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Clinical Trial Results:
Efficacy and Safety of 3-Week Fixed-Dose Asenapine Treatment in Pediatric Acute Manic or Mixed Episodes Associated with Bipolar I Disorder (Protocol No. P06107)

Summary
EudraCT number	2010-022647-38
Trial protocol	Outside EU/EEA
Global end of trial date	17 Sep 2013

Results information
Results version number	v1(current)
This version publication date	20 Apr 2016
First version publication date	24 Jun 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

P06107

ISRCTN number

US NCT number

NCT01244815

WHO universal trial number (UTN)

Other trial identifiers

Merck Registration number: MK-8274-038

Sponsor organisation name

Merck Sharp & Dohme Corp.

Sponsor organisation address

2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033

Public contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000228-PIP01-08

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

17 Sep 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Sep 2013

Was the trial ended prematurely?

Main objective of the trial

Efficacy and safety of asenapine for the treatment of bipolar I disorder (manic or mixed episodes) will be evaluated in participants between 10 and 17 years old, who are either hospitalized or non-hospitalized. In this 3-weeks, double-blind, parallel design trial, eligible participants will be randomized to receive one out of three fixed dose levels of asenapine, or placebo. Study primary hypothesis is that at least one asenapine dose is superior to placebo as measured by the change from baseline to Day 21 in Young Mania Rating Scale (Y-MRS) total score. Concurrent use of psychotropics is prohibited, except use of short-acting benzodiazepines and psychostimulants approved for treatment of attention deficit hyperactivity disorder (ADHD). Participants who complete the trial may be offered to continue treatment with asenapine for an extended period of time. Follow-up information on safety parameters will be collected in all participants within 30 days following treatment discontinuation.

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measure defined for this individual study was in place for the protection of trial subjects: For participants whose symptoms worsen or are not adequately controlled on assigned treatment, rescue medication may be administered during the trial in the following circumstances. For the control of agitation, anxiety, insomnia, restlessness, or akathisia and extrapyramidal symptoms (EPS) some benzodiazepines and EPS medications (i.e., anticholinergics) are allowed. Benadryl (diphenhydramine) and beta blockers are also permitted, provided that they are not taken within 8 hours of efficacy assessments.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Jun 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Russian Federation: 26

Country: Number of subjects enrolled

United States: 378

Worldwide total number of subjects

404

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

335

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 537 participants were screened to determine eligibility for entry into the trial, of which 133 were excluded and not randomized.

Period 1 title

Randomization through Start Treatment

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants receive placebo twice daily (BID) for 21 days.

Arm type

Placebo

Investigational medicinal product name

Placebo to match asenapine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Placebo tablets to match asenapine tablets, administered sublingually BID

Asenapine 2.5 mg BID

Arm description

Participants receive asenapine 2.5 mg BID for 21 days.

Arm type

Experimental

Investigational medicinal product name

asenapine

Investigational medicinal product code

Other name

SCH 900274, Saphris®

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Asenapine tablets, administered sublingually BID at one of three dose levels (2.5 mg, 5.0 mg, or 10.0 mg)

Asenapine 5.0 mg BID

Arm description

Participants receive asenapine 2.5 mg BID through Day 3. On Day 4 participants receive asenapine 2.5 mg in the morning and 5.0 mg in the evening. Participants receive asenapine 5.0 mg BID for the remainder of the 21-day treatment period.

Arm type

Experimental

Investigational medicinal product name

asenapine

Investigational medicinal product code

Other name

SCH 900274, Saphris®

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Asenapine tablets, administered sublingually BID at one of three dose levels (2.5 mg, 5.0 mg, or 10.0 mg)

Asenapine 10.0 mg BID

Arm description

Participants receive asenapine 2.5 mg BID through Day 3. On Day 4 participants receive asenapine 2.5 mg in the morning and 5.0 mg in the evening. On Day 5 and 6 participants receive asenapine 5.0 mg BID. On Day 7 participants receive asenapine 5.0 mg in the morning and 10.0 mg in the evening. Participants receive asenapine 10.0 mg BID for the remainder of the 21-day treatment period.

Arm type

Experimental

Investigational medicinal product name

asenapine

Investigational medicinal product code

Other name

SCH 900274, Saphris®

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Asenapine tablets, administered sublingually BID at one of three dose levels (2.5 mg, 5.0 mg, or 10.0 mg)

Number of subjects in period 1	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Started	101	105	99	99
Completed	101	104	99	99
Not completed	0	1	0	0
Not Treated	-	1	-	-

Period 2 title

Treatment through Study Completion

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants receive placebo BID for 21 days.

Arm type

Placebo

Investigational medicinal product name

Placebo to match asenapine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Placebo tablets to match asenapine tablets, administered sublingually BID

Asenapine 2.5 mg BID

Arm description

Participants receive asenapine 2.5 mg BID for 21 days.

Arm type

Experimental

Investigational medicinal product name

asenapine

Investigational medicinal product code

Other name

SCH 900274, Saphris®

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Asenapine tablets, administered sublingually BID at one of three dose levels (2.5 mg, 5.0 mg, or 10.0 mg)

Asenapine 5.0 mg BID

Arm description

Arm type

Experimental

Investigational medicinal product name

asenapine

Investigational medicinal product code

Other name

SCH 900274, Saphris®

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Asenapine tablets, administered sublingually BID at one of three dose levels (2.5 mg, 5.0 mg, or 10.0 mg)

Asenapine 10.0 mg BID

Arm description

Arm type

Experimental

Investigational medicinal product name

asenapine

Investigational medicinal product code

Other name

SCH 900274, Saphris®

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Asenapine tablets, administered sublingually BID at one of three dose levels (2.5 mg, 5.0 mg, or 10.0 mg)

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: The participants who started Period 1 are those randomized, one of whom did not receive study drug. The participants who started Period 2 are those who received study drug. The baseline demographics table presents data for participants treated, therefore Period 2 was set as the baseline period.

