Trial Outcomes & Findings for 12 Week Study of the Safety/Efficacy of Asenapine When Added to Lithium/Valproate in the Treatment of Bipolar Disorder (A7501008 / P05844 / MK-8274-017) (NCT NCT00145470)

Results Overview

The least squares mean change from baseline in Y-MRS score at day 21 was assessed. The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a last observation carried forward (LOCF) analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

326 participants

Primary outcome timeframe

Baseline and Day 21

Results posted on

2024-05-21

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Overall Study STARTED	167	159
Overall Study Treated	166	158
Overall Study COMPLETED	55	61
Overall Study NOT COMPLETED	112	98

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Overall Study Adverse Event	19	25
Overall Study Lack of Efficacy	27	13
Overall Study Withdrawal by Subject	36	34
Overall Study Lost to Follow-up	21	17
Overall Study Reason Not Reported	9	9

Baseline Characteristics

12 Week Study of the Safety/Efficacy of Asenapine When Added to Lithium/Valproate in the Treatment of Bipolar Disorder (A7501008 / P05844 / MK-8274-017)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=166 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=158 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.	Total n=324 Participants Total of all reporting groups
Age, Continuous	39.0 Years STANDARD_DEVIATION 11.97 • n=5 Participants	39.6 Years STANDARD_DEVIATION 11.71 • n=7 Participants	39.3 Years STANDARD_DEVIATION 11.83 • n=5 Participants
Sex: Female, Male Female	69 Participants n=5 Participants	68 Participants n=7 Participants	137 Participants n=5 Participants
Sex: Female, Male Male	97 Participants n=5 Participants	90 Participants n=7 Participants	187 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Day 21

Population: Includes all randomized participants receiving ≥1 dose of study treatment, having ≥1 post-dose Y-MRS assessment.

The least squares mean change from baseline in Y-MRS score at day 21 was assessed. The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a last observation carried forward (LOCF) analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Score at Day 21 Baseline	28.2 Score on a Scale Standard Error 0.45	27.9 Score on a Scale Standard Error 0.46
Least Squares Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Score at Day 21 Change from Baseline at Day 21	-7.9 Score on a Scale Standard Error 0.76	-10.3 Score on a Scale Standard Error 0.79

SECONDARY outcome

Timeframe: Up to Day 114

Population: Includes all randomized participants receiving ≥1 dose of study treatment.

The number of participants experiencing an AE was assessed. An AE is any untoward or unfavorable medical occurrence in a participant, including any abnormal sign, symptom, or disease, temporally associated with the use of the investigational product, whether or not considered related to the investigational product.

Outcome measures

Outcome measures
Measure	Placebo n=166 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=158 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Number of Participants Experiencing an Adverse Event (AE)	114 Participants	116 Participants

SECONDARY outcome

Timeframe: Up to Day 84

Population: Includes all randomized participants receiving ≥1 dose of study treatment.

The number of participants discontinuing study treatment due to an AE was assessed. An AE is any untoward or unfavorable medical occurrence in a participant, including any abnormal sign, symptom, or disease, temporally associated with the use of the investigational product, whether or not considered related to the investigational product.

Outcome measures

Outcome measures
Measure	Placebo n=166 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=158 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Number of Participants Discontinuing Study Treatment Due to an AE	18 Participants	25 Participants

SECONDARY outcome

Timeframe: Baseline and Day 42

Population: Includes all randomized participants receiving ≥1 dose of study treatment, having ≥1 post-dose Y-MRS assessment.

The least squares mean change from baseline in Y-MRS score at day 42 was assessed. The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Score at Day 42 Baseline	28.2 Score on a Scale Standard Error 0.45	27.9 Score on a Scale Standard Error 0.46
Least Squares Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Score at Day 42 Change from Baseline at Day 42	-8.7 Score on a Scale Standard Error 0.84	-11.4 Score on a Scale Standard Error 0.88

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Includes all randomized participants receiving ≥1 dose of study treatment, having ≥1 post-dose Y-MRS assessment.

