Double-Blind Placebo-Controlled Trial of Riluzole in Pediatric Bipolar Disorder
Study Details
Study Description
Brief Summary
Pediatric Bipolar Disorder (BD) is uncommon in children. Its symptoms include periods of manic behavior (being overly happy or giddy, feeling grandiose, feeling a decreased need for sleep, having too much energy, moving more than usual, talking fast, having speeded-up thoughts and other symptoms). Sometimes there also is depression (extreme feelings of sadness or irritability, not taking pleasure in things, even ones that used to be enjoyable, feeling worthless or guilty, sleeping too much or having trouble getting to or staying asleep, feeling slowed down or restless, having wishes to be dead or suicidal ideas, and other symptoms). Pediatric BD is often difficult to treat; children may respond only partially to the medications now available or have too many side effects to tolerate them.
Riluzole is a medication that is thought to work on a brain chemical called glutamate that may be involved in symptoms of depression and BD. Previous research studies have shown that riluzole may help adults with BD who have depression and adults who have depression, anxiety disorders, or obsessive-compulsive disorders. Riluzole may also be helpful for children with obsessive-compulsive disorder. However, it has never been given to children with BD.
This study will evaluate the effectiveness of riluzole in 80 patients between 9 and 17 years of age who have BD and symptoms of anxiety. Participants must have tried at least two other medications that have not been effective.
The study will consist of four phases carried out over 4 to 5 months. Most children will be inpatients at the Pediatric Behavioral Health Unit for at least part of the study.
In Phase 1, each patient will undergo blood and urine tests, and will gradually taper off his or her medication. The duration of this phase depends on the medication that the patient was receiving before starting the study.
In Phase 2, the patient will remain off all medication for 1 week. Throughout this time, patients will be monitored carefully and medication will be restarted if needed.
In Phase 3, which lasts 8 weeks, patients will be assigned randomly to receive only riluzole or only a placebo. Those who receive riluzole will have the dose adjusted as needed. Patients and families will be informed of which drug they were on at the end of this phase. Patients who improved on riluzole may continue to receive it from NIH for 1 month and will then be prepared for discharge from the study. Patients who received placebo and improved, and those who received riluzole but did not improve, will be treated with standard medications as appropriate and prepared for discharge from the study.
Phase 4 is for patients who received placebo and did not improve. They will be given the chance to try riluzole for 8 weeks and, if it is effective, continue it for an additional 4 weeks while they prepare to be discharged from the study.
Patients will not be able to receive riluzole at the National Institutes of Health after the completion of the study. However, the child's doctor may be able to prescribe riluzole as an off-label use.
Most patients will be admitted to the Pediatric Behavioral Health Unit at the National Institutes of Health Clinical Center during the medication withdrawal part of the study (Phases 1 and 2). From Phase 3 on, a patient may participate as an inpatient, outpatient, or in day treatment, depending on what is in his or her best interests.
All participants in this study will be invited to also enroll in the National Institute of Mental Health protocol 00-M-0198, The Phenomenology and Neurophysiology of Affective Dysregulation In Children And Adolescents With Bipolar Disorder. Some research tests for that protocol will be done during the medication-free period of this protocol.
...
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
OBJECTIVE: To test the efficacy of riluzole in youth with bipolar disorder
STUDY POPULATION: Youth, ages 9-17, with DSM-IV bipolar disorder, who have failed to respond to two adequate trials of medication, one with an atypical antipsychotic medication, and the second with either a mood stabilizing medication or a second atypical antipsychotic medication.
DESIGN: Medication withdrawal, followed by a 15-day dose stabilization phase and a 6-week double-blind, placebo-controlled treatment trial. The first two phases will be completed as inpatients or in day treatment, while the third phase can be completed either in those settings or as an outpatient. Individuals who received placebo will be offered an 8-week open trial of riluzole followed by an additional 4 weeks if they respond, while those who received riluzole in the placebo-controlled trial and wish to continue it will receive 4 weeks of open treatment. Thus, all patients will have the opportunity to receive a total of 12 weeks of riluzole treatment.
