Aripiprazole in Children and Adolescents With Bipolar I Disorder

This study has been completed.

Sponsor:

Information provided by:

Otsuka Pharmaceutical Development & Commercialization, Inc.

ClinicalTrials.gov Identifier:

NCT00110461

First received: May 9, 2005

Last updated: April 19, 2012

Last verified: April 2012

History of Changes

Results First Received: August 11, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Bipolar Disorder
Interventions:	Drug: Aripiprazole Drug: placebo

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
Participants were recruited from 59 centers in the United States between March 2005 and February 2007. A total of 413 subjects were screened for enrollment, with 296 subjects assigned to double-blind treatment.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants were screened over a 28-day period.

Reporting Groups

	Description
Aripiprazole 10 mg/Day	Dose was titrated to a target dose of 10 mg/day as follows: Starting dose 2 mg/day, increased to 5 mg/day on Day 3, 10 mg/day on Day 5. One dose reduction to 5 mg/day was allowed in the extension phase. Following a dose reduction, the dose could be up titrated to 10 mg/day if needed.
Aripiprazole 30 mg/Day	Dose was titrated to a target dose of 30 mg/day as follows: Starting dose 2 mg/day, increased to 5 mg/day on Day 3, 10 mg/day on Day 5, 15 mg/day on Day 7, 20 mg/day on Day 9, 25 mg/day on Day 11, and 30 mg/day on Day 13. One dose reduction to 15 mg/day was allowed in the extension phase. Following a dose reduction, the dose could be up titrated to 20 mg/day if needed.
Placebo	Participants were given a single pill administered once daily.

Participant Flow for 2 periods

Period 1: 30-Week, Double-blind Treatment Phase

	Aripiprazole 10 mg/Day	Aripiprazole 30 mg/Day	Placebo
STARTED	98	99	99
COMPLETED	34	22	12
NOT COMPLETED	64	77	87

Period 2: Acute Phase

	Aripiprazole 10 mg/Day	Aripiprazole 30 mg/Day	Placebo
STARTED	98	99	99
COMPLETED	84	77	76
NOT COMPLETED	14	22	23

Baseline Characteristics

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Reporting Groups

	Description
Aripiprazole 10 mg/Day	Dose was titrated to a target dose of 10 mg/day as follows: Starting dose 2 mg/day, increased to 5 mg/day on Day 3, 10 mg/day on Day 5. One dose reduction to 5 mg/day was allowed in the extension phase. Following a dose reduction, the dose could be up titrated to 10 mg/day if needed.
Aripiprazole 30 mg/Day	Dose was titrated to a target dose of 30 mg/day as follows: Starting dose 2 mg/day, increased to 5 mg/day on Day 3, 10 mg/day on Day 5, 15 mg/day on Day 7, 20 mg/day on Day 9, 25 mg/day on Day 11, and 30 mg/day on Day 13. One dose reduction to 15 mg/day was allowed in the extension phase. Following a dose reduction, the dose could be up titrated to 20 mg/day if needed.
Placebo	Participants were given a single pill administered once daily.
Total	Total of all reporting groups