The least squares mean change from baseline in Y-MRS score at day 84 was assessed. The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Score at Day 84 Baseline	28.2 Score on a Scale Standard Error 0.45	27.9 Score on a Scale Standard Error 0.46
Least Squares Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Score at Day 84 Change from Baseline at Day 84	-9.3 Score on a Scale Standard Error 0.89	-12.7 Score on a Scale Standard Error 0.92

SECONDARY outcome

Timeframe: Up to Day 84

Population: Includes all randomized participants receiving ≥1 dose of study treatment, having ≥1 post-dose Y-MRS assessment.

The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. At pre-specified time points, the number of participants achieving Y-MRS responder status was assessed, defined as the number of participants with a 50% decrease from baseline in Y-MRS total score. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Responder Status Day 3	10 Participants	13 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Responder Status Day 7	25 Participants	22 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Responder Status Day 14	34 Participants	46 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Responder Status Day 21	44 Participants	53 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Responder Status Day 42	52 Participants	67 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Responder Status Day 63	52 Participants	66 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Responder Status Day 84	56 Participants	74 Participants

SECONDARY outcome

Timeframe: Up to Day 84

Population: Includes all randomized participants receiving ≥1 dose of study treatment, having ≥1 post-dose Y-MRS assessment.

The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. At pre-specified time points, the number of participants achieving Y-MRS remitter status was assessed, defined as the number of participants with a Y-MRS total score of 12 or lower. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Remitter Status Day 7	21 Participants	19 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Remitter Status Day 14	32 Participants	42 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Remitter Status Day 3	8 Participants	11 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Remitter Status Day 21	35 Participants	52 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Remitter Status Day 42	46 Participants	64 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Remitter Status Day 63	46 Participants	63 Participants
Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Remitter Status Day 84	49 Participants	67 Participants

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in CGI-BP severity of mania score at day 21 was assessed. The CGI-BP severity of mania scale is a clinician-rated scale for assessing the severity of manic symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Mania Score at Day 21 Baseline	4.5 Score on a Scale Standard Error 0.06	4.5 Score on a Scale Standard Error 0.07
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Mania Score at Day 21 Change from Baseline at Day 21	-0.8 Score on a Scale Standard Error 0.09	-1.1 Score on a Scale Standard Error 0.10

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in CGI-BP severity of mania score at day 84 was assessed. The CGI-BP severity of mania scale is a clinician-rated scale for assessing the severity of manic symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Mania Score at Day 84 Baseline	4.5 Score on a Scale Standard Error 0.06	4.5 Score on a Scale Standard Error 0.07
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Mania Score at Day 84 Change from Baseline at Day 84	-1.0 Score on a Scale Standard Error 0.11	-1.5 Score on a Scale Standard Error 0.12

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in CGI-BP severity of depression score at day 21 was assessed. The CGI-BP severity of depression scale is a clinician-rated scale for assessing the severity of depressive symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Depression Score at Day 21 Baseline	2.3 Score on a Scale Standard Error 0.08	2.3 Score on a Scale Standard Error 0.08
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Depression Score at Day 21 Change from Baseline at Day 21	-0.1 Score on a Scale Standard Error 0.07	-0.2 Score on a Scale Standard Error 0.08

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in CGI-BP severity of depression score at day 84 was assessed. The CGI-BP severity of depression scale is a clinician-rated scale for assessing the severity of depressive symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Depression Score at Day 84 Baseline	2.3 Score on a Scale Standard Error 0.08	2.3 Score on a Scale Standard Error 0.08
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Depression Score at Day 84 Change from Baseline at Day 84	-0.1 Score on a Scale Standard Error 0.09	-0.1 Score on a Scale Standard Error 0.09

