Trial Outcomes & Findings for A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group-comparison Trial of Aripiprazole in the Treatment of Patients With Bipolar Disorder Experiencing a Manic or Mixed Episode (NCT NCT00606281)

Last Updated: 2014-02-12

Results Overview

Using LOCF datasets, change in YMRS total score from baseline (Day 1) to endpoint (Day 21) was evaluated through analysis of covariance(ANCOVA). YMRS is composed of 11 evaluation items with 5 rating levels each. Items rated on a scale of 0 to 4 (comprising 5 rating levels of one point each) are 1) elevated mood, 2) increased motor activity/energy, 3) sexual interest, 4) sleep, 7) language-thought disorder, 10) appearance, and 11) insight. Items rated on a scale of 0 to 8 (comprising 5 rating levels of two points each) are 5) irritability, 6) speech (rate and amount), 8) content, and 9) disruptive-aggressive behavior. YMRS ranges from 0 (best possible outcome) to 60 (worst possible outcome).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

258 participants

Primary outcome timeframe

Day1, Day21

Results posted on

2014-02-12

Participant Flow

Participant milestones

Participant milestones
Measure	Aripiprazole Subjects were administered 24 mg/day of aripiprazole once daily for 21 days. If there was a problem with tolerability, the dose could be reduced to 12 mg/day.	Placebo Subjects were administered placebo once daily for 21 days.
Overall Study STARTED	128	130
Overall Study COMPLETED	72	64
Overall Study NOT COMPLETED	56	66

Reasons for withdrawal

Reasons for withdrawal
Measure	Aripiprazole Subjects were administered 24 mg/day of aripiprazole once daily for 21 days. If there was a problem with tolerability, the dose could be reduced to 12 mg/day.	Placebo Subjects were administered placebo once daily for 21 days.
Overall Study Adverse Event	11	12
Overall Study Death	1	0
Overall Study Lack of Efficacy	28	35
Overall Study Physician Decision	0	1
Overall Study Protocol Violation	3	3
Overall Study Withdrawal by Subject	11	13
Overall Study Progression to depressive phase	1	1
Overall Study Change of residence or other commitments	1	1

Baseline Characteristics

A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group-comparison Trial of Aripiprazole in the Treatment of Patients With Bipolar Disorder Experiencing a Manic or Mixed Episode

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Aripiprazole n=122 Participants Subjects were administered 24 mg/day of aripiprazole once daily for 21 days. If there was a problem with tolerability, the dose could be reduced to 12 mg/day.	Placebo n=125 Participants Subjects were administered placebo once daily for 21 days.	Total n=247 Participants Total of all reporting groups
Age, Continuous	37.5 years STANDARD_DEVIATION 12.46 • n=99 Participants	37.8 years STANDARD_DEVIATION 12.69 • n=107 Participants	37.6 years STANDARD_DEVIATION 12.50 • n=206 Participants
Age, Categorical <=18 years	3 Participants n=99 Participants	2 Participants n=107 Participants	5 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	119 Participants n=99 Participants	123 Participants n=107 Participants	242 Participants n=206 Participants
Age, Categorical >=65 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Sex: Female, Male Female	70 Participants n=99 Participants	75 Participants n=107 Participants	145 Participants n=206 Participants
Sex: Female, Male Male	52 Participants n=99 Participants	50 Participants n=107 Participants	102 Participants n=206 Participants
Region of Enrollment Taiwan	17 participants n=99 Participants	18 participants n=107 Participants	35 participants n=206 Participants
Region of Enrollment China	28 participants n=99 Participants	28 participants n=107 Participants	56 participants n=206 Participants
Region of Enrollment Japan	39 participants n=99 Participants	40 participants n=107 Participants	79 participants n=206 Participants
Region of Enrollment Indonesia	7 participants n=99 Participants	8 participants n=107 Participants	15 participants n=206 Participants
Region of Enrollment Malaysia	12 participants n=99 Participants	13 participants n=107 Participants	25 participants n=206 Participants
Region of Enrollment Philippines	19 participants n=99 Participants	18 participants n=107 Participants	37 participants n=206 Participants

PRIMARY outcome

Timeframe: Day1, Day21

Population: Full analysis set (FAS): The FAS consisted of subjects who had received at least one dose of investigational product and for whom the post-dosing efficacy parameter data had been obtained. Cases of GCP violation were excluded from analysis.

Outcome measures

Outcome measures
Measure	Aripiprazole n=122 Participants Subjects were administered 24 mg/day of aripiprazole once daily for 21 days. If there was a problem with tolerability, the dose could be reduced to 12 mg/day.	Placebo n=125 Participants Subjects were administered placebo once daily for 21 days.
Young Mania Rating Scale (YMRS)	-11.3 scores on a scale Standard Error 1.31	-5.3 scores on a scale Standard Error 1.29

SECONDARY outcome

Timeframe: Day1, Day21

Population: FAS: The FAS consisted of subjects who had received at least one dose of investigational product and for whom the post-dosing efficacy parameter data had been obtained. Cases of GCP violation were excluded from analysis.

