Study of Outcome and Safety of Lithium, Divalproex and Risperidone for Mania in Children and Adolescents (TEAM)

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00057681
First received: April 4, 2003
Last updated: March 27, 2013
Last verified: March 2013
Results First Received: May 29, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Bipolar Disorder
Interventions: Drug: Lithium carbonate
Drug: Valproate
Drug: Risperidone

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Recruitment was from media advertisements and clinical referrals from 2003 to 2008. There were a total of N=379 subjects randomized to 1 of the 3 group strata. The strata were (1) medication-naive strategy, (2) add-on strategy, and (3) cross-taper strategy. Analyses have only been conducted on the N=279 subjects in the first stratum.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Randomized Medication - Lithium Participants will receive treatment with lithium for 8 to 16 weeks. At the initial dispensing visit, dose was 150mg qHS for 2 days, then 150mg BID for subjects <25kg; 150mg BID for 2 days, then 300mg BID for subjects 25-50kg; 300mg BID for 2 days, then 300mg AM / 600mg PM for subjects >50kg. Dose was adjusted to achieve blood levels of 0.8 mEq/L at week 1, 0.9-1.0 mEq/L at weeks 2-3, and 1.1-1.3 mEq/L at weeks 4-7.
Randomized Medication - Divalproex Sodium Participants will receive treatment with divalproex sodium for 8 to 16 weeks. At the initial dispensing visit, dose was 125mg qHS for 2 days, then 125mg BID for subjects <25kg; 250mg qHS for 2 days, then 125mg AM / 250mg PM for subjects 25-50kg; 250mg qHS for 2 days, then 250mg BID for subjects >50kg. Dose was adjusted to achieve blood levels of 75 ug/ml at week 1, 100-110 ug/ml at weeks 2-3, and 111-125 ug/ml at weeks 4-7.
Randomized Medication - Risperidone Participants will receive treatment with risperidone for 8 to 16 weeks. At the initial dispensing visit, dose was 0.25mg qHS for 2 days, then 0.25mg BID for subjects <25kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects 25-50kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects >50kg. Dose was adjusted at weeks 2-3 to 0.5mg BID for subjects <25kg, 1.0mg BID for subjects 25-50kg and >50kg. Dose was adjusted at weeks 4-5 to 1.0mg BID for subjects <25kg, 1.5mg BID for subjects 25-50kg, 2.0kg BID for subjects >50kg. Dose was adjusted at weeks 6-7 to 2.0mg BID for subjects <25kg, 2.0mg AM / 3.0mg PM for subjects 25-50kg, 3.0mg BID for subjects >50kg.

Participant Flow:   Overall Study
    Randomized Medication - Lithium     Randomized Medication - Divalproex Sodium     Randomized Medication - Risperidone  
STARTED     137     139     103  
COMPLETED     72     67     69  
NOT COMPLETED     65     72     34  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Randomized Medication - Lithium Participants will receive treatment with lithium for 8 to 16 weeks. At the initial dispensing visit, dose was 150mg qHS for 2 days, then 150mg BID for subjects <25kg; 150mg BID for 2 days, then 300mg BID for subjects 25-50kg; 300mg BID for 2 days, then 300mg AM / 600mg PM for subjects >50kg. Dose was adjusted to achieve blood levels of 0.8 mEq/L at week 1, 0.9-1.0 mEq/L at weeks 2-3, and 1.1-1.3 mEq/L at weeks 4-7.
Randomized Medication - Divalproex Sodium Participants will receive treatment with divalproex sodium for 8 to 16 weeks. At the initial dispensing visit, dose was 125mg qHS for 2 days, then 125mg BID for subjects <25kg; 250mg qHS for 2 days, then 125mg AM / 250mg PM for subjects 25-50kg; 250mg qHS for 2 days, then 250mg BID for subjects >50kg. Dose was adjusted to achieve blood levels of 75 ug/ml at week 1, 100-110 ug/ml at weeks 2-3, and 111-125 ug/ml at weeks 4-7.
Randomized Medication - Risperidone Participants will receive treatment with risperidone for 8 to 16 weeks. At the initial dispensing visit, dose was 0.25mg qHS for 2 days, then 0.25mg BID for subjects <25kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects 25-50kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects >50kg. Dose was adjusted at weeks 2-3 to 0.5mg BID for subjects <25kg, 1.0mg BID for subjects 25-50kg and >50kg. Dose was adjusted at weeks 4-5 to 1.0mg BID for subjects <25kg, 1.5mg BID for subjects 25-50kg, 2.0kg BID for subjects >50kg. Dose was adjusted at weeks 6-7 to 2.0mg BID for subjects <25kg, 2.0mg AM / 3.0mg PM for subjects 25-50kg, 3.0mg BID for subjects >50kg.
Total Total of all reporting groups

Baseline Measures
    Randomized Medication - Lithium     Randomized Medication - Divalproex Sodium     Randomized Medication - Risperidone     Total  
Number of Participants  
[units: participants]
  137     139     103     379  
Age  
[units: participants]
       
