Trial Outcomes & Findings for Efficacy, Safety, and Tolerability of an Intramuscular Formulation of Aripiprazole (OPC-14597) as Maintenance Treatment in Bipolar I Patients (NCT NCT01567527)

NCT ID: NCT01567527

Last Updated: 2018-08-24

Results Overview

This endpoint was defined as meeting any of the following criteria: 1. Hospitalization for any mood episode OR 2. Any of the following: 1. YMRS total score ≥ 15 OR 2. MADRS total score ≥ 15 OR 3. CGI-BP-S score \> 4 (overall score) OR 3. SAE of worsening disease (bipolar I disorder) OR 4. Discontinuation due to lack of efficacy or discontinuation due to an AE of worsening disease OR 5. Clinical worsening with the need for treatment of symptoms of an underlying mood disorder by addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, or increase greater than the allowed benzodiazepine doses, or 6. Active suicidality, which is defined as a score of 4 or more on the MADRS item 10 OR an answer of "yes" on question 4 or 5 on the C-SSRS. The time to event is presented in the following table.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 731 participants
• Primary outcome timeframe: Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52).
• Results posted on: 2018-08-24

Participant Flow

This trial was conducted in 1175 subjects (including 444 screen failures) at 103 trial sites in the following 7 countries: Canada, Japan, Republic of Korea, Poland, Romania, Taiwan, and the United States (US).

The trial consisted of a screening phase and 4 phases. In Conversion, Oral Stabilization and IM Depot Stabilization Phases, there was a single treatment group. In Double-blind, Placebo-controlled Phase, there were 2 treatment groups. All Outcome Measures were assessed in the Double-blind, Placebo-controlled Phase of the study.

Participant milestones

Measure	Conversion Phase. During the Oral Conversion Phase, subjects were cross-titrated from other antipsychotics to oral non-generic aripiprazole monotherapy.	Oral Aripiprazole Stabilization Phase. During the Oral Stabilization Phase, subjects were stabilized on an oral dose of aripiprazole. 632 subjects entered the Oral Stabilization Phase (367 subjects entered from the Conversation Phase and 265 subjects entered the Oral Stabilization Phase directly).	Intramuscular (IM) Depot Stabilization Phase. During the Depot Stabilization Phase, subjects were stabilized on aripiprazole IM depot. The subjects were assigned to aripiprazole IM depot in the IM Depot Stabilization Phase for a minimum of 12 weeks and a maximum of 28 weeks. To proceed to the Double-blind, Placebo-controlled Phase, subjects were required to meet all the protocol-defined stability criteria for a minimum of 8 consecutive weeks (4 consecutive biweekly visits).	Double-blind Placebo-controlled Phase - Aripiprazole IM Depot. Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks. A total of 266 subjects entered Double-blind Placebo-controlled phase. Of the 266 subjects, 133 were randomized to aripiprazole IM depot treatment. Since one subject withdrew consent to participate prior to receiving an injection, only 132 subjects received aripiprazole IM depot treatment.	Double-blind Placebo-controlled Phase - Placebo. Subjects received placebo intramuscularly up to 52 weeks. A total of 266 subjects entered double-blind placebo-controlled Phase. Of the 266 subjects, 133 were randomized to placebo treatment.
Conversion Phase. STARTED	466	0	0	0	0
Conversion Phase. COMPLETED	367	0	0	0	0
Conversion Phase. NOT COMPLETED	99	0	0	0	0
Oral Aripiprazole Stabilization Phase. STARTED	0	632	0	0	0
Oral Aripiprazole Stabilization Phase. COMPLETED	0	425	0	0	0
Oral Aripiprazole Stabilization Phase. NOT COMPLETED	0	207	0	0	0
IM Depot Stabilization. STARTED	0	0	425	0	0
IM Depot Stabilization. COMPLETED	0	0	266	0	0
IM Depot Stabilization. NOT COMPLETED	0	0	159	0	0
Double-blind, Placebo-controlled Phase STARTED	0	0	0	133	133
Double-blind, Placebo-controlled Phase COMPLETED	0	0	0	64	38
Double-blind, Placebo-controlled Phase NOT COMPLETED	0	0	0	69	95