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in CGI-BP severity of severity of overall bipolar illness score at day 21 was assessed. The CGI-BP severity of overall bipolar illness scale is a clinician-rated scale for assessing the severity of overall symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Overall Bipolar Illness Score at Day 21 Baseline	4.6 Score on a Scale Standard Error 0.05	4.6 Score on a Scale Standard Error 0.06
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Overall Bipolar Illness Score at Day 21 Change from Baseline at Day 21	-0.7 Score on a Scale Standard Error 0.09	-1.0 Score on a Scale Standard Error 0.09

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in CGI-BP severity of severity of overall bipolar illness score at day 84 was assessed. The CGI-BP severity of overall bipolar illness scale is a clinician-rated scale for assessing the severity of overall symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Overall Bipolar Illness Score at Day 84 Baseline	4.6 Score on a Scale Standard Error 0.05	4.6 Score on a Scale Standard Error 0.06
Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Overall Bipolar Illness Score at Day 84 Change from Baseline at Day 84	-0.8 Score on a Scale Standard Error 0.11	-1.2 Score on a Scale Standard Error 0.11

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in MADRS score at day 21 was assessed. The MARDS is a clinician-rated scale for assessing the severity of symptoms of depression, composed of 10 items. For the 10 items, scores range from 0 (symptoms absent) to 6 (severe). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater severity of depression. Further, decreases in depression severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Score at Day 21 Baseline	11.4 Score on a Scale Standard Error 0.48	11.3 Score on a Scale Standard Error 0.50
Least Squares Mean Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Score at Day 21 Change from Baseline at Day 21	-2.2 Score on a Scale Standard Error 0.51	-2.9 Score on a Scale Standard Error 0.54

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in MADRS score at day 84 was assessed. The MARDS is a clinician-rated scale for assessing the severity of symptoms of depression, composed of 10 items. For the 10 items, scores range from 0 (symptoms absent) to 6 (severe). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater severity of depression. Further, decreases in depression severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Score at Day 84 Change from Baseline at Day 84	-1.7 Score on a Scale Standard Error 0.64	-1.6 Score on a Scale Standard Error 0.68
Least Squares Mean Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Score at Day 84 Baseline	11.4 Score on a Scale Standard Error 0.48	11.3 Score on a Scale Standard Error 0.50

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in PANSS score at day 21 was assessed. The PANSS assesses the severity of schizophrenia symptoms through a clinician-rated inventory of 30 items organized in 3 subscales: 1) positive subscale (7 items); 2) negative subscale (7 items); and 3) general psychopathology subscale (16 items). For each item, symptoms are scored from 1 (absent) to 7 (extreme) and add to a total PANSS score (range: 30-210). Higher scores reflect more severe symptoms of schizophrenia. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Score at Day 21 Baseline	67.1 Score on a Scale Standard Error 0.95	65.1 Score on a Scale Standard Error 0.99
Least Squares Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Score at Day 21 Change from Baseline at Day 21	-5.4 Score on a Scale Standard Error 1.09	-7.2 Score on a Scale Standard Error 1.16

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in PANSS score at day 84 was assessed. The PANSS assesses the severity of schizophrenia symptoms through a clinician-rated inventory of 30 items organized in 3 subscales: 1) positive subscale (7 items); 2) negative subscale (7 items); and 3) general psychopathology subscale (16 items). For each item, symptoms are scored from 1 (absent) to 7 (extreme) and add to a total PANSS score (range: 30-210). Higher scores reflect more severe symptoms of schizophrenia. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Score at Day 84 Baseline	67.1 Score on a Scale Standard Error 0.95	65.1 Score on a Scale Standard Error 0.99
Least Squares Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Score at Day 84 Change from Baseline at Day 84	-6.0 Score on a Scale Standard Error 1.32	-7.4 Score on a Scale Standard Error 1.39