Baseline Measures

	Aripiprazole 10 mg/Day	Aripiprazole 30 mg/Day	Placebo	Total
Number of Participants [units: participants]	98	99	99	296
Age [units: years] Mean ± Standard Deviation	13.70 ± 2.17	13.31 ± 2.32	13.28 ± 2.12	13.43 ± 2.21
Gender [units: participants]
Female	46	48	43	137
Male	52	51	56	159
Ethnicity (NIH/OMB) [units: participants]
Hispanic or Latino	6	10	15	31
Not Hispanic or Latino	92	89	84	265
Unknown or Not Reported	0	0	0	0
Race (NIH/OMB) [units: participants]
American Indian or Alaska Native	0	0	0	0
Asian	0	0	0	0
Native Hawaiian or Other Pacific Islander	2	0	0	2
Black or African American	24	18	23	65
White	65	68	60	193
More than one race	2	2	2	6
Unknown or Not Reported	5	11	14	30
Height [units: centimeters (cm)] Mean ± Standard Deviation	161.05 ± 12.45	158.37 ± 12.21	158.69 ± 11.63	159.36 ± 12.12
Weight [units: kilograms (kg)] Mean ± Standard Deviation	63.76 ± 20.11	60.49 ± 21.50	60.48 ± 17.31	61.57 ± 19.71
Body Mass Index (BMI) [units: kg/m^2] Mean ± Standard Deviation	24.15 ± 5.37	23.66 ± 6.70	23.68 ± 4.98	23.83 ± 5.72
Young Mania Rating Scale Score (Y-MRS) ^[1] [units: points] Mean ± Standard Deviation	29.8 ± 6.5	29.5 ± 6.3	30.7 ± 6.8	30.0 ± 6.5
Children's Depression Rating Scale - Revised (CDRS-R) Suicidal Ideation Score ^[2] [units: points] Mean ± Standard Deviation	1.1 ± 0.4	1.1 ± 0.5	1.2 ± 0.5	1.2 ± 0.5
Treatment given for previous episodes [units: participants]
Yes	57	50	63	170
No	41	49	36	126

[1]	The Y-MRS consists of 11 items assessing the core symptoms of mania. Each item has 5 defined grades of severity. Minimum score on the scale is 0 (absent or normal); maximum score on the scale is 60 (worse outcome or more severe symptoms).
[2]	The CDRS-R is used to diagnose depression and monitor treatment response. The interviewer rates 17 symptom areas (including those that sever as DSM-IV criteria for diagnosis of depression), among them suicidal ideation. Most of the 17 symptom areas are rated on a 7-point scale. The Suicide Ideation Score is rated on a 7-point scale, where the minimum score on the scale is 1 (better outcome) and the maximum score is 7 (worse outcome).

[1]

The Y-MRS consists of 11 items assessing the core symptoms of mania. Each item has 5 defined grades of severity. Minimum score on the scale is 0 (absent or normal); maximum score on the scale is 60 (worse outcome or more severe symptoms).

[2]

The CDRS-R is used to diagnose depression and monitor treatment response. The interviewer rates 17 symptom areas (including those that sever as DSM-IV criteria for diagnosis of depression), among them suicidal ideation. Most of the 17 symptom areas are rated on a 7-point scale. The Suicide Ideation Score is rated on a 7-point scale, where the minimum score on the scale is 1 (better outcome) and the maximum score is 7 (worse outcome).

Outcome Measures

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1. Primary:

Change in Young Mania Rating Scale (Y-MRS) Total Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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2. Secondary:

Change in Young Mania Rating Scale (Y-MRS) Total Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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3. Secondary:

Change in Children’s Global Assessment Scale (CGAS) Total Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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4. Secondary:

Change in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Mania Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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5. Secondary:

Change in Children’s Depression Rating Scale-Revised (CDRS-R) Total Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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6. Secondary:

Change in General Behavior Inventory Scale (GBI) Total Parent/Guardian Version Mania Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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7. Secondary:

Change in Attention Deficit Hyperactivity Disorders Rating Scale (ADHD-RS-IV) Total Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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8. Secondary:

Change in Children's Global Assessment (CGAS) Total Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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9. Secondary:

Change in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Mania Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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10. Secondary:

Change in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Depression Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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11. Secondary:

Change in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Depression Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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12. Secondary:

Change in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Overall Illness Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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13. Secondary:

Change in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Overall Illness Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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14. Secondary:

Change in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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15. Secondary:

Change in General Behavior Inventory Scale (GBI) Total Parent/Guardian Version Mania Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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16. Secondary:

Change in General Behavior Inventory Scale (GBI) Total Subject Version Mania Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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17. Secondary:

Change in General Behavior Inventory Scale (GBI) Total Subject Version Mania Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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18. Secondary:

Change in General Behavior Inventory Scale (GBI) Total Parent/Guardian Version Depression Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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19. Secondary:

Change in General Behavior Inventory Scale (GBI) Total Parent/Guardian Version Depression Score at Week 30 [ Time Frame: Baseline and Week 30 ]

Show Outcome Measure 19

20. Secondary:

Change in General Behavior Inventory Scale (GBI) Total Subject Version Depression Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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21. Secondary:

Change in General Behavior Inventory Scale (GBI) Total Subject Version Depression Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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22. Secondary:

Change in Attention Deficit Hyperactivity Disorders Rating Scale (ADHD-RS-IV) Total Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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23. Secondary:

Subject Response to Treatment at Week 4 [ Time Frame: Baseline and Week 4 ]

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24. Secondary:

Subject Response to Treatment at Week 30 [ Time Frame: Baseline and Week 30 ]

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25. Secondary:

Change From Previous Phase in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Mania Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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26. Secondary:

Change From Previous Phase in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Mania Score at Week 30 [ Time Frame: Baseline and Week 30 ]

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27. Secondary:

Change From Previous Phase in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Depression Score at Week 4 [ Time Frame: Baseline and Week 4 ]

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28. Secondary:

Change From Previous Phase in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Depression Score at Week 30 [ Time Frame: Baseline and Week 30 ]

Show Outcome Measure 28

29. Secondary:

Change From Previous Phase in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Overall Illness Score at Week 4 [ Time Frame: Baseline and Week 4 ]

Show Outcome Measure 29

30. Secondary:

Change From Previous Phase in Clinical Global Impressions Scale-Bipolar Version (CGI-BP) Severity Overall Illness Score at Week 30 [ Time Frame: Baseline and Week 30 ]

Show Outcome Measure 30

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS 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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: PIs may not publish trial results for 18 months - 2 years after trial is completed.

Limitations and Caveats

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
Primary efficacy endpoint is change from baseline in Y-MRS total score. Only randomized subjects with both baseline and 1+ post-baseline were included in primary efficacy analysis so # randomized is different from # included in the efficacy analysis.

Results Point of Contact:

Name/Title: Andy Forbes
Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.
e-mail: andy.forbes@otsuka-us.com

No publications provided by Otsuka Pharmaceutical Development & Commercialization, Inc.

Publications automatically indexed to this study:

Youngstrom E, Zhao J, Mankoski R, Forbes RA, Marcus RM, Carson W, McQuade R, Findling RL. Clinical significance of treatment effects with aripiprazole versus placebo in a study of manic or mixed episodes associated with pediatric bipolar I disorder. J Child Adolesc Psychopharmacol. 2013 Mar;23(2):72-9. doi: 10.1089/cap.2012.0024. Epub 2013 Mar 12.

Findling RL, Correll CU, Nyilas M, Forbes RA, McQuade RD, Jin N, Ivanova S, Mankoski R, Carson WH, Carlson GA. Aripiprazole for the treatment of pediatric bipolar I disorder: a 30-week, randomized, placebo-controlled study. Bipolar Disord. 2013 Mar;15(2):138-49. doi: 10.1111/bdi.12042.

Mankoski R, Zhao J, Carson WH, Mathew SJ, Forbes RA. Young mania rating scale line item analysis in pediatric subjects with bipolar I disorder treated with aripiprazole in a short-term, double-blind, randomized study. J Child Adolesc Psychopharmacol. 2011 Aug;21(4):359-64. Epub 2011 Aug 8.

Findling RL, Nyilas M, Forbes RA, McQuade RD, Jin N, Iwamoto T, Ivanova S, Carson WH, Chang K. Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2009 Oct;70(10):1441-51.

Responsible Party:	Arifulla Khan, MD, Northwest Clinical Research Center
ClinicalTrials.gov Identifier:	NCT00110461 History of Changes
Other Study ID Numbers:	31-03-240
Study First Received:	May 9, 2005
Results First Received:	August 11, 2011
Last Updated:	April 19, 2012
Health Authority:	United States: Food and Drug Administration

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