Trial Outcomes & Findings for Study of Outcome and Safety of Lithium, Divalproex and Risperidone for Mania in Children and Adolescents (NCT NCT00057681)
NCT ID: NCT00057681
Last Updated: 2013-04-04
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
379 participants
Primary outcome timeframe
Measured at Week 8
Results posted on
2013-04-04
Participant Flow
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.
Participant milestones
| Measure |
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.
|
|---|---|---|---|
|
Overall Study
STARTED
|
137
|
139
|
103
|
|
Overall Study
COMPLETED
|
72
|
67
|
69
|
|
Overall Study
NOT COMPLETED
|
65
|
72
|
34
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Study of Outcome and Safety of Lithium, Divalproex and Risperidone for Mania in Children and Adolescents
Baseline characteristics by cohort
| Measure |
Randomized Medication - Lithium
n=137 Participants
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
n=139 Participants
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
n=103 Participants
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
n=379 Participants
Total of all reporting groups
|
|---|---|---|---|---|
|
Age, Categorical
<=18 years
|
137 Participants
n=5 Participants
|
139 Participants
n=7 Participants
|
103 Participants
n=5 Participants
|
379 Participants
n=4 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
|
Age Continuous
|
9.92 years
STANDARD_DEVIATION 2.79 • n=5 Participants
|
9.85 years
STANDARD_DEVIATION 2.37 • n=7 Participants
|
10.99 years
STANDARD_DEVIATION 2.95 • n=5 Participants
|
10.19 years
STANDARD_DEVIATION 2.73 • n=4 Participants
|
|
Sex: Female, Male
Female
|
53 Participants
n=5 Participants
|
70 Participants
n=7 Participants
|
52 Participants
n=5 Participants
|
175 Participants
n=4 Participants
|
|
Sex: Female, Male
Male
|
84 Participants
n=5 Participants
|
69 Participants
n=7 Participants
|
51 Participants
n=5 Participants
|
204 Participants
n=4 Participants
|
|
Region of Enrollment
United States
|
137 participants
n=5 Participants
|
139 participants
n=7 Participants
|
103 participants
n=5 Participants
|
379 participants
n=4 Participants
|
PRIMARY outcome
Timeframe: Measured at Week 8Population: CGI-BP mania improvement data were analyzed for all subjects completing 8 weeks of the study.
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.
Outcome measures
| Measure |
Randomized Medication - Lithium
n=72 Participants
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
n=67 Participants
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
n=69 Participants
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.
|
|---|---|---|---|
|
Clinical Global Impressions-Bipolar Mania Improvement
|
2.49 units on a scale
Standard Deviation 1.05
|
2.73 units on a scale
Standard Deviation 1.08
|
1.70 units on a scale
Standard Deviation 0.63
|
SECONDARY outcome
Timeframe: Measured at Week 8Population: Modified Side Effects Form for Children and Adolescents data were analyzed for all subjects completing 8 weeks of the study.
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.
Outcome measures
| Measure |
Randomized Medication - Lithium
n=72 Participants
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
n=67 Participants
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
n=69 Participants
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.
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|---|---|---|---|
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Modified Side Effects Form for Children and Adolescents
|
5.11 side effects at week 8
Standard Deviation 3.54
|
4.95 side effects at week 8
Standard Deviation 3.29
|
3.70 side effects at week 8
Standard Deviation 2.42
|
SECONDARY outcome
Timeframe: Measured at Week 8Population: KMRS data were analyzed for all subjects completing 8 weeks of the study.
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.
Outcome measures
| Measure |
Randomized Medication - Lithium
n=72 Participants
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
n=67 Participants
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
n=69 Participants
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.
|
|---|---|---|---|
|
K-SADS Mania Rating Scale
|
24.06 units on a scale
Standard Deviation 12.11
|
26.31 units on a scale
Standard Deviation 11.71
|
14.58 units on a scale
Standard Deviation 7.47
|
Adverse Events
Randomized Medication - Lithium
Serious events: 6 serious events
Other events: 0 other events
Deaths: 0 deaths
Randomized Medication - Divalproex Sodium
Serious events: 4 serious events
Other events: 0 other events
Deaths: 0 deaths
Randomized Medication - Risperidone
Serious events: 5 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Randomized Medication - Lithium
n=137 participants at risk
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
n=139 participants at risk
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
n=103 participants at risk
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.
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|---|---|---|---|
|
Psychiatric disorders
Hospitalization
|
3.6%
5/137 • Number of events 5
|
2.9%
4/139 • Number of events 4
|
4.9%
5/103 • Number of events 5
|
|
Psychiatric disorders
Event requiring intervention to prevent permanent impairment or damage
|
0.73%
1/137 • Number of events 1
|
0.00%
0/139
|
0.00%
0/103
|
Other adverse events
Adverse event data not reported
Additional Information
Barbara Geller, M.D.
Washington University in St. Louis
Phone: 314-747-3657
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place