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in HAM-A score at day 21 was assessed. The HAM-A is a clinician-rated instrument for assessing anxiety symptoms, composed of 14 items. For the 14 items, scores range from 0 (not present) to 4 (severe). Scores for individual items add to a total score (range: 0-56), with higher scores indicating greater severity of anxiety. Further, decreases in anxiety severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Score at Day 21 Baseline	9.3 Score on a Scale Standard Error 0.42	8.8 Score on a Scale Standard Error 0.43
Least Squares Mean Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Score at Day 21 Change from Baseline at Day 21	-2.1 Score on a Scale Standard Error 0.39	-2.4 Score on a Scale Standard Error 0.41

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in HAM-A score at day 84 was assessed. The HAM-A is a clinician-rated instrument for assessing anxiety symptoms, composed of 14 items. For the 14 items, scores range from 0 (not present) to 4 (severe). Scores for individual items add to a total score (range: 0-56), with higher scores indicating greater severity of anxiety. Further, decreases in anxiety severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Score at Day 84 Baseline	9.3 Score on a Scale Standard Error 0.42	8.8 Score on a Scale Standard Error 0.43
Least Squares Mean Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Score at Day 84 Change from Baseline at Day 84	-2.1 Score on a Scale Standard Error 0.44	-2.1 Score on a Scale Standard Error 0.47

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in ISST-Modified score at day 21 was assessed. The ISST-Modified is a clinician-rated scale for rating suicidality, composed of 12 items (score range: 0-2). Scores for the 12 items add to a total ISST-Modified score (range: 0-24), with higher scores indicating increased severity of suicidal thinking. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in InterSePT Scale for Suicidal Thinking - Modified Version (ISST-Modified) Score at Day 21 Baseline	0.6 Score on a Scale Standard Error 0.14	0.4 Score on a Scale Standard Error 0.14
Least Squares Mean Change From Baseline in InterSePT Scale for Suicidal Thinking - Modified Version (ISST-Modified) Score at Day 21 Change from Baseline at Day 21	-0.0 Score on a Scale Standard Error 0.12	0.0 Score on a Scale Standard Error 0.13

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in ISST-Modified score at day 84 was assessed. The ISST-Modified is a clinician-rated scale for rating suicidality, composed of 12 items (score range: 0-2). Scores for the 12 items add to a total ISST-Modified score (range: 0-24), with higher scores indicating increased severity of suicidal thinking. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in InterSePT Scale for Suicidal Thinking - Modified Version (ISST-Modified) Score at Day 84 Baseline	0.6 Score on a Scale Standard Error 0.14	0.4 Score on a Scale Standard Error 0.14
Least Squares Mean Change From Baseline in InterSePT Scale for Suicidal Thinking - Modified Version (ISST-Modified) Score at Day 84 Change from Baseline at Day 84	-0.0 Score on a Scale Standard Error 0.15	0.3 Score on a Scale Standard Error 0.16

