Placebo Controlled Trial of Valproate and Risperidone in Young Children With Bipolar Disorders

This study has been completed.
Sponsor:
Collaborator:
Stanley Medical Research Institute
Information provided by:
Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier:
NCT00221403
First received: September 14, 2005
Last updated: June 24, 2011
Last verified: June 2011
  Purpose

The primary aim of this proposal is to conduct a preliminary controlled trial of valproate and risperidone in children ages 3-7 yr. with bipolar disorders. A secondary aim is to carefully characterize these subjects using clinical rating scales and develop pilot data on a very young cohort of children with bipolar disorders that can be used to support an application to NIMH for a prospective, longitudinal study that will provide important information about the course, medication response, neurobiology and outcome of these patients.


Condition Intervention Phase
Bipolar Disorder
Drug: Risperidone Valproate
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Placebo Controlled Trial of Valproate and Risperidone in Young Children With Bipolar Disorders

Resource links provided by NLM:


Further study details as provided by Children's Hospital Medical Center, Cincinnati:

Primary Outcome Measures:
  • YMRS & CGI-I [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
  • YMRS [ Time Frame: 6 Weesk ] [ Designated as safety issue: No ]

Enrollment: 46
Study Start Date: September 2004
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Risperidone Valproate
    liquid, BID dosing.
  Hide Detailed Description

Detailed Description:

It is now recognized that pediatric bipolar disorders are highly prevalent and that they seriously disrupt the lives of children and adolescents, with studies showing poorer academic performance, disturbed interpersonal relationships, increased rates of substance abuse, legal difficulties, multiple hospitalizations, and increased rates of both suicide attempts and completions (Akiskal, Downs et al. 1985; Lewinsohn, Klein et al. 1995; Strober, Schmidt-Lackner et al. 1995). We are seeing an increasing number of very young children, ages 3-7 years, with either frank symptoms of BP I disorder. Over 50% of these young patients have a first-degree relative with a bipolar disorder and all of these patient's families are significantly impacted by their BP symptoms. Many of these young BP patients have been treated with stimulants or antidepressants and few have been treated with mood stabilizing agents. Therefore, it is necessary to provide controlled studies of psychotropics in this younger bipolar population to provide clinical practice with an appropriate evidence-base.

Several major questions exist about these very young bipolar patients:

  • What is the response of these very young bipolar patients to mood stabilizers and or atypical antipsychotics?
  • Will non-responders to mono-therapy with either valproate or risperidone respond to treatment with both agents?
  • How can we best characterize these patients clinically?
  • What is the long-term outcome of these patients?
  • Will earlier treatment lead to better outcomes?

The clinical use of mood stabilizers and atypical antipsychotic agents in children and adolescents with bipolar disorders has increased significantly over the past few years, despite the fact that only limited research has suggested that these agents are effective in this population. Common clinical practice is to have patients continue on medications for some time following remission, although the length of continuation treatment varies and available guidelines are based on consensus, not controlled trials. The increased number of medications prescribed has led to concern about over prescribing of psychotropics in children and adolescents (Zito, Safer et al. 2000; Zito, Safer et al. 2003). Therefore, it is necessary to provide additional controlled studies of mood stabilizing agents in this younger bipolar population to guide clinical practice.

There is an overwhelming need for controlled trials of the various mood stabilizers and atypical antipsychotics that are now available and being used in the community with these young bipolar patients. Currently, we have the most experience with valproate and risperidone in bipolar children, ages 8 - 17 yr. and based on clinical experience, believe that these two agents are the safest and most likely to be efficacious in children ages 3-7 years. These agents are widely used in the community and controlled data are desperately needed regarding the effectiveness of these agents in bipolar children, ages 3-7 years. There are no specific behavioral treatments or psychotherapies that have been shown to be efficacious for these patients.

Power Analysis (Provided by Dr. Judy Bean)

Since this is a preliminary study prior to a larger controlled trial, the percent of responders receiving one of the drugs will be compared to the percent of responders in the placebo arm. The children will be randomized to achieve 24 total children in each drug arm and 12 in the placebo arm. This 2:2:1 randomization scheme was selected because the expectation is that the percent of responders, in each of the drug arms, will be greater than the percent in the placebo arm. The expectation is that 60% of the children receiving risperidone will respond (Frazier, Meyer et al. 1999), as compared to only 8% in the placebo group (Geller, Cooper et al. 1998). Power was calculated for a one-sided test since if placebo does better no application will be made to NIH. Using nQuery®, version 5.0, a chi-square test, with a 0.05 significance level, will have 96% power to detect the difference. For valproate, the percent of responders is expected to be 55%(Kowatch, Suppes et al. 2000), as compared to the 8% in the placebo arm. Again, using a chi-square test with a .05 significance level, the power will be 86 with 24 in the valproate arm and 12 in the placebo arm. This pilot study does not power to determine if the two drug arms are equivalent.

  Eligibility

Ages Eligible for Study:   3 Years to 7 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female patients, 3-7 years 11 months of age.
  2. Each patient's authorized legal guardian must understand the nature of the study and must provide written informed consent. Each patient must also give assent to study participation.
  3. Patients must have a diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) bipolar disorder and must currently display an acute manic, hypomanic or mixed episode as determined by DSM-IV criteria. This includes the following diagnoses: 296.4x, Bipolar I Disorder, Most Recent Episode Manic; 296.6x, Bipolar I Disorder, Most recent Episode Mixed; and 296.0x, Bipolar I Disorder, Single Manic Episode, Bipolar II Disorder, Most Recent Episode Hypomanic.
  4. Patients must have an initial score (at day 0) on the YMRS total score of at least 20.
  5. Subjects and their caretakers should be fluent in English.

Exclusion Criteria:

  1. Clinically significant or unstable hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, hematologic or other systemic medical conditions.
  2. Neurologic disorders including epilepsy, stroke, or severe head trauma.
  3. Clinically significant laboratory abnormalities, on any of the following tests: CBC with differential, electrolytes, BUN, creatinine, hepatic transaminases, urinalysis, thyroid indices (T3, Total T4, Free T4, TSH), and EKG.
  4. Mania due to a general medical condition or substance-induced mania (DSM-IV).
  5. Mental retardation (IQ <70), evidence of Fetal Alcohol Syndrome or an Alcohol-Related Neurodevelopmental Disorder.
  6. History of hypersensitivity to or intolerance of risperidone or valproate.
  7. Prior history of risperidone or valproate non-response.
  8. Judged clinically to be at serious suicidal risk.
  9. Participation in a clinical trial of another investigational drug within 1 month (30 days) prior to study entry.
  10. Treatment with an injectable depot neuroleptic within less than one dosing interval between depot neuroleptic injections and day 0.

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  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00221403

Locations
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45267
United States, Wisconsin
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53201
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Stanley Medical Research Institute
Investigators
Principal Investigator: Robert A Kowatch, MD University of Cincinnati
  More Information

No publications provided

Responsible Party: Robert A. Kowatch, CCHMC
ClinicalTrials.gov Identifier: NCT00221403     History of Changes
Other Study ID Numbers: 03-12-26
Study First Received: September 14, 2005
Last Updated: June 24, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Children's Hospital Medical Center, Cincinnati:
child
adolescent
bipolar disorder

Additional relevant MeSH terms:
Bipolar Disorder
Disease
Affective Disorders, Psychotic
Mood Disorders
Mental Disorders
Pathologic Processes
Valproic Acid
Risperidone
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Serotonin Antagonists
Serotonin Agents
Antipsychotic Agents
Dopamine Antagonists
Dopamine Agents

ClinicalTrials.gov processed this record on September 30, 2014