<=18 years     137     139     103     379  
Between 18 and 65 years     0     0     0     0  
>=65 years     0     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation
  9.92  ± 2.79     9.85  ± 2.37     10.99  ± 2.95     10.19  ± 2.73  
Gender  
[units: participants]
       
Female     53     70     52     175  
Male     84     69     51     204  
Region of Enrollment  
[units: participants]
       
United States     137     139     103     379  



  Outcome Measures
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1.  Primary:   Clinical Global Impressions-Bipolar Mania Improvement   [ Time Frame: Measured at Week 8 ]

Measure Type Primary
Measure Title Clinical Global Impressions-Bipolar Mania Improvement
Measure Description The Clinical Global Impressions-Bipolar (CGI-BP) assessment instrument measured improvement in mania, depression, and overall bipolar illness. The primary outcome measure was mania improvement, which measured the change in mania from baseline. Scores were 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse.
Time Frame Measured at Week 8  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
CGI-BP mania improvement data were analyzed for all subjects completing 8 weeks of the study.

Reporting Groups
  Description
Randomized Medication - Lithium Participants will receive treatment with lithium for 8 to 16 weeks. At the initial dispensing visit, dose was 150mg qHS for 2 days, then 150mg BID for subjects <25kg; 150mg BID for 2 days, then 300mg BID for subjects 25-50kg; 300mg BID for 2 days, then 300mg AM / 600mg PM for subjects >50kg. Dose was adjusted to achieve blood levels of 0.8 mEq/L at week 1, 0.9-1.0 mEq/L at weeks 2-3, and 1.1-1.3 mEq/L at weeks 4-7.
Randomized Medication - Divalproex Sodium Participants will receive treatment with divalproex sodium for 8 to 16 weeks. At the initial dispensing visit, dose was 125mg qHS for 2 days, then 125mg BID for subjects <25kg; 250mg qHS for 2 days, then 125mg AM / 250mg PM for subjects 25-50kg; 250mg qHS for 2 days, then 250mg BID for subjects >50kg. Dose was adjusted to achieve blood levels of 75 ug/ml at week 1, 100-110 ug/ml at weeks 2-3, and 111-125 ug/ml at weeks 4-7.
Randomized Medication - Risperidone Participants will receive treatment with risperidone for 8 to 16 weeks. At the initial dispensing visit, dose was 0.25mg qHS for 2 days, then 0.25mg BID for subjects <25kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects 25-50kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects >50kg. Dose was adjusted at weeks 2-3 to 0.5mg BID for subjects <25kg, 1.0mg BID for subjects 25-50kg and >50kg. Dose was adjusted at weeks 4-5 to 1.0mg BID for subjects <25kg, 1.5mg BID for subjects 25-50kg, 2.0kg BID for subjects >50kg. Dose was adjusted at weeks 6-7 to 2.0mg BID for subjects <25kg, 2.0mg AM / 3.0mg PM for subjects 25-50kg, 3.0mg BID for subjects >50kg.

Measured Values
    Randomized Medication - Lithium     Randomized Medication - Divalproex Sodium     Randomized Medication - Risperidone  
Number of Participants Analyzed  
[units: participants]
  72     67     69  
Clinical Global Impressions-Bipolar Mania Improvement  
[units: units on a scale]
Mean ± Standard Deviation
  2.49  ± 1.05     2.73  ± 1.08     1.70  ± 0.63  

No statistical analysis provided for Clinical Global Impressions-Bipolar Mania Improvement



2.  Secondary:   Modified Side Effects Form for Children and Adolescents   [ Time Frame: Measured at Week 8 ]

Measure Type Secondary
Measure Title Modified Side Effects Form for Children and Adolescents
Measure Description The Modified Side Effects Form for Children and Adolescents includes 62 potential side effects, with measures of frequency and severity for each item. Frequencies are 0=not present, 1=1-2 days, 2=3-4 days, 3=5-7 days. Severity scores are 0=not present, 1=mild (does not interfere with functioning), 2=moderate (some interference with functioning), 3=severe (functioning is significantly impaired because of side effects). Items for cardiovascular, gastrointestinal, central nervous system, ocular, mouth and nose, genito urinary, dermatology, musculo-skeletal, and other side effects are included. For analyses, side effects that were reported at any frequency and a severity of 2 or greater were considered present.
Time Frame Measured at Week 8  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Modified Side Effects Form for Children and Adolescents data were analyzed for all subjects completing 8 weeks of the study.