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

Nine neurocognitive tests with higher scores indicating better performance: 1. Verbal Memory test: recognize/remember/retrieve words (range 0-60) 2. Visual Memory test: recognize/remember/retrieve geometric figures (range 0-60) 3. Speed of Processing: recognize/process information. No min./max. score. Normative average (NA); correct answers: 65.1, avg. errors: 1.37 4. Social Acuity/Perception of Emotions test: perceive/respond to emotional cues. Min. score: -64/Max. score: 16 5. Reasoning: reason/respond to non-verbal, visual-abstract stimuli; scores range: -15 to 15 6. Executive Function: recognize rules/categories/decision making. No min./max. score. NA correct answers: 55.01/avg. errors: 5.28 7. Working Memory/Continuous Performance Task (CPT): perceive/attend to symbols. Min. score: -45/Max. score: 15 8. Sustained Attention: direct/focus on specific stimuli: Max. score (raw score); 45; Min. score: -170 9. Composite Memory: working+verbal+visual memory, Range 0-135.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Composite Memory - Baseline	81.6 Score on a Scale Standard Deviation 15.59	82.8 Score on a Scale Standard Deviation 13.48
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Sustained Attention - CFB at Day 21	0.3 Score on a Scale Standard Deviation 17.23	-0.8 Score on a Scale Standard Deviation 13.91
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Verbal Memory - Baseline	43.6 Score on a Scale Standard Deviation 9.01	44.6 Score on a Scale Standard Deviation 8.36
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Visual Memory - Baseline	38.0 Score on a Scale Standard Deviation 7.89	38.2 Score on a Scale Standard Deviation 6.51
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Processing Speed - Baseline	34.3 Score on a Scale Standard Deviation 25.85	39.5 Score on a Scale Standard Deviation 14.28
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Social Acuity - Baseline	2.8 Score on a Scale Standard Deviation 6.90	2.7 Score on a Scale Standard Deviation 6.67
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Reasoning - Baseline	2.1 Score on a Scale Standard Deviation 5.54	1.3 Score on a Scale Standard Deviation 5.07
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Executive Functioning - Baseline	17.6 Score on a Scale Standard Deviation 26.06	16.9 Score on a Scale Standard Deviation 25.59
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Working Memory - Baseline	2.9 Score on a Scale Standard Deviation 6.56	2.9 Score on a Scale Standard Deviation 5.72
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Sustained Attention - Baseline	14.0 Score on a Scale Standard Deviation 16.83	13.5 Score on a Scale Standard Deviation 14.64
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Verbal Memory - CFB at Day 21	-0.8 Score on a Scale Standard Deviation 7.66	0.8 Score on a Scale Standard Deviation 8.54
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Visual Memory - CFB at Day 21	-0.3 Score on a Scale Standard Deviation 8.08	-0.4 Score on a Scale Standard Deviation 7.45
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Processing Speed - CFB at Day 21	3.8 Score on a Scale Standard Deviation 16.82	4.2 Score on a Scale Standard Deviation 11.97
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Social Acuity - CFB at Day 21	1.0 Score on a Scale Standard Deviation 4.76	0.3 Score on a Scale Standard Deviation 5.46
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Reasoning - CFB at Day 21	0.3 Score on a Scale Standard Deviation 4.39	0.7 Score on a Scale Standard Deviation 4.33
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Executive Functioning - CFB at Day 21	4.4 Score on a Scale Standard Deviation 16.55	10.1 Score on a Scale Standard Deviation 18.45
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Working Memory - CFB at Day 21	0.2 Score on a Scale Standard Deviation 7.16	-0.4 Score on a Scale Standard Deviation 5.83
Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Composite Memory - CFB at Day 21	-1.1 Score on a Scale Standard Deviation 13.65	0.5 Score on a Scale Standard Deviation 13.43

