administration was also titrated. Laboratory assays were obtained at 2, 4, 8, and 12 weeks after starting the open-label riluzole, as they had been during double-blind. Subsequently, testing was less frequent. | 30 |
| Placebo Placebo capsules were prepared by NIH Clinical Center Pharmacy to appear identical to active drug capsules. Dose was titrated upward as if active drug. Follow-up and laboratory studies were identical for active drug and placebo arms. At the end of the double-blind phase, subjects could elect to take open-label drug, which was titrated upward to the maximum dose, 100 mg daily.
Study blind was not broken for subjects or investigators until the final subject had completed the double-blind phase of the study. | 30 |
| Total | 60 |
Baseline characteristics
| Characteristic | Placebo | Riluzole | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 30 Participants | 30 Participants | 60 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 14.17 years STANDARD_DEVIATION 2.58 | 14.78 years STANDARD_DEVIATION 2.1 | 14.47 years STANDARD_DEVIATION 2.35 |
| Region of Enrollment United States | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 16 Participants |
| Sex: Female, Male Male | 22 Participants | 22 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 30 | 29 / 30 |
| serious Total, serious adverse events | 1 / 30 | 0 / 30 |
Outcome results
Primary
Children's Yale-Brown Obsessive-Compulsive Scale Scores (CY-BOCS)
CY-BOCS is a 0-40 point scale of obsessive-compulsive symptom severity, higher number indicates more severe obsessive-compulsive symptoms. Comparison of 12 weeks scores for placebo and riluzole groups.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riluzole | Children's Yale-Brown Obsessive-Compulsive Scale Scores (CY-BOCS) | 21.72 units on a scale | Standard Deviation 6.43 |
| Placebo | Children's Yale-Brown Obsessive-Compulsive Scale Scores (CY-BOCS) | 23.30 units on a scale | Standard Deviation 4.64 |
Primary
Much/Very Much Improved on Clinical Global Impressions - Improvement Score (CGI-I)
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Riluzole | Much/Very Much Improved on Clinical Global Impressions - Improvement Score (CGI-I) | 3 participants |
| Placebo | Much/Very Much Improved on Clinical Global Impressions - Improvement Score (CGI-I) | 4 participants |
p-value: 0.959Chi-squared