OUTCOME MEASURES: Clinical rating scales, including the Pediatric Anxiety Rating Scale and the Clinical Global Improvement Scale
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| No Intervention: Medication Taper All participants begin with gradual tapering to the point of discontinuing medication |
|
| No Intervention: Random assignment to placebo Once they are medication-free, 50% of participants are randomized to placebo |
|
| Active Comparator: Random assignment to riluzole One they are medication-free, 50% of participants are randomized to riluzole |
Drug: Riluzole
|
Outcome Measures
Primary Outcome Measures
- Clinical Global Impression--Improvement [8 week trial with the study running for about 4 years.]
This is a clinician rated measure that is a standard in pharmacological trials. the scores range from 1 to 8 with 5 being unchanged, 1 being completely recovered and 8 being markedly worse.
- Pediatric Anxiety Scale [Weekly for 8 weeks]
A standard measure of severity of anxiety over the previous week. The score ranges from a total of 0-25, with 0 being absence of symptoms and impairment, and 25 being marked symptoms and severe impairment. The outcome measure for each participant is the change in PARS, that is, the difference at week 8 compared to baseline (when medication-free).
Eligibility Criteria
Criteria
-
INCLUSION CRITERIA:
-
Boys and girls
-
Ages 9-17 years of age
-
Meet DSM-IV criteria for bipolar disorder.
-
The child must have a primary caregiver who can accompany him or her on trips to NIMH, provide reliable history and information, and complete rating scales.
-
Patients must have a psychiatrist who provides clinical care for their BPD.
-
All youth accepted into the study must be able to complete self-rating forms and to cooperate with other study procedures.
-
Previous treatment failure as defined by:
-
Failure to respond to an adequate trial (adequate dose for at least two weeks) of a mood stabilizer (either lithium or divalproex) plus an adequate trial (sufficient dose for an adequate duration) of an atypical antipsychotic (such as risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole)
-
Failure to respond to an adequate trial (sufficient dose for an adequate duration) of two atypical antipsychotics (such as risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole) or
-
Evidence of intolerance (severe weight gain or other side effects) of a mood stabilizer or atypical antipsychotic agent.
- The child is failing his/her current treatment as defined by (all 3 met):
-
The child's current CGAS score must be less than 60.
-
The child's current psychiatrist must agree that the child's response to his/her current treatment is no more than minimal or there are drug side effects that are proving problematic. According to this criterion, it would be clinically appropriate to change the child's current treatment.
-
On the basis of record review and interviews with child and parent, the research team agrees that the child's response to his/her current treatment is no more than minimal.
- Subject has a PARS score of greater than or equal to 10, derived from the total of the following individual items: 3 (overall severity of anxious feelings), 5 (overall avoidance), 6 (interference with family), and 7 (interference outside of the home). In addition, patients must score 3 or higher (i.e., in the clinical range) on at least one of the four items noted above.
EXCLUSION CRITERIA:
-
I.Q. less than 70
-
Autistic disorder or severe pervasive developmental disorder; psychosis that interferes with the child's capacity to understand and comply with study procedures;
-
Unstable medical illness (e.g. severe asthma) or contraindication to riluzole
-
Medical illness that could cause the symptoms of bipolar illness (e.g. multiple sclerosis, thyroid disease);
-
Pregnancy
-
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 two-fold elevation of serum transaminases (ALT/SGPT, AST/SGOT), gamma glutamate (GGT), or bilirubin.
-
Documented history of hypersensitivity or intolerance to riluzole.
-
Substance abuse within two months of study entry
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Institute of Mental Health (NIMH)
Investigators
- Principal Investigator: Ellen Leibenluft, MD, NIH, NIMH-IRP
Study Documents (Full-Text)
None provided.More Information
Publications
- Amiel JM, Mathew SJ. Glutamate and anxiety disorders. Curr Psychiatry Rep. 2007 Aug;9(4):278-83. Review.