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

Nine neurocognitive tests with higher scores indicating better performance: 1. Verbal Memory test: recognize/remember/retrieve words (range 0-60) 2. Visual Memory test: recognize/remember/retrieve geometric figures (range 0-60) 3. Speed of Processing: recognize/process information. No min./max. score. Normative average (NA); correct answers: 65.1, avg. errors: 1.37 4. Social Acuity/Perception of Emotions test: perceive/respond to emotional cues. Min. score: -64/Max. score: 16 5. Reasoning: reason/respond to non-verbal, visual-abstract stimuli; scores range: -15 to 15 6. Executive Function: recognize rules/categories/decision making. No min./max. score. NA correct answers: 55.01/avg. errors: 5.28 7. Working Memory/Continuous Performance Task (CPT): perceive/attend to symbols. Min. score: -45/Max. score: 15 8. Sustained Attention: direct/focus on specific stimuli: Max. score (raw score); 45; Min. score: -170 9. Composite Memory: working+verbal+visual memory, Range 0-135.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Composite Memory - CFB at Day 84	-0.0 Score on a Scale Standard Deviation 14.16	-0.7 Score on a Scale Standard Deviation 13.63
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Processing Speed - Baseline	34.3 Score on a Scale Standard Deviation 25.85	39.5 Score on a Scale Standard Deviation 14.28
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Social Acuity - Baseline	2.8 Score on a Scale Standard Deviation 6.90	2.7 Score on a Scale Standard Deviation 6.67
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Reasoning - Baseline	2.1 Score on a Scale Standard Deviation 5.54	1.3 Score on a Scale Standard Deviation 5.07
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Executive Functioning - Baseline	17.6 Score on a Scale Standard Deviation 26.06	16.9 Score on a Scale Standard Deviation 25.59
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Working Memory - Baseline	2.9 Score on a Scale Standard Deviation 6.56	2.9 Score on a Scale Standard Deviation 5.72
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Sustained Attention - Baseline	14.0 Score on a Scale Standard Deviation 16.83	13.5 Score on a Scale Standard Deviation 14.64
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Composite Memory - Baseline	81.6 Score on a Scale Standard Deviation 15.59	82.8 Score on a Scale Standard Deviation 13.48
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Verbal Memory - CFB at Day 84	-0.0 Score on a Scale Standard Deviation 7.97	-0.3 Score on a Scale Standard Deviation 8.63
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Visual Memory - CFB at Day 84	0.0 Score on a Scale Standard Deviation 7.47	-0.5 Score on a Scale Standard Deviation 7.19
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Processing Speed - CFB at Day 84	3.6 Score on a Scale Standard Deviation 16.31	-1.4 Score on a Scale Standard Deviation 61.50
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Social Acuity - CFB at Day 84	0.7 Score on a Scale Standard Deviation 5.04	0.9 Score on a Scale Standard Deviation 5.70
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Reasoning - CFB at Day 84	-0.1 Score on a Scale Standard Deviation 4.81	1.0 Score on a Scale Standard Deviation 4.88
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Executive Functioning - CFB at Day 84	3.9 Score on a Scale Standard Deviation 19.37	10.2 Score on a Scale Standard Deviation 19.97
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Working Memory - CFB at Day 84	-0.2 Score on a Scale Standard Deviation 7.06	-0.4 Score on a Scale Standard Deviation 5.98
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Sustained Attention - CFB at Day 84	-0.5 Score on a Scale Standard Deviation 18.17	0.5 Score on a Scale Standard Deviation 15.11
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Verbal Memory - Baseline	43.6 Score on a Scale Standard Deviation 9.01	44.6 Score on a Scale Standard Deviation 8.36
Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery Visual Memory - Baseline	38.0 Score on a Scale Standard Deviation 7.89	38.2 Score on a Scale Standard Deviation 6.51

SECONDARY outcome

Timeframe: Day 84

Population: Per protocol, the analysis population for this endpoint includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment.

The percentage of participants determined to be ready to discharge at day 84 was estimated (Kaplan-Meier), using the readiness to discharge questionnaire (RDQ). The RDQ is clinician-rated scale to assess readiness for discharge, composed of 7 items. Of the 7 items, only the first 5 items were utilized: 1. Not actively suicidal/homicidal; 2. Adequate control over aggression and impulsivity; 3. Able to carry out basic activities of daily life; 4. Able to take medicine independently; and 5. Delusions and hallucinations do not significantly interfere with functioning. For the 5 items, the clinician provided a response (Strongly Disagree; Disagree; Agree; or Strongly Agree) at each pre-specified visit. The first visit at which the responses to the first 5 items on the RDQ are "Strongly Agree" or "Agree," was defined as the point a participant was ready to discharge.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Percentage of Participants Determined to be Ready to Discharge at Day 84 (Kaplan-Meier Estimation)	74.1 Percentage of Participants Interval 64.0 to 84.2	89.7 Percentage of Participants Interval 75.0 to 100.0