Number of subjects in period 2 ^[2]	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Started	101	104	99	99
Completed	87	88	88	87
Not completed	14	16	11	12
Consent withdrawn by subject	-	2	-	3
Adverse event, non-fatal	4	7	5	5
Did Not Meet Protocol Eligibility	-	1	-	-
Treatment Failure	-	-	-	1
Lost to follow-up	3	2	3	2
Protocol deviation	7	4	3	1

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The worldwide number enrolled in the trial presents participants randomized; one of these participants did not receive study drug. The participants who started Period 2 ("baseline period") are those who received study drug. The baseline demographics table presents data for participants treated, therefore Period 2 was set as the baseline period.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants receive placebo BID for 21 days.

Reporting group title

Asenapine 2.5 mg BID

Reporting group description

Participants receive asenapine 2.5 mg BID for 21 days.

Reporting group title

Asenapine 5.0 mg BID

Reporting group description

Reporting group title

Asenapine 10.0 mg BID

Reporting group description

Reporting group values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID	Total
Number of subjects	101	104	99	99	403
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	13.7 ( 2 )	13.7 ( 2.1 )	13.8 ( 2 )	13.9 ( 2.1 )	-
Gender categorical
Units: Subjects
Female	63	52	56	41	212
Male	38	52	43	58	191
Y-MRS total score
Y-MRS is an 11-item instrument for assessing the severity of manic episodes. Seven of the 11 items are rated on a scale of 0-4 and 4 are rated on a scale of 0-8, with higher scores indicating greater severity of symptoms. The Y-MRS total score for each participant is the sum of the ratings for the 11 individual items, and can range from 0-60. Summary statistics presented are for efficacy population (Full Analysis Set [FAS]): N=98, 101, 98 and 98 for Placebo, asenapine 2.5 mg BID, asenapine 5.0 mg BID and asenapine 10.0 mg BID groups, respectively.
Units: score on a scale
arithmetic mean (standard deviation)	29.9 ( 5.5 )	29.5 ( 5.7 )	30.3 ( 5.9 )	30.2 ( 5.6 )	-
Clinical Global Impression Scale for use in Bipolar Disorder (CGI-BP) overall score
CGI-BP overall score is obtained using a 7-point scale assessing the severity of the participant’s overall bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. Summary statistics presented are for efficacy population (FAS): N=98, 101, 98 and 98 for Placebo, asenapine 2.5 mg BID, asenapine 5.0 mg BID and asenapine 10.0 mg BID groups, respectively.
Units: score on a scale
arithmetic mean (standard deviation)	4.3 ( 0.5 )	4.5 ( 0.6 )	4.4 ( 0.6 )	4.4 ( 0.6 )	-
CGI-BP mania score
CGI-BP mania score is obtained using a 7-point scale assessing the severity of the mania component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. Summary statistics presented are for efficacy population (FAS): N=98, 101, 98 and 98 for Placebo, asenapine 2.5 mg BID, asenapine 5.0 mg BID and asenapine 10.0 mg BID groups, respectively.
Units: score on a scale
arithmetic mean (standard deviation)	4.3 ( 0.5 )	4.5 ( 0.6 )	4.4 ( 0.6 )	4.4 ( 0.6 )	-
CGI-BP depression score
CGI-BP depression score is obtained using a 7-point scale assessing the severity of the depression component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. Summary statistics presented are for efficacy population (FAS) except as noted: N=97 (baseline value not available for 1 FAS participant in this group), 101, 98 and 98 for Placebo, asenapine 2.5 mg BID, asenapine 5.0 mg BID and asenapine 10.0 mg BID groups, respectively.
Units: score on a scale
arithmetic mean (standard deviation)	2.9 ( 1.3 )	2.8 ( 1.3 )	2.9 ( 1.4 )	2.8 ( 1.2 )	-
Children's Depression Rating Scale, Revised (CDRS-R) total score
CDRS-R is a 17-item instrument for assessing depression in children. Items are rated on a scale of 1-7 (14 items) or 1-5 (3 items); higher scores indicate more severe symptoms. CDRS-R total score is sum of ratings for the 17 items (range: 17-113). Summary statistics presented are for efficacy population (FAS) except as noted: N=97 (baseline value not available for 1 FAS participant in this group), 99 (baseline value not available for 2 FAS participants in this group), 98 and 98 for Placebo, asenapine 2.5 mg BID, asenapine 5.0 mg BID and asenapine 10.0 mg BID groups, respectively.
Units: score on a scale
arithmetic mean (standard deviation)	34.5 ( 10.2 )	33.7 ( 9 )	35.2 ( 11.9 )	34.1 ( 9 )	-
Children’s Global Assessment Scale (CGAS) score - current functioning
CGAS is a 100-point scale measuring psychological, social, and school functioning in children aged 6-17. Minimum scores ranged from 1-10, representing the need for constant supervision (worse result) to maximum scores of 91-100, representing superior functioning (better result). Summary statistics presented are for efficacy population (FAS): N=98, 101, 98 and 98 for Placebo, asenapine 2.5 mg BID, asenapine 5.0 mg BID and asenapine 10.0 mg BID groups, respectively.
Units: score on a scale
arithmetic mean (standard deviation)	49 ( 7.9 )	49.6 ( 7.4 )	48.4 ( 7.4 )	49.1 ( 6.7 )	-
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) total score
PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. The participant is asked to rate 15 items reflecting quality of life on a scale of 1=very poor to 5=very good. The PQ-LES-Q total score (sum of Items 1-14) ranged from 14 to 70 with a higher score indicating better quality of life. Summary statistics presented are for efficacy population (FAS): N=98, 101, 98 and 98 for Placebo, asenapine 2.5 mg BID, asenapine 5.0 mg BID and asenapine 10.0 mg BID groups, respectively.
Units: score on a scale
arithmetic mean (standard deviation)	48.7 ( 9.7 )	49.1 ( 9.6 )	49.5 ( 9.1 )	49.1 ( 10.5 )	-
PQ-LES-Q overall score (i.e., item 15)
PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. The participant is asked to rate 15 items reflecting quality of life on a scale of 1=very poor to 5=very good. The PQ-LES-Q overall score (Item 15, a global assessment of quality of life) ranged from 1 to 5 with a higher score indicating better quality of life. Summary statistics presented are for efficacy population (FAS): N=98, 101, 98 and 98 for Placebo, asenapine 2.5 mg BID, asenapine 5.0 mg BID and asenapine 10.0 mg BID groups, respectively.
Units: score on a scale
arithmetic mean (standard deviation)	3.7 ( 1 )	3.8 ( 1 )	3.8 ( 0.9 )	3.8 ( 1 )	-

