Open-label Study to Evaluate the Effectiveness of an Intramuscular Formulation of Aripiprazole (OPC-14597) as Maintenance Treatment in Patients With Bipolar I Disorder (ATLAS)

• ClinicalTrials.gov Identifier: NCT01710709
• Recruitment Status: Completed
• First Posted: October 19, 2012
• Results First Posted: August 8, 2018
• Last Update Posted: September 21, 2018
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborator: H. Lundbeck A/S
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Bipolar I
• Intervention: Drug: Aripiprazole
• Enrollment: 748

Participant Flow

Recruitment Details	This open-label, single-arm, uncontrolled trial evaluated aripiprazole intramuscular (IM) depot as maintenance treatment for participants with bipolar I disorder. Enrolled participants included those who had completed Trial 31-08-250 (NCT01567527) as well as de novo participants who had not participated in Trial 31-08-250.
Pre-assignment Details	Screening period was from Day -42 to Day -2. Participants from the Trial 31-08-250 entered directly into the IM Depot Maintenance Phase of Trial 31-08-252. For de novo participants, this trial consisted of Phases A-C (Conversion Phase, Oral Stabilization Phase, and IM Depot Maintenance Phase).

Arm/Group Title	Phase C: Open-Label IM Depot Maintenance Phase
Arm/Group Description	All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. Note: Data for Open-label aripiprazole IM depot maintenance phase (Phase C) is presented in the table below which included both rollover participants (those who had completed Trial 31-08-250 and entered into the Open-label aripiprazole IM depot maintenance phase directly) and de novo participants (ie, those who did not participate in Trial 31-08-250 and went through Screening phase, Conversion Phase, and Oral aripiprazole stabilization phase).
Period Title: Overall Study
Started	464
Completed	291
Not Completed	173
Reason Not Completed
Lost to Follow-up	29
Adverse Event	48
Participant met withdrawal criteria	33
Participant withdrawn by investigator	2
Withdrawal by Subject	53
Protocol Violation	5
Lack of Efficacy	3

Baseline Characteristics

Arm/Group Title		Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description		All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
Overall Number of Baseline Participants		464
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	464 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	458 98.7%
	>=65 years	6 1.3%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	464 participants
		41.1 (11.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	464 participants
	Female	268 57.8%
	Male	196 42.2%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	464 participants
Canada		3
South Korea		6
Romania		10
Hungary		4
United States		322
Japan		75
Taiwan		1
Poland		28
Malaysia		10
France		5

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	An adverse event (AE) is defined as any untoward medical occurrence in a patient or participant enrolled in the clinical trial and which does not necessarily have to have a causal relationship with the investigational medicinal product (IMP). AEs were assessed as a criteria for safety and tolerability.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

IM Depot Maintenance Phase Safety Sample: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase. TEAEs = Treatment-emergent adverse events. discount. = discontinued (used in the table below)

Arm/Group Title	Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description:	All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
Overall Number of Participants Analyzed	464
Measure Type: Count of Participants; Unit of Measure: Participants
Participants with adverse events	374
Participants with TEAEs	374
Participants with serious TEAEs	30
Participants with severe TEAEs	41
Participants discontinued from IMP due to AEs	47
Participants discont. from IMP due to AEs or death	48
Deaths	1

2. Primary Outcome

Title	Injection Site Pain Measured by the Visual Analog Scale (VAS)
Description	Injection-site pain was evaluated by mean visual analog scale (VAS) scores as reported by the participant after each injection at visits where an injection occurred. Ratings ranged from 0 (no pain) to 100 (unbearably painful).
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of aripiprazole IM depot in Phase C. It is equivalent to safety set (SAF) for Phase C.

Number analyzed = Total number of participants with at least one observation of the given parameter.

Arm/Group Title		Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description:		All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
Overall Number of Participants Analyzed		464
Mean (Standard Deviation); Unit of Measure: Units on a scale
1ST Injection	Number Analyzed	462 participants
		4.9 (10.7)
2ND Injection	Number Analyzed	435 participants
		4.1 (8.4)
3RD Injection	Number Analyzed	422 participants
		3.4 (7.5)
4TH Injection	Number Analyzed	402 participants
		3.6 (8.6)
5TH Injection	Number Analyzed	387 participants
		2.9 (7.9)
6TH Injection	Number Analyzed	366 participants
		2.4 (5.8)
7TH Injection	Number Analyzed	353 participants
		2.6 (7.0)
8TH Injection	Number Analyzed	293 participants
		2.4 (4.9)
9TH Injection	Number Analyzed	284 participants
		2.6 (6.6)
10TH Injection	Number Analyzed	264 participants
		2.5 (7.5)
11TH Injection	Number Analyzed	255 participants
		2.4 (6.3)
12TH Injection	Number Analyzed	247 participants
		1.8 (4.3)
13TH Injection	Number Analyzed	223 participants
		2.2 (5.5)
Last Injection	Number Analyzed	463 participants
		2.4 (5.9)