Reasons for withdrawal

Measure	Conversion Phase. During the Oral Conversion Phase, subjects were cross-titrated from other antipsychotics to oral non-generic aripiprazole monotherapy.	Oral Aripiprazole Stabilization Phase. During the Oral Stabilization Phase, subjects were stabilized on an oral dose of aripiprazole. 632 subjects entered the Oral Stabilization Phase (367 subjects entered from the Conversation Phase and 265 subjects entered the Oral Stabilization Phase directly).	Intramuscular (IM) Depot Stabilization Phase. During the Depot Stabilization Phase, subjects were stabilized on aripiprazole IM depot. The subjects were assigned to aripiprazole IM depot in the IM Depot Stabilization Phase for a minimum of 12 weeks and a maximum of 28 weeks. To proceed to the Double-blind, Placebo-controlled Phase, subjects were required to meet all the protocol-defined stability criteria for a minimum of 8 consecutive weeks (4 consecutive biweekly visits).	Double-blind Placebo-controlled Phase - Aripiprazole IM Depot. Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks. A total of 266 subjects entered Double-blind Placebo-controlled phase. Of the 266 subjects, 133 were randomized to aripiprazole IM depot treatment. Since one subject withdrew consent to participate prior to receiving an injection, only 132 subjects received aripiprazole IM depot treatment.	Double-blind Placebo-controlled Phase - Placebo. Subjects received placebo intramuscularly up to 52 weeks. A total of 266 subjects entered double-blind placebo-controlled Phase. Of the 266 subjects, 133 were randomized to placebo treatment.
Conversion Phase. Protocol deviation	3	0	0	0	0
Conversion Phase. Met withdrawal criteria	10	0	0	0	0
Conversion Phase. Withdrawal by Subject	32	0	0	0	0
Conversion Phase. Lost to Follow-up	16	0	0	0	0
Conversion Phase. Lack of Efficacy	2	0	0	0	0
Conversion Phase. Adverse Event	33	0	0	0	0
Conversion Phase. Withdrawn by the investigator	3	0	0	0	0
Oral Aripiprazole Stabilization Phase. Met withdrawal criteria	0	41	0	0	0
Oral Aripiprazole Stabilization Phase. Withdrawal by Subject	0	45	0	0	0
Oral Aripiprazole Stabilization Phase. Lost to Follow-up	0	44	0	0	0
Oral Aripiprazole Stabilization Phase. Lack of Efficacy	0	12	0	0	0
Oral Aripiprazole Stabilization Phase. Adverse Event	0	63	0	0	0
Oral Aripiprazole Stabilization Phase. Withdrawn by the investigator	0	2	0	0	0
IM Depot Stabilization. Protocol deviation	0	0	5	0	0
IM Depot Stabilization. Met withdrawal criteria	0	0	26	0	0
IM Depot Stabilization. Withdrawal by Subject	0	0	56	0	0
IM Depot Stabilization. Sponsor discontinued study	0	0	1	0	0
IM Depot Stabilization. Lost to Follow-up	0	0	21	0	0
IM Depot Stabilization. Lack of Efficacy	0	0	7	0	0
IM Depot Stabilization. Adverse Event	0	0	37	0	0
IM Depot Stabilization. Withdrawn by the investigator	0	0	6	0	0
Double-blind, Placebo-controlled Phase Protocol deviation	0	0	0	1	1
Double-blind, Placebo-controlled Phase Recurrence of any mood episode with AE	0	0	0	16	33
Double-blind, Placebo-controlled Phase Met withdrawal criteria	0	0	0	4	7
Double-blind, Placebo-controlled Phase AE without recurrence of any moodepisode	0	0	0	7	1
Double-blind, Placebo-controlled Phase Withdrawal by Subject	0	0	0	13	10
Double-blind, Placebo-controlled Phase Sponsor discontinued study	0	0	0	1	3
Double-blind, Placebo-controlled Phase Recurrence of any mood episode withoutAE	0	0	0	19	35
Double-blind, Placebo-controlled Phase Lost to Follow-up	0	0	0	8	5