End points

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Reporting group title

Placebo

Reporting group description

Participants receive placebo twice daily (BID) for 21 days.

Reporting group title

Asenapine 2.5 mg BID

Reporting group description

Participants receive asenapine 2.5 mg BID for 21 days.

Reporting group title

Asenapine 5.0 mg BID

Reporting group description

Reporting group title

Asenapine 10.0 mg BID

Reporting group description

Reporting group title

Placebo

Reporting group description

Participants receive placebo BID for 21 days.

Reporting group title

Asenapine 2.5 mg BID

Reporting group description

Participants receive asenapine 2.5 mg BID for 21 days.

Reporting group title

Asenapine 5.0 mg BID

Reporting group description

Reporting group title

Asenapine 10.0 mg BID

Reporting group description

Primary: Change from Baseline in Y-MRS Total Score at Day 21

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End point title

Change from Baseline in Y-MRS Total Score at Day 21

End point description

Y-MRS is an 11-item clinician-rated instrument for assessing severity of manic episodes. Severity of each item is rated based on the participant’s assessment of his or her condition and clinician’s observations during the interview. Seven of the 11 items are rated on a scale of 0-4 and 4 are rated on a scale of 0-8, with higher scores indicating greater severity of symptoms. The Y-MRS total score for each participant is the sum of the ratings for the 11 individual items, and can range from 0-60, with higher scores indicating greater severity of symptoms. The reported measure is the change from baseline at Day 21; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included an on-treatment Day 21 value of Y-MRS total score must be available for a participant.

End point type

Primary

End point timeframe

Baseline and Day 21

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	79	88	87	81
Units: score on a scale
arithmetic mean (standard deviation)	-9.6 ( 7.8 )	-12.3 ( 9 )	-15.1 ( 9.5 )	-15.9 ( 9.1 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± standard deviation (SD) change from baseline is 79 for placebo and 88 for asenapine 2.5 mg (total – 167). Mixed model for repeated measures (MMRM) analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008 ^[1]

Method

MMRM

Parameter type

Difference in Least Squares (LS) Means

Point estimate

-3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-5.6

upper limit

-0.8

Notes
[1] - p-value is adjusted by Hochberg's method for testing three asenapine groups versus the placebo group.

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 79 for placebo and 87 for asenapine 5.0 mg (total – 166). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

166

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[2]

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-5.3

Confidence interval

level

95%

sides

2-sided

lower limit

-7.7

upper limit

-2.9

Notes
[2] - p-value is adjusted by Hochberg's method for testing three asenapine groups versus the placebo group.

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 79 for placebo and 81 for asenapine 10.0 mg (total – 160). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[3]

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-6.2

Confidence interval

level

95%

sides

2-sided

lower limit

-8.6

upper limit

-3.8

Notes
[3] - p-value is adjusted by Hochberg's method for testing three asenapine groups versus the placebo group.

Analysis of Dose-response Relationship: Pattern 1

Statistical analysis description

Analysis of dose-response relationship is a Secondary study endpoint. Number of participants for calculation of reported mean ± SD changes from baseline is 335 (total for 4 groups). Multiple contrast testing using MMRM model (based on FAS population, total N = 395) was used to evaluate 7 pre-defined dose-response patterns. Model includes terms of (pooled) site, treatment, visit, baseline, and interaction of visit by treatment and baseline by visit.

Comparison groups

Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID v Asenapine 10.0 mg BID

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001 ^[4]

Method

MMRM

Confidence interval

Notes
[4] - p-value (adjusted to control Type I error) for dose-response pattern 1 (Placebo<2.5 mg=5.0 mg=10.0 mg). Value of t-statistic associated with contrast of MMRM model for pattern 1 is -4.92. Lower value indicates pattern provides better fit to data.