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in Q-LES-Q score at day 21 was assessed. The Q-LES-Q is a participant-completed questionnaire to assess general satisfaction with activities such as physical health, mood, work, household tasks, social and family relationships, leisure activities, and overall satisfaction, composed of 16 items. For each of the 16 items, scores range from 0 (very poor) to 5 (very good), with scores for all items adding to a total score (range: 0-80); higher scores indicate better quality of life. Further, decreases in quality of life are reflected by a negative change from baseline.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), General Activities Subscale Score at Day 21 Baseline	61.0 Score on a Scale Standard Error 1.53	61.3 Score on a Scale Standard Error 1.58
Least Squares Mean Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), General Activities Subscale Score at Day 21 Change from Baseline at Day 21	3.9 Score on a Scale Standard Error 1.63	4.6 Score on a Scale Standard Error 1.50

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

The least squares mean change from baseline in Q-LES-Q score at day 84 was assessed. The Q-LES-Q is a participant-completed questionnaire to assess general satisfaction with activities such as physical health, mood, work, household tasks, social and family relationships, leisure activities, and overall satisfaction, composed of 16 items. For each of the 16 items, scores range from 0 (very poor) to 5 (very good), with scores for all items adding to a total score (range: 0-80); higher scores indicate better quality of life. Further, decreases in quality of life are reflected by a negative change from baseline.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), General Activities Subscale Score at Day 84 Baseline	61.0 Score on a Scale Standard Error 1.53	61.3 Score on a Scale Standard Error 1.58
Least Squares Mean Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), General Activities Subscale Score at Day 84 Change from Baseline at Day 84	-3.7 Score on a Scale Standard Error 3.10	-1.1 Score on a Scale Standard Error 2.60

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

Least squares mean change from baseline at day 21 in quality of life was assessed, as determined by SF-36v2. The SF-36v2 is a self-administered questionnaire, measuring 8 domains: Physical Functioning (PF); Role-Physical (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role-Emotional (RE); and Mental Health (MH). These 8 concepts are further organized into a Physical Component Summary (PCS; composite of PF, RP, BP, and GH) and a Mental Component Summary (MCS; composite of VT, SF, RE, and MH). The SF-36v2 domains and composite summaries were scored using a norm-based scoring approach, yielding a mean of 50 and standard deviation of 10 based on the norms from the 1998 SF-36 United States general population norms. For the PCS and MCS, scores range from 0 to 100, with higher scores indicating better quality of life. Further, decreases in quality of life (by PCS and MCS) are reflected by a negative change from baseline.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline at Day 21 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) PCS - Baseline	50.49 Score on a Scale Standard Error 0.728	51.64 Score on a Scale Standard Error 0.739
Least Squares Mean Change From Baseline at Day 21 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) PCS - Change from Baseline at Day 21	-0.72 Score on a Scale Standard Error 0.929	-2.47 Score on a Scale Standard Error 0.848
Least Squares Mean Change From Baseline at Day 21 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) MCS - Baseline	40.83 Score on a Scale Standard Error 1.085	39.03 Score on a Scale Standard Error 1.100
Least Squares Mean Change From Baseline at Day 21 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) MCS - Change from Baseline at Day 21	2.29 Score on a Scale Standard Error 1.273	5.93 Score on a Scale Standard Error 1.174

SECONDARY outcome

Timeframe: Baseline and Day 21

Population: Per protocol, the overall analysis population includes all randomized participants receiving ≥1 dose of study treatment, with ≥1 post-dose Y-MRS assessment. For Baseline / Change from Baseline data, includes only participants of the overall analysis population with an observation at the time indicated for the respective endpoint.