Baseline Characteristics

Efficacy, Safety, and Tolerability of an Intramuscular Formulation of Aripiprazole (OPC-14597) as Maintenance Treatment in Bipolar I Patients

Baseline characteristics by cohort

Measure	Aripiprazole Depot n=133 Participants Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Placebo n=133 Participants Subjects received placebo intramuscularly up to 52 weeks.	Total n=266 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	133 Participants n=5 Participants	132 Participants n=7 Participants	265 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Age, Continuous	40.6 years STANDARD_DEVIATION 10.8 • n=5 Participants	40.6 years STANDARD_DEVIATION 11.2 • n=7 Participants	40.6 years STANDARD_DEVIATION 11.0 • n=5 Participants
Sex: Female, Male Female	83 Participants n=5 Participants	70 Participants n=7 Participants	153 Participants n=5 Participants
Sex: Female, Male Male	50 Participants n=5 Participants	63 Participants n=7 Participants	113 Participants n=5 Participants
Region of Enrollment Canada	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment South Korea	7 Participants n=5 Participants	7 Participants n=7 Participants	14 Participants n=5 Participants
Region of Enrollment Romania	8 Participants n=5 Participants	12 Participants n=7 Participants	20 Participants n=5 Participants
Region of Enrollment United States	101 Participants n=5 Participants	102 Participants n=7 Participants	203 Participants n=5 Participants
Region of Enrollment Japan	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Region of Enrollment Taiwan	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment Poland	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Age at first manic episode (years)	25.2 years STANDARD_DEVIATION 10.3 • n=5 Participants	24.8 years STANDARD_DEVIATION 9.9 • n=7 Participants	25.0 years STANDARD_DEVIATION 10.1 • n=5 Participants
Number of mood episodes past 12 months	2.2 Mood episodes STANDARD_DEVIATION 1.2 • n=5 Participants	2.2 Mood episodes STANDARD_DEVIATION 1.1 • n=7 Participants	2.2 Mood episodes STANDARD_DEVIATION 1.2 • n=5 Participants
Duration of disease prior to enrollment (years)	12.1 years STANDARD_DEVIATION 9.2 • n=5 Participants	13.6 years STANDARD_DEVIATION 9.8 • n=7 Participants	12.9 years STANDARD_DEVIATION 9.5 • n=5 Participants
Number of prior hospitalizations for a mood episode	3.5 Prior hospitalization for mood episode STANDARD_DEVIATION 3.9 • n=5 Participants	3.5 Prior hospitalization for mood episode STANDARD_DEVIATION 4.1 • n=7 Participants	3.5 Prior hospitalization for mood episode STANDARD_DEVIATION 4.0 • n=5 Participants
Young-Mania Rating Scale (YMRS) Total Score	2.9 Scores on a scale STANDARD_DEVIATION 3.5 • n=5 Participants	2.6 Scores on a scale STANDARD_DEVIATION 3.0 • n=7 Participants	2.8 Scores on a scale STANDARD_DEVIATION 3.3 • n=5 Participants
Montgomery Asberg Depression Rating Scale (MADRS) Total Score	3.0 Scores on a scale STANDARD_DEVIATION 3.4 • n=5 Participants	2.4 Scores on a scale STANDARD_DEVIATION 3.4 • n=7 Participants	2.7 Scores on a scale STANDARD_DEVIATION 3.4 • n=5 Participants
Clinical Global Impressions - Bipolar Version Severity (CGI-BP-S) - Mania	1.5 Scores on a scale STANDARD_DEVIATION 0.7 • n=5 Participants	1.4 Scores on a scale STANDARD_DEVIATION 0.6 • n=7 Participants	1.5 Scores on a scale STANDARD_DEVIATION 0.7 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52).

