Bipolar DisorderPhase 3NCT00221403
Placebo Controlled Trial of Valproate and Risperidone in Young Children With Bipolar Disorders
A Phase 3 study testing Risperidone oral solution and Valproate Oral Solution in people with Bipolar Disorder, run by Children's Hospital Medical Center, Cincinnati at 2 sites in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 3 to 7 years
- Conditions the study is for
- Bipolar Disorder
- What is being tested?
- Risperidone oral solution and Valproate Oral Solution
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 46 participants
- Where
- 2 sitesUnited States
- Study dates
- Sep 2004to May 2011
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 to 7 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Male or female patients, 3-7 years 11 months of age.
- 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.
- 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.
- Patients must have an initial score (at day 0) on the YMRS total score of at least 20.
- Subjects and their caretakers should be fluent in English.
Who cannot join
- Clinically significant or unstable hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, hematologic or other systemic medical conditions.
- Neurologic disorders including epilepsy, stroke, or severe head trauma.
- 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.
- Mania due to a general medical condition or substance-induced mania (DSM-IV).
- Mental retardation (IQ <70), evidence of Fetal Alcohol Syndrome or an Alcohol-Related Neurodevelopmental Disorder.
- History of hypersensitivity to or intolerance of risperidone or valproate.
Show all 11Show fewer
- Prior history of risperidone or valproate non-response.
- Judged clinically to be at serious suicidal risk.
- Participation in a clinical trial of another investigational drug within 1 month (30 days) prior to study entry.
- Treatment with an injectable depot neuroleptic within less than one dosing interval between depot neuroleptic injections and day 0.
- -
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45267
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, 53201
About this study
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.
Read the 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.
- Conditions
- Bipolar Disorder
- Being tested
- Risperidone oral solution, Valproate Oral Solution, Placebo
- Keywords
- child, adolescent, bipolar disorder
- Medical subject headings
- Bipolar Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Risperidone oral solutionDrug
Also called Risperdal
liquid, BID dosing.
Valproate Oral SolutionDrug
Also called VPA
liquid, BID dosing.
PlaceboOther
liquid, BID dosing.
| Study group | Role | What they receive |
|---|---|---|
| Valproate (VPA) | Active comparator | VPA was administered in liquid form, matched for taste and color with the placebo. Medication was administered in a double-blinded manner on a twice-daily basis. Patients randomized to VPA were administered an initial dose of 10 mg/kg/day on a twice daily schedule beginning on day 0. VPA levels were adjusted to achieve a blood level of 80-100 lg/mL. An independent, unblinded study psychiatrist adjusted VPA doses to achieve a therapeutic level Receives: Drug: Valproate Oral Solution |
| Risperidone | Active comparator | Risperidone was administered in liquid form matched for taste and color to the placebo. Medications were administered in a double-blinded manner on a twice-daily basis. Receives: Drug: Risperidone oral solution |
| Placebo | Placebo comparator | The placebo was administered in liquid form, matched for taste and color with the active comparator. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
YMRS
Young Mania Rating Scale (YMRS) total scores change from baseline by treatment group. The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in manic symptoms.
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Sep 2005 (estimated)
- Study startSep 2004
- Primary completionMay 2011
- Study completionMay 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Bipolar DisorderStudies of the same condition, open and under way.
- More trials run by Children's Hospital Medical Center, CincinnatiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 46 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Medical Center, Cincinnati
- Sponsor type
- University, hospital or other
- Collaborators
- Stanley Medical Research Institute
- Responsible party
- Sponsor
- Investigators
- Robert A Kowatch, MD, Principal investigator, University of Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00221403
- Sponsor's protocol ID
- 2008-0835
- Status last verified
- Sep 2020
- First submitted
- 14 Sep 2005
- Last updated
- 20 Oct 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Kowatch RA, Scheffer RE, Monroe E, Delgado S, Altaye M, Lagory D. Placebo-controlled trial of valproic Acid versus risperidone in children 3-7 years of age with bipolar I disorder. J Child Adolesc Psychopharmacol. 2015 May;25(4):306-13. doi: 10.1089/cap.2014.0166.
PubMed 25978742
Study at a glance
From the registry record, last updated by the sponsor on 20 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Placebo Controlled Trial of Valproate and Risperidone in Young Children With Bipolar Disorders
- ClinicalTrials.gov ID
- NCT00221403
- Acronym / sponsor ID
- 2008-0835
- Conditions
- Bipolar Disorder
- Keywords
- child, adolescent, bipolar disorder
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 46 participants (actual)
- Lead sponsor
- Children's Hospital Medical Center, CincinnatiUniversity, hospital or other
- Collaborators
- Stanley Medical Research Institute
- Study start
- Sep 2004
- Primary completion
- May 2011 (actual)
- Study completion
- May 2011 (actual)
- First posted
- 22 Sep 2005 (estimated)
- Results
- Posted 20 Oct 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Valproate (VPA) | Active comparator | Drug: Valproate Oral SolutionVPA was administered in liquid form, matched for taste and color with the placebo. Medication was administered in a double-blinded manner on a twice-daily basis. Patients randomized to VPA were administered an initial dose of 10 mg/kg/day on a twice daily schedule beginning on day 0. VPA levels were adjusted to achieve a blood level of 80-100 lg/mL. An independent, unblinded study psychiatrist adjusted VPA doses to achieve a therapeutic level |
| Risperidone | Active comparator | Drug: Risperidone oral solutionRisperidone was administered in liquid form matched for taste and color to the placebo. Medications were administered in a double-blinded manner on a twice-daily basis. |
| Placebo | Placebo comparator | Other: PlaceboThe placebo was administered in liquid form, matched for taste and color with the active comparator. |
Who may qualify
- Ages
- 3 to 7 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- Male or female patients, 3-7 years 11 months of age.
- 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.
- 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.
- Patients must have an initial score (at day 0) on the YMRS total score of at least 20.
- Subjects and their caretakers should be fluent in English.
Key exclusion criteria (11 listed)
- Clinically significant or unstable hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, hematologic or other systemic medical conditions.
- Neurologic disorders including epilepsy, stroke, or severe head trauma.
- 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.
- Mania due to a general medical condition or substance-induced mania (DSM-IV).
- Mental retardation (IQ <70), evidence of Fetal Alcohol Syndrome or an Alcohol-Related Neurodevelopmental Disorder.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Risperidone oral solutionAlso: Risperdalliquid, BID dosing. | Drug | Risperidone |
| Valproate Oral SolutionAlso: VPAliquid, BID dosing. | Drug | Valproate (VPA) |
| Placeboliquid, BID dosing. | Other | Placebo |
Primary outcome
YMRS
Time frame: 6 weeks
Young Mania Rating Scale (YMRS) total scores change from baseline by treatment group. The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in manic symptoms.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Oct 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 25978742Kowatch RA, Scheffer RE, Monroe E, Delgado S, Altaye M, Lagory D. Placebo-controlled trial of valproic Acid versus risperidone in children 3-7 years of age with bipolar I disorder. J Child Adolesc Psychopharmacol. 2015 May;25(4):306-13. doi: 10.1089/cap.2014.0166.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert A Kowatch, MD principal investigator
University of Cincinnati
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Risperidone oral solution and Valproate Oral Solution in people with Bipolar Disorder, run by Children's Hospital Medical Center, Cincinnati at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
YMRS (time frame: 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00221403, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Oct 2020.