Least squares mean change from baseline at day 84 in quality of life was assessed, as determined by SF-36v2. The SF-36v2 is a self-administered questionnaire, measuring 8 domains: Physical Functioning (PF); Role-Physical (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role-Emotional (RE); and Mental Health (MH). These 8 concepts are further organized into a Physical Component Summary (PCS; composite of PF, RP, BP, and GH) and a Mental Component Summary (MCS; composite of VT, SF, RE, and MH). The SF-36v2 domains and composite summaries were scored using a norm-based scoring approach, yielding a mean of 50 and standard deviation of 10 based on the norms from the 1998 SF-36 United States general population norms. For the PCS and MCS, scores range from 0 to 100, with higher scores indicating better quality of life. Further, decreases in quality of life (by PCS and MCS) are reflected by a negative change from baseline.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=155 Participants Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Least Squares Mean Change From Baseline at Day 84 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) PCS - Baseline	50.49 Score on a Scale Standard Error 0.728	51.64 Score on a Scale Standard Error 0.739
Least Squares Mean Change From Baseline at Day 84 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) PCS - Change from Baseline at Day 84	1.37 Score on a Scale Standard Error 1.238	-0.95 Score on a Scale Standard Error 1.079
Least Squares Mean Change From Baseline at Day 84 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) MCS - Baseline	40.83 Score on a Scale Standard Error 1.085	39.03 Score on a Scale Standard Error 1.100
Least Squares Mean Change From Baseline at Day 84 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) MCS - Change from Baseline at Day 84	-1.05 Score on a Scale Standard Error 2.278	2.49 Score on a Scale Standard Error 1.985

Adverse Events

Placebo

Serious events: 24 serious events

Other events: 76 other events

Deaths: 0 deaths

Asenapine

Serious events: 21 serious events

Other events: 91 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=166 participants at risk Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=158 participants at risk Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Gastrointestinal disorders Diarrhoea	7.2% 12/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	1.9% 3/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Gastrointestinal disorders Nausea	6.0% 10/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	6.3% 10/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Gastrointestinal disorders Hypoaesthesia Oral	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	5.7% 9/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Investigations Weight Increased	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	5.1% 8/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Nervous system disorders Headache	13.9% 23/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	13.9% 22/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Nervous system disorders Tremor	5.4% 9/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	4.4% 7/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Nervous system disorders Akathisia	5.4% 9/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	3.2% 5/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Nervous system disorders Sedation	6.0% 10/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	13.3% 21/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Nervous system disorders Somnolence	4.2% 7/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	11.4% 18/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Nervous system disorders Dizziness	3.0% 5/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	5.1% 8/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Agitation	5.4% 9/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	6.3% 10/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Insomnia	9.6% 16/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	12.7% 20/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Mania	5.4% 9/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	3.2% 5/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Except for compelling legal reasons, neither the sponsor nor the investigator will communicate to third parties any result of the clinical trial before the clinical trial report (CTR) has been released by the sponsor.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=166 participants at risk Participants received placebo on Days 1-84 as a fast-dissolving sublingual (SL) tablet, given twice daily (BID).	Asenapine n=158 participants at risk Participants received asenapine as a fast-dissolving SL tablet, BID. On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability.
Cardiac disorders Arteriosclerosis Coronary Artery	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.00% 0/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Cardiac disorders Cardiac Failure Congestive	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Infections and infestations Arthritis Bacterial	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.00% 0/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Infections and infestations Gastroenteritis Viral	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Infections and infestations Malaria	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.00% 0/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Injury, poisoning and procedural complications Accidental Overdose	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.00% 0/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Injury, poisoning and procedural complications Intentional Overdose	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Metabolism and nutrition disorders Diabetes Mellitus	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Alcoholism	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Bipolar I Disorder	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	1.9% 3/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Depression	1.8% 3/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	1.9% 3/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Depressive Symptom	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	1.3% 2/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Major Depression	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Mania	7.8% 13/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	5.1% 8/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Psychotic Disorder	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.00% 0/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Suicidal Ideation	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Psychiatric disorders Suicide Attempt	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.00% 0/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Renal and urinary disorders Nephrolithiasis	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Renal and urinary disorders Renal Failure	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Social circumstances Drug Abuser	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Nervous system disorders Dystonia	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Nervous system disorders Psychomotor Hyperactivity	0.60% 1/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.00% 0/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.
Nervous system disorders Transient Ischaemic Attack	0.00% 0/166 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.	0.63% 1/158 • Up to Day 114 Includes all participants receiving study treatment. Additionally, serious adverse events were coded using MedDRA 10, while other adverse events were coded using MedDRA 9.1.