Analysis of Dose-response Relationship: Pattern 2

Statistical analysis description

Comparison groups

Asenapine 2.5 mg BID v Asenapine 5.0 mg BID v Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001 ^[5]

Method

MMRM

Confidence interval

Notes
[5] - p-value (adjusted to control Type I error) for dose-response pattern 2 (Placebo=2.5 mg<5.0 mg=10.0 mg). Value of t-statistic associated with contrast of MMRM model for pattern 2 is -4.87. Lower value indicates pattern provides better fit to data.

Analysis of Dose-response Relationship: Pattern 3

Statistical analysis description

Comparison groups

Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID v Asenapine 10.0 mg BID

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0021 ^[6]

Method

MMRM

Confidence interval

Notes
[6] - p-value (adjusted to control Type I error) for dose-response pattern 3 (Placebo=2.5 mg=5.0 mg<10.0 mg). Value of t-statistic associated with contrast of MMRM model for pattern 3 is -3.40. Lower value indicates pattern provides better fit to data.

Analysis of Dose-response Relationship: Pattern 4

Statistical analysis description

Comparison groups

Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID v Asenapine 10.0 mg BID

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001 ^[7]

Method

MMRM

Confidence interval

Notes
[7] - p-value (adjusted to control Type I error) for dose-response pattern 4 (Placebo<2.5 mg<5.0 mg<10.0 mg). Value of t-statistic associated with contrast of MMRM model for pattern 4 is -5.28. Lower value indicates pattern provides better fit to data.

Analysis of Dose-response Relationship: Pattern 5

Statistical analysis description

Comparison groups

Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID v Asenapine 10.0 mg BID

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001 ^[8]

Method

MMRM

Confidence interval

Notes
[8] - p-value (adjusted to control Type I error) for dose-response pattern 5 (Placebo=2.5 mg<5.0 mg<10.0 mg). Value of t-statistic associated with contrast of MMRM model for pattern 5 is -4.64. Lower value indicates pattern provides better fit to data.

Analysis of Dose-response Relationship: Pattern 6

Statistical analysis description

Comparison groups

Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID v Asenapine 10.0 mg BID

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001 ^[9]

Method

MMRM

Confidence interval

Notes
[9] - p-value (adjusted to control Type I error) for dose-response pattern 6 (Placebo<2.5 mg=5.0 mg<10.0 mg). Value of t-statistic associated with contrast of MMRM model for pattern 6 is -5.07. Lower value indicates pattern provides better fit to data.

Analysis of Dose-response Relationship: Pattern 7

Statistical analysis description

Comparison groups

Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID v Asenapine 10.0 mg BID

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001 ^[10]

Method

MMRM

Confidence interval

Notes
[10] - p-value (adjusted to control Type I error) for dose-response pattern 7 (Placebo<2.5 mg<5.0 mg=10.0 mg). Value of t-statistic associated with contrast of MMRM model for pattern 7 is -5.49. Lower value indicates pattern provides better fit to data.

Secondary: Change from Baseline in CGI-BP Overall Score at Day 21

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End point title

Change from Baseline in CGI-BP Overall Score at Day 21

End point description

Change from baseline in CGI-BP overall score at Day 21 is the Key Secondary Outcome Measure. The CGI-BP is a clinician-rated instrument for assessing bipolar illness that includes subscales assessing mania and depression. This measure reports one item within the CGI-BP, which is a 7-point scale assessing the severity of the participant’s overall bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 21; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 21 value of CGI-BP overall score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 21

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	79	88	87	81
Units: score on a scale
arithmetic mean (standard deviation)	-0.7 ( 0.9 )	-1.3 ( 1.1 )	-1.4 ( 1 )	-1.4 ( 1 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 79 for placebo and 88 for asenapine 2.5 mg (total – 167). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[11]

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.3

Notes
[11] - p-value is adjusted by Hochberg's method for testing three asenapine groups versus the placebo group.

Comparison by Treatment Group

Statistical analysis description

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

166

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[12]

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.4

Notes
[12] - p-value is adjusted by Hochberg's method for testing three asenapine groups versus the placebo group.

Comparison by Treatment Group

Statistical analysis description

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[13]

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

-0.4

Notes
[13] - p-value is adjusted by Hochberg's method for testing three asenapine groups versus the placebo group.

Secondary: Total Y-MRS 50% Responders at Days 4, 7, 14 and 21

Top of page

End point title

Total Y-MRS 50% Responders at Days 4, 7, 14 and 21

End point description

Total Y-MRS 50% responder was defined as a participant with reduction from baseline to identified visit of ≥50% in Y-MRS total score. Y-MRS is an 11-item clinician-rated instrument for assessing the severity of manic episodes. The Y-MRS total score for each participant is sum of the ratings for the 11 individual items, and can range from 0-60 with higher scores indicating greater severity of symptoms. Last-Observation-Carried-Forward (LOCF) approach was used; if at a given visit no Y-MRS total score was available for determining whether a participant was a responder, the last available post-baseline on-treatment assessment prior to that visit was used. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included for a visit, a Y-MRS total score must be available for that visit or a prior post-baseline on-treatment visit.