Population: All randomized subjects who received at least one injection of investigational medicinal product (IMP) and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified intent-to-treat (ITT) population.

This endpoint was defined as meeting any of the following criteria:

1. Hospitalization for any mood episode OR

2. Any of the following:

1. YMRS total score ≥ 15 OR

2. MADRS total score ≥ 15 OR

3. CGI-BP-S score > 4 (overall score) OR

3. SAE of worsening disease (bipolar I disorder) OR

4. Discontinuation due to lack of efficacy or discontinuation due to an AE of worsening disease OR

5. Clinical worsening with the need for treatment of symptoms of an underlying mood disorder by addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, or increase greater than the allowed benzodiazepine doses, or

6. Active suicidality, which is defined as a score of 4 or more on the MADRS item 10 OR an answer of "yes" on question 4 or 5 on the C-SSRS.

The time to event is presented in the following table.

Outcome measures

Measure	Aripiprazole IM Depot n=132 Participants Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Placebo n=133 Participants Subjects received placebo intramuscularly up to 52 weeks.
Time From Randomization to Recurrence of Any Mood Episode During Double-bind Placebo-controlled Phase.	NA Days Here NA means values which were not estimable. The values for median and its 95% confidence interval of time to recurrence were not estimable due to the number of subjects with event was low.	308 Days Interval 178.0 to Here NA means values which were not estimable. The upper limit of 95% confidence interval of time to recurrence was not estimable in Placebo arm due to the number of subjects with event was low.

SECONDARY outcome

Timeframe: Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52).

Population: All randomized subjects who received at least one injection of IMP and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified ITT population.

To assess the proportion of subjects who met criteria for recurrence of any mood episode (manic, mixed or depressive). Hierarchical procedure was used to preserve the overall Type I error at 0.05.

Outcome measures

Measure	Aripiprazole IM Depot n=132 Participants Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Placebo n=133 Participants Subjects received placebo intramuscularly up to 52 weeks.
Number of Subjects Meeting Criteria for Recurrence of Any Mood Episode.	35 Participants	68 Participants

SECONDARY outcome

Timeframe: Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52).

Population: All randomized subjects who received at least one injection of IMP and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified ITT population.

CGI-BP-S assessed the subject's severity of Illness (mania) based on a 7-point scale ranging from 1 (normal/ not ill at all) to 7 (very severely ill).

Outcome measures

Measure	Aripiprazole IM Depot n=131 Participants Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Placebo n=133 Participants Subjects received placebo intramuscularly up to 52 weeks.
Mean Change From Randomization to Endpoint in the CGI-BP-S (Mania) Score.	-0.16 Units on a scale Standard Error 0.058	0.27 Units on a scale Standard Error 0.126

SECONDARY outcome

Timeframe: Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52).

Population: All randomized subjects who received at least one injection of IMP and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified ITT population.

Analysis of time from randomization to recurrence defined by hospitalization for a mood episode (Double-blind, Placebo-controlled Phase efficacy sample).

Time to recurrence is presented in the following table.

Outcome measures

Measure	Aripiprazole IM Depot n=132 Participants Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Placebo n=133 Participants Subjects received placebo intramuscularly up to 52 weeks.
Time From Randomization to Recurrence Defined by Hospitalization for a Mood Episode.	NA Days Here NA means values which were not estimable. The values for median and its 95% confidence interval of time to recurrence were not estimable due to the number of subjects with event was low.	NA Days Here NA means values which were not estimable. The values for median and its 95% confidence interval of time to recurrence were not estimable in Placebo arm due to the number of subjects with event was low.

Adverse Events

Conversion Phase.