3. Primary Outcome

Title	Number of Participants With Clinically Significant Abnormal Laboratory Test Results
Description	Standard safety variables to be analyzed included clinical laboratory tests. Incidence of treatment emergent adverse events (TEAEs) of potential clinical relevance included abnormal values in serum chemistry, hematology, urinalysis, and other laboratory test that were identified based on pre-defined criteria. Abnormal laboratory values in participants were reported as serious adverse event/adverse events (SAE/AEs) and are reported in the SAE/other AE section of this report.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

IM Depot Maintenance Phase Safety Sample: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase.

Arm/Group Title	Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description:	All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
Overall Number of Participants Analyzed	464
Measure Type: Count of Participants; Unit of Measure: Participants
Fasting cholesterol	53
Fasting glucose	39
Fasting low-density lipoprotein cholesterol	32
Fasting triglycerides	124

4. Primary Outcome

Title	Number of Participants With Clinically Significant Abnormal Vital Signs
Description	TEAEs of potential clinical relevance included abnormal values in body weight, systolic and diastolic blood pressure, heart rate, and body temperature that were identified based on pre-defined criteria. Abnormal laboratory values in participants were reported as SAE/AEs and are reported in the SAE/other AE section of this report.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

IM Depot Maintenance Phase Safety Sample: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase.

Arm/Group Title		Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description:		All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
Overall Number of Participants Analyzed		464
Measure Type: Count of Participants; Unit of Measure: Participants
Weight gain of ≥ 7%	Number Analyzed	454 participants
		93 20.5%
Weight loss of ≥ 7%	Number Analyzed	454 participants
		66 14.5%
Blood pressure increased	Number Analyzed	464 participants
		4 0.9%
Heart rate increased	Number Analyzed	464 participants
		3 0.6%
Blood pressure decreased	Number Analyzed	464 participants
		2 0.4%
Body temperature	Number Analyzed	464 participants
		0 0.0%

5. Primary Outcome

Title	Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECGs)
Description	Twelve-lead ECGs were recorded at specified visits. For each time point, three 12-lead ECG recordings were obtained approximately 5 minutes apart. Additional 12-lead ECGs were permitted to be obtained at the investigator's discretion and were to always be obtained in the event of an early termination. The ECGs were evaluated at the investigational site to determine the participant's eligibility and to monitor safety during the trial.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

IM Depot Maintenance Phase Safety Sample: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase.

Arm/Group Title		Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description:		All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
Overall Number of Participants Analyzed		464
Measure Type: Count of Participants; Unit of Measure: Participants
Symmetrical T-wave inversion	Number Analyzed	412 participants
		9
Supraventricular premature beat	Number Analyzed	412 participants
		8
Ventricular premature beat	Number Analyzed	412 participants
		4
Myocardial ischemia	Number Analyzed	412 participants
		2

6. Primary Outcome

Title	Extrapyramidal Symptoms Will be Assessed by Mean Change From Baseline on Abnormal Involuntary Movement Scale(AIMS), Simpson-Angus Scale (SAS), Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS Only Used in Japan) and Barnes Akathisia Rating Scale (BARS)
Description	AIMS: 10 items described dyskinesia signs; 0-absence/no awareness; 4-severe condition/severe distress. Total score for Items 1-10 ranges from 0 to 40; a higher score reflects severe condition. SAS:Consisted of 10 parkinsonism signs;1-no symptoms;5-severe.Total score for Items 1-10 ranges from 1 to 50;a higher score reflects severe condition.DIEPSS:A 9-item rating scale (8 assessed individual symptoms [4 categories of parkinsonism, akathisia, dystonia & dyskinesia]+1 assessed general severity) was used;0-no symptoms/normal, 4-severe.Total score (8 individual symptom items) was in range of 0 to 32 (a higher score reflects severe condition).BARS:Consisted of 4 items related to akathisia:objective observation, subjective feelings of restlessness, distress, global clinical evaluation.Only BARS global clinical assessment score has been presented and rated using scale:0-absence of symptoms;5-severe akathisia.Total BARS global score ranges from 0 to 5,a higher score reflects severe condition.
Time Frame	Baseline, Week 28, and Week 52

Outcome Measure Data

Analysis Population Description

IM Depot Maintenance Phase Safety Sample: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase.