End point type

Secondary

End point timeframe

Baseline and Days 4, 7, 14 and 21

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	98	101	98	98
Units: participants
Day 4 (n=95, 98, 93, 90)	7	19	20	13
Day 7 (n=98, 101, 98, 98)	14	33	31	37
Day 14 (n=98, 101, 98, 98)	20	36	50	50
Day 21 (n=98, 101, 98, 98)	27	42	53	51

Comparison by Treatment Group: Day 4

Statistical analysis description

Analysis is for asenapine versus placebo on Day 4 (LOCF). Logistic regression model included terms of treatment and baseline Y-MRS total score. Odds ratio (OR) was adjusted for baseline. An OR of >1 means that asenapine has a higher probability of achieving Total Y-MRS 50% response. Number in FAS for groups compared: placebo – 98, asenapine 2.5 mg – 101 (total – 199). Day 4 analysis includes only those in FAS with Day 4 data (LOCF): placebo – 95, asenapine 2.5 mg – 98 (total – 193).

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.018 ^[14]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

7.6

Notes
[14] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 4

Statistical analysis description

Analysis is for asenapine versus placebo on Day 4 (LOCF). Logistic regression model included terms of treatment and baseline Y-MRS total score. OR was adjusted for baseline. An OR of >1 means that asenapine has a higher probability of achieving Total Y-MRS 50% response. Number in FAS for groups compared: placebo – 98, asenapine 5.0 mg – 98 (total – 196). Day 4 analysis includes only those in FAS with Day 4 data (LOCF): placebo – 95, asenapine 5.0 mg – 93 (total – 188).

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.008 ^[15]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.4

Confidence interval

level

95%

sides

2-sided

lower limit

1.4

upper limit

8.6

Notes
[15] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 4

Statistical analysis description

Analysis is for asenapine versus placebo on Day 4 (LOCF). Logistic regression model included terms of treatment and baseline Y-MRS total score. OR was adjusted for baseline. An OR of >1 means that asenapine has a higher probability of achieving Total Y-MRS 50% response. Number in FAS for groups compared: placebo – 98, asenapine 10.0 mg – 98 (total – 196). Day 4 analysis includes only those in FAS with Day 4 data (LOCF): placebo – 95, asenapine 10.0 mg – 90 (total – 185).

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.129 ^[16]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

5.6

Notes
[16] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 7

Statistical analysis description

Analysis is for asenapine versus placebo on Day 7 (LOCF). Logistic regression model included terms of treatment and baseline Y-MRS total score. OR was adjusted for baseline. An OR of >1 means that asenapine has a higher probability of achieving Total Y-MRS 50% response.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.003 ^[17]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.4

upper limit

5.9

Notes
[17] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 7

Statistical analysis description

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.005 ^[18]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.4

upper limit

5.6

Notes
[18] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 7

Statistical analysis description

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[19]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.6

Confidence interval

level

95%

sides

2-sided

lower limit

1.8

upper limit

7.3

Notes
[19] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 14

Statistical analysis description

Analysis is for asenapine versus placebo on Day 14 (LOCF). Logistic regression model included terms of treatment and baseline Y-MRS total score. OR was adjusted for baseline. An OR of >1 means that asenapine has a higher probability of achieving Total Y-MRS 50% response.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.018 ^[20]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.2

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

4.1

Notes
[20] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 14

Statistical analysis description

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[21]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

2.2

upper limit

7.6

Notes
[21] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 14

Statistical analysis description

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[22]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

2.2

upper limit

7.6

Notes
[22] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 21

Statistical analysis description

Analysis is for asenapine versus placebo on Day 21 (LOCF). Logistic regression model included terms of treatment and baseline Y-MRS total score. OR was adjusted for baseline. An OR of >1 means that asenapine has a higher probability of achieving Total Y-MRS 50% response.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.042 ^[23]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

3.4

Notes
[23] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 21

Statistical analysis description

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[24]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.2

Confidence interval

level

95%

sides

2-sided

lower limit

1.7

upper limit

5.8

Notes
[24] - 95% Confidence Interval and p-value are based on Wald statistic.

Comparison by Treatment Group: Day 21

Statistical analysis description

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[25]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.6

upper limit

5.3

Notes
[25] - 95% Confidence Interval and p-value are based on Wald statistic.

Secondary: Change from Baseline in CGI-BP Mania Score at Day 4

Top of page

End point title

Change from Baseline in CGI-BP Mania Score at Day 4

End point description

The CGI-BP is a clinician-rated instrument for assessing bipolar illness that includes subscales assessing mania and depression. This measure reports one item within the CGI-BP, which is a 7-point scale assessing the severity of the mania component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 4; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 4 value of CGI-BP mania score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 4

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	93	97	93	90
Units: score on a scale
arithmetic mean (standard deviation)	-0.3 ( 0.6 )	-0.6 ( 0.8 )	-0.5 ( 0.7 )	-0.5 ( 0.8 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 93 for placebo and 97 for asenapine 2.5 mg (total – 190). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

190

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.014

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.45

upper limit

-0.05

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 93 for placebo and 93 for asenapine 5.0 mg (total – 186). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.107

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

0.04

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 93 for placebo and 90 for asenapine 10.0 mg (total – 183). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

183

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.039

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

-0.01

Secondary: Change from Baseline in CGI-BP Mania Score at Day 7

Top of page

End point title

Change from Baseline in CGI-BP Mania Score at Day 7

End point description

The CGI-BP is a clinician-rated instrument for assessing bipolar illness that includes subscales assessing mania and depression. This measure reports one item within the CGI-BP, which is a 7-point scale assessing the severity of the mania component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 7; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 7 value of CGI-BP mania score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 7