Serious events: 32 serious events

Other events: 180 other events

Deaths: 0 deaths

Oral Aripiprazole Stabilization Phase.

Serious events: 35 serious events

Other events: 196 other events

Deaths: 1 deaths

IM Depot Stabilization Phase.

Serious events: 36 serious events

Other events: 194 other events

Deaths: 0 deaths

Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase.

Serious events: 10 serious events

Other events: 66 other events

Deaths: 1 deaths

Placebo-Double-blind, Placebo-controlled Phase.

Serious events: 25 serious events

Other events: 62 other events

Deaths: 0 deaths

Serious adverse events

Measure	Conversion Phase. n=459 participants at risk During the Oral Conversion Phase, subjects were cross-titrated from other antipsychotics to oral non-generic aripiprazole monotherapy. Received Oral aripiprazole at a target starting dose of 15 mg/day.	Oral Aripiprazole Stabilization Phase. n=614 participants at risk Subjects received oral aripiprazole dose ranging from 15 mg to 30 mg daily.	IM Depot Stabilization Phase. n=425 participants at risk During the depot stabilization phase, subjects were stabilized on aripiprazole depot.	Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase. n=132 participants at risk Subjects received IM depot aripiprazole 400 mg or 300 mg, once a month injection.	Placebo-Double-blind, Placebo-controlled Phase. n=133 participants at risk Subjects received IM Depot Placebo, once a month injection.
Vascular disorders Thrombosis	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Injury, poisoning and procedural complications Radius fracture	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.75% 1/133 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.16% 1/614 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Injury, poisoning and procedural complications Head injury	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Cardiac disorders Atrial Fibrillation	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Cardiac disorders Acute myocardial infarction	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Cardiac disorders Myocardial infarction	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.16% 1/614 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Respiratory, thoracic and mediastinal disorders Asthma	0.22% 1/459 • Number of events 2 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Nervous system disorders Akathisia	0.65% 3/459 • Number of events 3 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.16% 1/614 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Nervous system disorders Brain injury	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Nervous system disorders Transient ischaemic attack	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Nervous system disorders Radiculopathy	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Nervous system disorders Tremor	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Affect lability	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Affective disorder	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.75% 1/133 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Aggression	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.75% 1/133 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Bipolar disorder	1.3% 6/459 • Number of events 6 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.33% 2/614 • Number of events 2 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	2.3% 3/133 • Number of events 3 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Bipolar I disorder	0.87% 4/459 • Number of events 4 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.16% 1/614 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.94% 4/425 • Number of events 4 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	1.5% 2/132 • Number of events 2 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	2.3% 3/133 • Number of events 3 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Hypomania	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Major depression	0.22% 1/459 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.16% 1/614 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	1.5% 2/133 • Number of events 2 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Mania	2.8% 13/459 • Number of events 14 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	2.8% 17/614 • Number of events 17 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	1.6% 7/425 • Number of events 7 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	1.5% 2/132 • Number of events 2 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	7.5% 10/133 • Number of events 10 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Suicide attempt	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.75% 1/133 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Anxiety	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Depressed mood	0.44% 2/459 • Number of events 2 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.16% 1/614 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Depression	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.65% 4/614 • Number of events 4 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	1.9% 8/425 • Number of events 8 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Depressive symptom	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.33% 2/614 • Number of events 2 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Insomnia	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.16% 1/614 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Suicidal ideation	0.44% 2/459 • Number of events 2 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.49% 3/614 • Number of events 3 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.71% 3/425 • Number of events 3 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Gastrointestinal disorders Colitis ulcerative	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.75% 1/133 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.76% 1/132 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Gastrointestinal disorders Abdominal pain	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Gastrointestinal disorders Food poisoning	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.16% 1/614 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Hepatobiliary disorders Cholestasis	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.16% 1/614 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Reproductive system and breast disorders Pelvic adhesions	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.75% 1/133 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Infections and infestations Pneumonia	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.75% 1/133 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Infections and infestations Pyelonephritis	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Infections and infestations Sepsis	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Infections and infestations Vulval abscess	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Renal and urinary disorders Acute Kidney Injury	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Renal and urinary disorders Nephrolithiasis	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Renal and urinary disorders Renal Tubular Necrosis	0.00% 0/459 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.24% 1/425 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Cardiac disorders Angina pectoris	0.22% 1/459 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Nervous system disorders Cerebrovascular accident	0.22% 1/459 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Nervous system disorders Extrapyramidal disorder	0.22% 1/459 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Agitation	0.22% 1/459 • Number of events 1 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/614 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/425 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/132 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	0.00% 0/133 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.