- Axelson D, Birmaher B, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Iyengar S, Bridge J, Keller M. Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry. 2006 Oct;63(10):1139-48.
- Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994 Mar 3;330(9):585-91.
- 090042
- 09-M-0042
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Riluzole | Placebo | Not Randomized |
|---|---|---|---|
| Arm/Group Description | Those randomized to riluzole | Those randomized to receive placebo | Those who withdrew prior to the decision to randomize |
| Period Title: Overall Study | |||
| STARTED | 3 | 2 | 1 |
| COMPLETED | 1 | 2 | 0 |
| NOT COMPLETED | 2 | 0 | 1 |
Baseline Characteristics
| Arm/Group Title | Riluzole | Placebo | Not Randomized | Total |
|---|---|---|---|---|
| Arm/Group Description | Total of all reporting groups | |||
| Overall Participants | 3 | 2 | 1 | 6 |
| Age (Count of Participants) | ||||
| LTE18 |
3
100%
|
2
100%
|
1
100%
|
6
100%
|
| BTWN |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| GTE65 |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
2
66.7%
|
0
0%
|
0
0%
|
2
33.3%
|
| Male |
1
33.3%
|
2
100%
|
1
100%
|
4
66.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
3
100%
|
2
100%
|
1
100%
|
6
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Hawaiian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
2
66.7%
|
2
100%
|
1
100%
|
5
83.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
1
33.3%
|
0
0%
|
0
0%
|
1
16.7%
|
Outcome Measures
| Title | Clinical Global Impression--Improvement |
|---|---|
| Description | This is a clinician rated measure that is a standard in pharmacological trials. the scores range from 1 to 8 with 5 being unchanged, 1 being completely recovered and 8 being markedly worse. |
| Time Frame | 8 week trial with the study running for about 4 years. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Riluzole | Placebo | Not Randomized |
|---|---|---|---|
| Arm/Group Description | The group randomized to riluzole | Those who withdrew prior to the decision to randomize | |
| Measure Participants | 3 | 2 | 0 |
| Mean (Standard Deviation) [units on a scale] |
4
(.82)
|
4
(1)
|
| Title | Pediatric Anxiety Scale |
|---|---|
| Description | A standard measure of severity of anxiety over the previous week. The score ranges from a total of 0-25, with 0 being absence of symptoms and impairment, and 25 being marked symptoms and severe impairment. The outcome measure for each participant is the change in PARS, that is, the difference at week 8 compared to baseline (when medication-free). |
| Time Frame | Weekly for 8 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Placebo | Not Randomized | Riluzole |
|---|---|---|---|
| Arm/Group Description | The group randomized to receive placebo | Participants who withdrew prior to the decision to randomize | The group randomized to receive riluzole |
| Measure Participants | 2 | 0 | 3 |
| Mean (Standard Deviation) [units on a scale] |
1.67
(3.09)
|
-2.5
(0.5)
|
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Riluzole | Placebo | Not Randomized | |||
| Arm/Group Description | ||||||
All Cause Mortality |
||||||
| Riluzole | Placebo | Not Randomized | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Riluzole | Placebo | Not Randomized | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/2 (0%) | 0/1 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Riluzole | Placebo | Not Randomized | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/3 (33.3%) | 0/2 (0%) | 0/1 (0%) | |||
| Psychiatric disorders | ||||||
| Anxiety | 1/3 (33.3%) | 1 | 0/2 (0%) | 0 | 0/1 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Kenneth Towbin, M.D., Chief Clinical Child and Adolescent Psychiatry |
|---|---|
| Organization | Emotion and Development Branch, NIMH-IRP |
| Phone | 301-402-4403 |
| Kenneth.Towbin@nih.gov |
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