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	95	98	95	97
Units: score on a scale
arithmetic mean (standard deviation)	-0.5 ( 0.7 )	-0.9 ( 0.9 )	-0.9 ( 1 )	-0.9 ( 0.9 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 95 for placebo and 98 for asenapine 2.5 mg (total – 193). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

193

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.006

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

-0.1

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 95 for placebo and 95 for asenapine 5.0 mg (total – 190). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

190

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.003

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-0.59

upper limit

-0.12

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 95 for placebo and 97 for asenapine 10.0 mg (total – 192). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

192

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.44

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

-0.21

Secondary: Change from Baseline in CGI-BP Mania Score at Day 14

Top of page

End point title

Change from Baseline in CGI-BP Mania Score at Day 14

End point description

The CGI-BP is a clinician-rated instrument for assessing bipolar illness that includes subscales assessing mania and depression. This measure reports one item within the CGI-BP, which is a 7-point scale assessing the severity of the mania component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 14; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 14 value of CGI-BP mania score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 14

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	89	91	90	91
Units: score on a scale
arithmetic mean (standard deviation)	-0.6 ( 1 )	-1.1 ( 1 )	-1.4 ( 1 )	-1.3 ( 1 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 89 for placebo and 91 for asenapine 2.5 mg (total – 180). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.011

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

-0.08

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 89 for placebo and 90 for asenapine 5.0 mg (total – 179). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.63

Confidence interval

level

95%

sides

2-sided

lower limit

-0.89

upper limit

-0.36

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 89 for placebo and 91 for asenapine 10.0 mg (total – 180). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

-0.35

Secondary: Change from Baseline in CGI-BP Mania Score at Day 21

Top of page

End point title

Change from Baseline in CGI-BP Mania Score at Day 21

End point description

The CGI-BP is a clinician-rated instrument for assessing bipolar illness that includes subscales assessing mania and depression. This measure reports one item within the CGI-BP, which is a 7-point scale assessing the severity of the mania component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 21; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 21 value of CGI-BP mania score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 21

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	79	88	87	81
Units: score on a scale
arithmetic mean (standard deviation)	-0.7 ( 0.9 )	-1.3 ( 1.1 )	-1.5 ( 1.1 )	-1.4 ( 1 )

Comparison by Treatment Group

Statistical analysis description

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.32

Comparison by Treatment Group

Statistical analysis description

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

166

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.75

Confidence interval

level

95%

sides

2-sided

lower limit

-1.04

upper limit

-0.46

Comparison by Treatment Group

Statistical analysis description

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.74

Confidence interval

level

95%

sides

2-sided

lower limit

-1.03

upper limit

-0.45

Secondary: Change from Baseline in CGI-BP Depression Score at Day 4

Top of page

End point title

Change from Baseline in CGI-BP Depression Score at Day 4

End point description

The CGI-BP is a clinician-rated instrument for assessing bipolar illness that includes subscales assessing mania and depression. This measure reports one item within the CGI-BP, which is a 7-point scale assessing the severity of the depression component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 4; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 4 value of CGI-BP depression score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 4

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	92	97	93	90
Units: score on a scale
arithmetic mean (standard deviation)	-0.2 ( 0.7 )	-0.3 ( 0.8 )	-0.2 ( 1 )	-0.1 ( 1 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 92 for placebo and 97 for asenapine 2.5 mg (total – 189). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.536

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

0.15

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 92 for placebo and 93 for asenapine 5.0 mg (total – 185). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

185

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.811

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.19

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 92 for placebo and 90 for asenapine 10.0 mg (total – 182). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.556

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.15

upper limit

0.28

Secondary: Change from Baseline in CGI-BP Depression Score at Day 7

Top of page

End point title

Change from Baseline in CGI-BP Depression Score at Day 7

End point description

The CGI-BP is a clinician-rated instrument for assessing bipolar illness that includes subscales assessing mania and depression. This measure reports one item within the CGI-BP, which is a 7-point scale assessing the severity of the depression component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 7; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 7 value of CGI-BP depression score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 7

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	94	98	95	97
Units: score on a scale
arithmetic mean (standard deviation)	-0.4 ( 0.9 )	-0.5 ( 0.8 )	-0.5 ( 1.1 )	-0.5 ( 0.9 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 94 for placebo and 98 for asenapine 2.5 mg (total – 192). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

192

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.053

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 94 for placebo and 95 for asenapine 5.0 mg (total – 189). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.094

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

0.03

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 94 for placebo and 97 for asenapine 10.0 mg (total – 191). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

191

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.178

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

0.07

Secondary: Change from Baseline in CGI-BP Depression Score at Day 14

Top of page

End point title

Change from Baseline in CGI-BP Depression Score at Day 14

End point description

The CGI-BP is a clinician-rated instrument for assessing bipolar illness that includes subscales assessing mania and depression. This measure reports one item within the CGI-BP, which is a 7-point scale assessing the severity of the depression component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 14; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 14 value of CGI-BP depression score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 14

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	88	91	90	91
Units: score on a scale
arithmetic mean (standard deviation)	-0.5 ( 1.1 )	-0.5 ( 1 )	-0.7 ( 1 )	-0.6 ( 1 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 88 for placebo and 91 for asenapine 2.5 mg (total – 179). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.506

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.33

upper limit

0.16

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 88 for placebo and 90 for asenapine 5.0 mg (total – 178). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.131