Other adverse events

Measure	Conversion Phase. n=459 participants at risk During the Oral Conversion Phase, subjects were cross-titrated from other antipsychotics to oral non-generic aripiprazole monotherapy. Received Oral aripiprazole at a target starting dose of 15 mg/day.	Oral Aripiprazole Stabilization Phase. n=614 participants at risk Subjects received oral aripiprazole dose ranging from 15 mg to 30 mg daily.	IM Depot Stabilization Phase. n=425 participants at risk During the depot stabilization phase, subjects were stabilized on aripiprazole depot.	Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase. n=132 participants at risk Subjects received IM depot aripiprazole 400 mg or 300 mg, once a month injection.	Placebo-Double-blind, Placebo-controlled Phase. n=133 participants at risk Subjects received IM Depot Placebo, once a month injection.
Investigations Weight increased	2.8% 13/459 • Number of events 13 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	3.6% 22/614 • Number of events 23 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	11.1% 47/425 • Number of events 47 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	23.5% 31/132 • Number of events 31 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	18.0% 24/133 • Number of events 25 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Nervous system disorders Akathisia	16.6% 76/459 • Number of events 84 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	15.3% 94/614 • Number of events 99 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	17.4% 74/425 • Number of events 82 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	20.5% 27/132 • Number of events 32 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	12.8% 17/133 • Number of events 20 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Nervous system disorders Headache	6.8% 31/459 • Number of events 64 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	2.1% 13/614 • Number of events 21 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	2.8% 12/425 • Number of events 12 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	3.0% 4/132 • Number of events 4 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	6.8% 9/133 • Number of events 10 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
General disorders Fatigue	3.1% 14/459 • Number of events 14 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	3.1% 19/614 • Number of events 19 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	5.2% 22/425 • Number of events 25 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	3.0% 4/132 • Number of events 4 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	3.8% 5/133 • Number of events 6 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Anxiety	4.1% 19/459 • Number of events 20 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	3.9% 24/614 • Number of events 24 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	7.1% 30/425 • Number of events 36 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	6.8% 9/132 • Number of events 9 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	4.5% 6/133 • Number of events 6 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Insomnia	7.6% 35/459 • Number of events 37 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	5.5% 34/614 • Number of events 35 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	9.6% 41/425 • Number of events 47 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	7.6% 10/132 • Number of events 11 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	7.5% 10/133 • Number of events 12 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Psychiatric disorders Restlessness	7.8% 36/459 • Number of events 45 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	5.2% 32/614 • Number of events 34 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	5.6% 24/425 • Number of events 25 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	4.5% 6/132 • Number of events 6 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	3.8% 5/133 • Number of events 5 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Infections and infestations Nasopharyngitis	3.9% 18/459 • Number of events 18 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	1.8% 11/614 • Number of events 11 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	5.2% 22/425 • Number of events 30 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	7.6% 10/132 • Number of events 13 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.	9.8% 13/133 • Number of events 29 • Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study). Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.

Additional Information

Joan Amatniek, Senior Director, Global Clinical Development

Otsuka Pharmaceutical Development & Commercialization, Inc.

Phone: (609) 512-4464

Email: joan.amatniek@otsuka-us.com

Results disclosure agreements

• Principal investigator is a sponsor employee Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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