Arm/Group Title		Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description:		All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant. Results using last observation carried forward (LOCF) were presented.
Overall Number of Participants Analyzed		464
Mean (Standard Deviation); Unit of Measure: Units on a scale
AIMS, Week 28	Number Analyzed	457 participants
		0.07 (1.00)
AIMS, Week 52	Number Analyzed	457 participants
		0.05 (0.97)
SAS, Week 28	Number Analyzed	377 participants
		0.21 (1.59)
SAS, Week 52	Number Analyzed	377 participants
		0.20 (1.58)
DIEPSS, Week 28	Number Analyzed	75 participants
		0.32 (1.29)
DIEPSS, Week 52	Number Analyzed	75 participants
		0.21 (1.11)
BARS, Week 28	Number Analyzed	457 participants
		0.05 (0.61)
BARS, Week 52	Number Analyzed	457 participants
		0.04 (0.60)

7. Primary Outcome

Title	Number of Participants Experiencing Suicidal Events and Their Classification According to the Completion of Columbia Suicide Severity Rating Scale (C-SSRS)
Description	Suicidality was monitored throughout the trial using the C-SSRS at every visit. The C-SSRS scale consisted of a screening/baseline evaluation that assessed the participant's lifetime experience and experience over the last 90 days with suicide events and suicidal ideation and a post-baseline/ "Since Last Visit" evaluation that focused on suicidality since the last trial visit.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

IM Depot Maintenance Phase Safety Sample: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase.

Arm/Group Title		Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description:		All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
Overall Number of Participants Analyzed		464
Measure Type: Count of Participants; Unit of Measure: Participants
Completed Suicide	Number Analyzed	463 participants
		0 0.0%
Suicide Attempt	Number Analyzed	463 participants
		3 0.6%
Preparatory action toward imminent suicide	Number Analyzed	463 participants
		4 0.9%
Suicidal ideation	Number Analyzed	463 participants
		46 9.9%
Non-suicidal self-injurious behavior	Number Analyzed	463 participants
		4 0.9%

8. Primary Outcome

Title	Number of Participants With Injection Site Evaluations (Pain, Redness, Swelling, Induration) Measured by Investigator Rating
Description	Injection-site reactions were assessed by the investigator (or qualified designee) and the participant. Investigators rated localized pain, redness, swelling, and induration at the most recent injection site using a 4-point categorical scale (absent, mild, moderate, severe) . The participant indicated the degree of pain at the most recent injection site using a VAS. Ratings ranged from 0 (no pain) to 100 (unbearably painful). Ratings included were: 0 = absent, 1 = mild, 2 = moderate, 3 = severe. These assessments occurred at trial visits where injections occurred (scheduled and unscheduled), beginning with the first dose of open-label aripiprazole IM depot administered at the final visit of the Oral Stabilization Phase and continued through the last injection prior to the end of the IM Depot Maintenance Phase/Early termination (ET) visit (ie, evaluations were not done at end of the IM Depot Maintenance Phase/ET visit).
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

IM Depot Maintenance Phase Safety Sample: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase.

Arm/Group Title	Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description:	All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
Overall Number of Participants Analyzed	464
Measure Type: Count of Participants; Unit of Measure: Participants
Injection Site Bruising	2 0.4%
Injection Site Erythema	1 0.2%
Injection Site Induration	1 0.2%
Injection Site Mass	2 0.4%
Injection Site Pain	34 7.3%
Injection Site Swelling	4 0.9%

9. Secondary Outcome

Title	Percentage of Participants Who Remained Stable at End of Treatment in Phase C
Description	The secondary objective was to evaluate the efficacy, as measured by the percentage of stable participants at baseline who remained stable at the end of treatment in the IM depot maintenance phase, of aripiprazole IM depot administered every 4 weeks for up to 52 weeks to subjects with bipolar I disorder.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

IM Depot Maintenance Phase Efficacy Sample: All participants who entered the IM Depot Maintenance Phase, received at least 1 dose of aripiprazole IM depot, and had at least 1 post-baseline efficacy evaluation in the IM Depot Maintenance Phase. Number analyzed is the number of participants evaluated at the specified trial week.

Arm/Group Title		Phase C: Open-label IM Depot Maintenance Phase
Arm/Group Description:		All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
Overall Number of Participants Analyzed		464
Measure Type: Number; Unit of Measure: Percentage of participants
Baseline	Number Analyzed	463 participants
		100.00
Week 2	Number Analyzed	430 participants
		96.98
Week 4	Number Analyzed	432 participants
		97.22
Week 8	Number Analyzed	413 participants
		95.64
Week 12	Number Analyzed	406 participants
		96.31
Week 16	Number Analyzed	396 participants
		96.46
Week 20	Number Analyzed	381 participants
		95.54
Week 24	Number Analyzed	361 participants
		96.40
Week 28	Number Analyzed	346 participants
		95.09
Week 32	Number Analyzed	287 participants
		97.91
Week 36	Number Analyzed	271 participants
		95.94
Week 40	Number Analyzed	255 participants
		98.04
Week 44	Number Analyzed	249 participants
		97.59
Week 48	Number Analyzed	243 participants
		97.53
Week 52	Number Analyzed	237 participants
		95.78
Last Visit	Number Analyzed	460 participants
		88.91