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.43

upper limit

0.06

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 88 for placebo and 91 for asenapine 10.0 mg (total – 179). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.211

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

0.09

Secondary: Change from Baseline in CGI-BP Depression Score at Day 21

Top of page

End point title

Change from Baseline in CGI-BP Depression Score at Day 21

End point description

The CGI-BP is a clinician-rated instrument for assessing bipolar illness that includes subscales assessing mania and depression. This measure reports one item within the CGI-BP, which is a 7-point scale assessing the severity of the depression component of the participant’s bipolar illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 21; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 21 value of CGI-BP depression score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 21

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	78	88	87	81
Units: score on a scale
arithmetic mean (standard deviation)	-0.4 ( 1 )	-0.6 ( 1.1 )	-0.8 ( 1.1 )	-0.6 ( 1 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 78 for placebo and 88 for asenapine 2.5 mg (total – 166). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

166

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.079

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.49

upper limit

0.03

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 78 for placebo and 87 for asenapine 5.0 mg (total – 165). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.01

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

-0.08

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 78 for placebo and 81 for asenapine 10.0 mg (total – 159). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

159

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.139

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

0.06

Secondary: Change from Baseline in CDRS-R Total Score at Day 7

Top of page

End point title

Change from Baseline in CDRS-R Total Score at Day 7

End point description

The CDRS-R is a 17-item clinician-rated instrument for assessing the presence and severity of depressive symptoms in children. Fourteen of the 17 items are rated on a scale of 1-7 and 3 of the items are rated on a scale of 1-5, with higher scores indicating greater severity of symptoms. The CDRS-R total score for each participant is the sum of the ratings for the 17 individual items, and can range from 17-113, with higher scores indicating greater severity of symptoms. The reported measure is the change from baseline at Day 7; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 7 value of CDRS-R total score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 7

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	94	95	91	95
Units: score on a scale
arithmetic mean (standard deviation)	-4.1 ( 8.1 )	-6.1 ( 7.1 )	-6.1 ( 8 )	-5.9 ( 8.5 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 94 for placebo and 95 for asenapine 2.5 mg (total – 189). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.004

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-2.61

Confidence interval

level

95%

sides

2-sided

lower limit

-4.38

upper limit

-0.83

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 94 for placebo and 91 for asenapine 5.0 mg (total – 185). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

185

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.017

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-2.17

Confidence interval

level

95%

sides

2-sided

lower limit

-3.95

upper limit

-0.39

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 94 for placebo and 95 for asenapine 10.0 mg (total – 189). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.017

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-2.16

Confidence interval

level

95%

sides

2-sided

lower limit

-3.93

upper limit

-0.38

Secondary: Change from Baseline in CDRS-R Total Score at Day 14

Top of page

End point title

Change from Baseline in CDRS-R Total Score at Day 14

End point description

The CDRS-R is a 17-item clinician-rated instrument for assessing the presence and severity of depressive symptoms in children. Fourteen of the 17 items are rated on a scale of 1-7 and 3 of the items are rated on a scale of 1-5, with higher scores indicating greater severity of symptoms. The CDRS-R total score for each participant is the sum of the ratings for the 17 individual items, and can range from 17-113, with higher scores indicating greater severity of symptoms. The reported measure is the change from baseline at Day 14; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 14 value of CDRS-R total score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 14

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	88	89	90	90
Units: score on a scale
arithmetic mean (standard deviation)	-5.5 ( 8.1 )	-5.8 ( 6.5 )	-8.7 ( 10.5 )	-6.6 ( 8.8 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 88 for placebo and 89 for asenapine 2.5 mg (total – 177). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.395

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-0.79

Confidence interval

level

95%

sides

2-sided

lower limit

-2.62

upper limit

1.04

Comparison by Treatment Group

Statistical analysis description

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.009

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-2.44

Confidence interval

level

95%

sides

2-sided

lower limit

-4.26

upper limit

-0.63

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 88 for placebo and 90 for asenapine 10.0 mg (total – 178). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.121

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-1.44

Confidence interval

level

95%

sides

2-sided

lower limit

-3.27

upper limit

0.38

Secondary: Change from Baseline in CDRS-R Total Score at Day 21

Top of page

End point title

Change from Baseline in CDRS-R Total Score at Day 21

End point description

The CDRS-R is a 17-item clinician-rated instrument for assessing the presence and severity of depressive symptoms in children. Fourteen of the 17 items are rated on a scale of 1-7 and 3 of the items are rated on a scale of 1-5, with higher scores indicating greater severity of symptoms. The CDRS-R total score for each participant is the sum of the ratings for the 17 individual items, and can range from 17-113, with higher scores indicating greater severity of symptoms. The reported measure is the change from baseline at Day 21; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 21 value of CDRS-R total score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 21

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	78	87	87	81
Units: score on a scale
arithmetic mean (standard deviation)	-6.1 ( 8.8 )	-6.9 ( 7.3 )	-8.7 ( 11.4 )	-6.8 ( 8.9 )

Comparison by Treatment Group

Statistical analysis description

Number of participants for calculation of reported mean ± SD change from baseline is 78 for placebo and 87 for asenapine 2.5 mg (total – 165). MMRM analysis uses FAS population (Number of participants: placebo – 98, asenapine 2.5 mg – 101, asenapine 5.0 mg – 98, asenapine 10.0 mg – 98, total – 395). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.135