CGI-BP severity of illness is a scale for overall evaluation of the severity of bipolar disorder; it comprises 3 components-mania, depression, and overall bipolar illness. CGI-BP severity of illness score (mania) ranges form 1 (normal, not ill) to 7 (very severely ill). Using LOCF datasets, change in CGI-BP severity of illness score (mania) from baseline (Day 1) to endpoint (Day 21) was evaluated through ANCOVA.

Outcome measures

Outcome measures
Measure	Aripiprazole n=122 Participants Subjects were administered 24 mg/day of aripiprazole once daily for 21 days. If there was a problem with tolerability, the dose could be reduced to 12 mg/day.	Placebo n=125 Participants Subjects were administered placebo once daily for 21 days.
Clinical Global Impression - Bipolar Version (CGI-BP), Severity of Illness Score (Mania)	-1.4 scores on a scale Standard Error 0.15	-0.7 scores on a scale Standard Error 0.15

Adverse Events

Aripiprazole

Serious events: 5 serious events

Other events: 69 other events

Deaths: 0 deaths

Placebo

Serious events: 9 serious events

Other events: 45 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Aripiprazole n=123 participants at risk Subjects were administered 24 mg/day of aripiprazole once daily for 21 days. If there was a problem with tolerability, the dose could be reduced to 12 mg/day.	Placebo n=125 participants at risk Subjects were administered placebo once daily for 21 days.
Gastrointestinal disorders Nausea	0.81% 1/123 • Number of events 1 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	0.00% 0/125 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Gastrointestinal disorders Vomiting	0.81% 1/123 • Number of events 1 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	0.00% 0/125 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Injury, poisoning and procedural complications Multiple Fractures	0.00% 0/123 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	0.80% 1/125 • Number of events 1 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.81% 1/123 • Number of events 1 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	0.00% 0/125 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Psychiatric disorders Bipolar Disorder	0.00% 0/123 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	0.80% 1/125 • Number of events 1 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Psychiatric disorders Bipolar I Disorder	0.81% 1/123 • Number of events 1 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	3.2% 4/125 • Number of events 4 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Psychiatric disorders Mania	2.4% 3/123 • Number of events 3 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	3.2% 4/125 • Number of events 4 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Skin and subcutaneous tissue disorders Drug Erption	0.81% 1/123 • Number of events 1 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	0.00% 0/125 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.

Other adverse events

Other adverse events
Measure	Aripiprazole n=123 participants at risk Subjects were administered 24 mg/day of aripiprazole once daily for 21 days. If there was a problem with tolerability, the dose could be reduced to 12 mg/day.	Placebo n=125 participants at risk Subjects were administered placebo once daily for 21 days.
Gastrointestinal disorders Constipation	8.1% 10/123 • Number of events 11 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	6.4% 8/125 • Number of events 9 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Gastrointestinal disorders Diarrhoea	7.3% 9/123 • Number of events 9 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	5.6% 7/125 • Number of events 8 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Gastrointestinal disorders Nausea	8.1% 10/123 • Number of events 11 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	4.0% 5/125 • Number of events 10 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Gastrointestinal disorders Salivary Hypersecretion	7.3% 9/123 • Number of events 10 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	2.4% 3/125 • Number of events 3 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Gastrointestinal disorders Vomiting	11.4% 14/123 • Number of events 23 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	4.8% 6/125 • Number of events 8 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Investigations Blood Creatine Phosphokinase Increased	6.5% 8/123 • Number of events 8 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	0.80% 1/125 • Number of events 1 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Nervous system disorders Akathisia	22.0% 27/123 • Number of events 33 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	5.6% 7/125 • Number of events 7 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Nervous system disorders Headache	6.5% 8/123 • Number of events 9 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	7.2% 9/125 • Number of events 13 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Nervous system disorders Tremor	12.2% 15/123 • Number of events 18 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	3.2% 4/125 • Number of events 4 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.
Psychiatric disorders Insomnia	16.3% 20/123 • Number of events 23 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.	9.6% 12/125 • Number of events 12 • 21 weeks 1 subject in the placebo group took the study medication (aripiprazole) before proper randomization and was later assigned to the placebo group by IVRS. It was decided to include this subject in the aripiprazole group for safety analysis. However, she was included in the placebo group for the FAS.

Additional Information

Director of Clinical Research and Development

Otsuka Pharmaceutical Co., Ltd.

Phone: +81-3-6361-7366

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place