Adverse Events

Time Frame	Phase C week 1 to week 52/early termination.
Adverse Event Reporting Description	All participants who had received at least one dose of aripiprazole IM depot were included in safety analysis.
Arm/Group Title	Phase C: Open-Label IM Depot Maintenance Phase
Arm/Group Description	All de novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. Aripiprazole IM depot injections were administered every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole IM depot 300 mg and 400 mg was permitted as often as necessary during the open-label treatment period. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant.
All-Cause Mortality
	Phase C: Open-Label IM Depot Maintenance Phase
	Affected / at Risk (%)
Total	1/464 (0.22%)
Serious Adverse Events
	Phase C: Open-Label IM Depot Maintenance Phase
	Affected / at Risk (%)	# Events
Total	30/464 (6.47%)
Cardiac disorders
Acute Myocardial Infarction * 1	1/464 (0.22%)	1
Cardiac Arrest * 1	1/464 (0.22%)	1
Myocardial Infarction * 1	1/464 (0.22%)	1
Prinzmetal Angina * 1	1/464 (0.22%)	3
Endocrine disorders
Hyperprolactinaemia * 1	1/464 (0.22%)	1
General disorders
Chest Pain * 1	2/464 (0.43%)	2
Hepatobiliary disorders
Cholecystitis Acute * 1	1/464 (0.22%)	1
Infections and infestations
Kidney Infection * 1	1/464 (0.22%)	1
Injury, poisoning and procedural complications
Arthropod Bite * 1	1/464 (0.22%)	1
Metabolism and nutrition disorders
Diabetes Mellitus * 1	1/464 (0.22%)	1
Diabetes Mellitus Inadequate Control * 1	1/464 (0.22%)	1
Obesity * 1	1/464 (0.22%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer * 1	1/464 (0.22%)	1
Nervous system disorders
Somnolence * 1	1/464 (0.22%)	1
Tardive Dyskinesia * 1	1/464 (0.22%)	1
Psychiatric disorders
Aggression * 1	1/464 (0.22%)	2
Bipolar Disorder * 1	2/464 (0.43%)	2
Bipolar I Disorder * 1	4/464 (0.86%)	4
Major Depression * 1	1/464 (0.22%)	1
Mania * 1	3/464 (0.65%)	3
Social Avoidant Behaviour * 1	1/464 (0.22%)	1
Suicidal Ideation * 1	4/464 (0.86%)	4
Suicide Attempt * 1	1/464 (0.22%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea * 1	1/464 (0.22%)	1
1 Term from vocabulary, MedDRA 19.0; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Phase C: Open-Label IM Depot Maintenance Phase
	Affected / at Risk (%)	# Events
Total	367/464 (79.09%)
General disorders
Injection site pain * 1	34/464 (7.33%)	50
Infections and infestations
Nasopharyngitis * 1	56/464 (12.07%)	87
Upper respiratory tract infection * 1	24/464 (5.17%)	27
Investigations
Weight increased * 1	62/464 (13.36%)	66
Nervous system disorders
Akathisia * 1	68/464 (14.66%)	79
Headache * 1	29/464 (6.25%)	37
Tremor * 1	28/464 (6.03%)	38
Psychiatric disorders
Anxiety * 1	46/464 (9.91%)	60
Depression * 1	26/464 (5.60%)	35
Insomnia * 1	51/464 (10.99%)	54
Restlessness * 1	23/464 (4.96%)	27
1 Term from vocabulary, MedDRA 19.0; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

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.

 

Results Point of Contact

• Name/Title: Global Clinical Development
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.
• EMail: DT-inquiry@otsuka.jp

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Calabrese JR, Jin N, Johnson B, Such P, Baker RA, Madera J, Hertel P, Ottinger J, Amatniek J, Kawasaki H. Aripiprazole once-monthly as maintenance treatment for bipolar I disorder: a 52-week, multicenter, open-label study. Int J Bipolar Disord. 2018 Jun 10;6(1):14. doi: 10.1186/s40345-018-0122-z.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01710709
• Other Study ID Numbers: 31-08-252
• First Submitted: October 17, 2012
• First Posted: October 19, 2012
• Results First Submitted: November 30, 2017
• Results First Posted: August 8, 2018
• Last Update Posted: September 21, 2018