Reporting Groups
  Description
Randomized Medication - Lithium Participants will receive treatment with lithium for 8 to 16 weeks. At the initial dispensing visit, dose was 150mg qHS for 2 days, then 150mg BID for subjects <25kg; 150mg BID for 2 days, then 300mg BID for subjects 25-50kg; 300mg BID for 2 days, then 300mg AM / 600mg PM for subjects >50kg. Dose was adjusted to achieve blood levels of 0.8 mEq/L at week 1, 0.9-1.0 mEq/L at weeks 2-3, and 1.1-1.3 mEq/L at weeks 4-7.
Randomized Medication - Divalproex Sodium Participants will receive treatment with divalproex sodium for 8 to 16 weeks. At the initial dispensing visit, dose was 125mg qHS for 2 days, then 125mg BID for subjects <25kg; 250mg qHS for 2 days, then 125mg AM / 250mg PM for subjects 25-50kg; 250mg qHS for 2 days, then 250mg BID for subjects >50kg. Dose was adjusted to achieve blood levels of 75 ug/ml at week 1, 100-110 ug/ml at weeks 2-3, and 111-125 ug/ml at weeks 4-7.
Randomized Medication - Risperidone Participants will receive treatment with risperidone for 8 to 16 weeks. At the initial dispensing visit, dose was 0.25mg qHS for 2 days, then 0.25mg BID for subjects <25kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects 25-50kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects >50kg. Dose was adjusted at weeks 2-3 to 0.5mg BID for subjects <25kg, 1.0mg BID for subjects 25-50kg and >50kg. Dose was adjusted at weeks 4-5 to 1.0mg BID for subjects <25kg, 1.5mg BID for subjects 25-50kg, 2.0kg BID for subjects >50kg. Dose was adjusted at weeks 6-7 to 2.0mg BID for subjects <25kg, 2.0mg AM / 3.0mg PM for subjects 25-50kg, 3.0mg BID for subjects >50kg.

Measured Values
    Randomized Medication - Lithium     Randomized Medication - Divalproex Sodium     Randomized Medication - Risperidone  
Number of Participants Analyzed  
[units: participants]
  72     67     69  
Modified Side Effects Form for Children and Adolescents  
[units: side effects at week 8]
Mean ± Standard Deviation
  5.11  ± 3.54     4.95  ± 3.29     3.70  ± 2.42  

No statistical analysis provided for Modified Side Effects Form for Children and Adolescents



3.  Secondary:   K-SADS Mania Rating Scale   [ Time Frame: Measured at Week 8 ]

Measure Type Secondary
Measure Title K-SADS Mania Rating Scale
Measure Description The K-SADS Mania Rating Scale (KMRS) is comprised of 15 items modified from WASH-U-KSADS items. The individual items are scored on a 1-6 severity scale and then these item scores are summed to create an overall KMRS score. Guidelines for interpretation are as follows: 0-11 = no or minimal mania, 12-17 = mild mania, 18-25 = moderate mania, 26+ = marked or worse mania. The maximum possible score is 64.
Time Frame Measured at Week 8  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
KMRS data were analyzed for all subjects completing 8 weeks of the study.

Reporting Groups
  Description
Randomized Medication - Lithium Participants will receive treatment with lithium for 8 to 16 weeks. At the initial dispensing visit, dose was 150mg qHS for 2 days, then 150mg BID for subjects <25kg; 150mg BID for 2 days, then 300mg BID for subjects 25-50kg; 300mg BID for 2 days, then 300mg AM / 600mg PM for subjects >50kg. Dose was adjusted to achieve blood levels of 0.8 mEq/L at week 1, 0.9-1.0 mEq/L at weeks 2-3, and 1.1-1.3 mEq/L at weeks 4-7.
Randomized Medication - Divalproex Sodium Participants will receive treatment with divalproex sodium for 8 to 16 weeks. At the initial dispensing visit, dose was 125mg qHS for 2 days, then 125mg BID for subjects <25kg; 250mg qHS for 2 days, then 125mg AM / 250mg PM for subjects 25-50kg; 250mg qHS for 2 days, then 250mg BID for subjects >50kg. Dose was adjusted to achieve blood levels of 75 ug/ml at week 1, 100-110 ug/ml at weeks 2-3, and 111-125 ug/ml at weeks 4-7.
Randomized Medication - Risperidone Participants will receive treatment with risperidone for 8 to 16 weeks. At the initial dispensing visit, dose was 0.25mg qHS for 2 days, then 0.25mg BID for subjects <25kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects 25-50kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects >50kg. Dose was adjusted at weeks 2-3 to 0.5mg BID for subjects <25kg, 1.0mg BID for subjects 25-50kg and >50kg. Dose was adjusted at weeks 4-5 to 1.0mg BID for subjects <25kg, 1.5mg BID for subjects 25-50kg, 2.0kg BID for subjects >50kg. Dose was adjusted at weeks 6-7 to 2.0mg BID for subjects <25kg, 2.0mg AM / 3.0mg PM for subjects 25-50kg, 3.0mg BID for subjects >50kg.

Measured Values
    Randomized Medication - Lithium     Randomized Medication - Divalproex Sodium     Randomized Medication - Risperidone  
Number of Participants Analyzed  
[units: participants]
  72     67     69  
K-SADS Mania Rating Scale  
[units: units on a scale]
Mean ± Standard Deviation
  24.06  ± 12.11     26.31  ± 11.71     14.58  ± 7.47  

No statistical analysis provided for K-SADS Mania Rating Scale




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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