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-1.44

Confidence interval

level

95%

sides

2-sided

lower limit

-3.33

upper limit

0.45

Comparison by Treatment Group

Statistical analysis description

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.023

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-2.19

Confidence interval

level

95%

sides

2-sided

lower limit

-4.08

upper limit

-0.3

Comparison by Treatment Group

Statistical analysis description

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

159

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.189

Method

MMRM

Parameter type

Difference in LS Means

Point estimate

-1.28

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

0.63

Secondary: Change from Baseline in CGAS Score at Day 21

Top of page

End point title

Change from Baseline in CGAS Score at Day 21

End point description

CGAS is a 100-point scale measuring psychological, social, and school functioning in children aged 6-17. Minimum scores ranged from 1-10, representing the need for constant supervision (worse result) to maximum scores of 91-100, representing superior functioning (better result). The reported measure is the change from baseline at Day 21; improvement in functioning is represented by positive values. This analysis used an LOCF approach; if no Day 21 value was available for a participant, the last available post-baseline on-treatment assessment prior to the Day 21 assessment was used. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included a baseline and at least 1 post-baseline on-treatment value of CGAS score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 21

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	84	93	91	85
Units: score on a scale
arithmetic mean (standard deviation)	6 ( 8.1 )	9.4 ( 9.5 )	13 ( 11.6 )	10.8 ( 9.7 )

Comparison by Treatment Group

Statistical analysis description

Analysis of covariance (ANCOVA) model includes terms of (pooled) site, treatment and baseline.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.002

Method

ANCOVA

Parameter type

Difference in LS Means

Point estimate

4.29

Confidence interval

level

95%

sides

2-sided

lower limit

1.56

upper limit

7.02

Comparison by Treatment Group

Statistical analysis description

ANCOVA model includes terms of (pooled) site, treatment and baseline.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Difference in LS Means

Point estimate

6.95

Confidence interval

level

95%

sides

2-sided

lower limit

4.22

upper limit

9.68

Comparison by Treatment Group

Statistical analysis description

ANCOVA model includes terms of (pooled) site, treatment and baseline.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Difference in LS Means

Point estimate

5.11

Confidence interval

level

95%

sides

2-sided

lower limit

2.31

upper limit

7.91

Secondary: Change from Baseline in PQ-LES-Q Total Score at Day 21

Top of page

End point title

Change from Baseline in PQ-LES-Q Total Score at Day 21

End point description

PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. Participant rates 15 items on scale of 1=very poor to 5=very good. Items 1-14 assess specific areas; Item 15 is a global assessment. PQ-LES-Q total score for each participant was sum of rating assigned to first 14 items, and ranged from 14 to 70 with higher score indicating better quality of life. Positive values of measure represent improvement in quality of life versus baseline. LOCF approach was used; if no Day 21 value was available for participant, last available post-baseline on-treatment assessment prior to Day 21 assessment was used. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included baseline and at least 1 post-baseline on-treatment value of PQ-LES-Q total score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 21

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	84	92	90	84
Units: score on a scale
arithmetic mean (standard deviation)	1.5 ( 8.2 )	3.7 ( 8.6 )	2.5 ( 10.8 )	4 ( 9.8 )

Comparison by Treatment Group

Statistical analysis description

ANCOVA model includes terms of (pooled) site, treatment and baseline.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.05

Method

ANCOVA

Parameter type

Difference in LS Means

Point estimate

2.24

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

4.48

Comparison by Treatment Group

Statistical analysis description

ANCOVA model includes terms of (pooled) site, treatment and baseline.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.239

Method

ANCOVA

Parameter type

Difference in LS Means

Point estimate

1.35

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

3.59

Comparison by Treatment Group

Statistical analysis description

ANCOVA model includes terms of (pooled) site, treatment and baseline.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

168

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.018

Method

ANCOVA

Parameter type

Difference in LS Means

Point estimate

2.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

5.08

Secondary: Change from Baseline in PQ-LES-Q Overall Score (i.e., Item 15) at Day 21

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End point title

Change from Baseline in PQ-LES-Q Overall Score (i.e., Item 15) at Day 21

End point description

PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. Participant rates 15 items on scale of 1=very poor to 5=very good. Items 1-14 assess specific areas; Item 15 is a global assessment of quality of life. The Item 15 result is defined to be the PQ-LES-Q overall score, and ranged from 1 to 5 with a higher score indicating better quality of life. Positive values of measure represent improvement in quality of life versus baseline. LOCF approach was used; if no Day 21 value was available for participant, last available post-baseline on-treatment assessment prior to Day 21 assessment was used. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment Y-MRS total score (this group is termed the efficacy FAS); also, to be included baseline and at least 1 post-baseline on-treatment value of PQ-LES-Q total score must be available for a participant.

End point type

Secondary

End point timeframe

Baseline and Day 21

End point values	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Number of subjects analysed	84	92	90	84
Units: score on a scale
arithmetic mean (standard deviation)	0 ( 0.9 )	0.4 ( 1 )	0.1 ( 1 )	0.2 ( 1.1 )

Comparison by Treatment Group

Statistical analysis description

ANCOVA model includes terms of (pooled) site, treatment and baseline.

Comparison groups

Asenapine 2.5 mg BID v Placebo

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.001

Method

ANCOVA

Parameter type

Difference in LS Means

Point estimate

0.39

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

0.62

Comparison by Treatment Group

Statistical analysis description

ANCOVA model includes terms of (pooled) site, treatment and baseline.

Comparison groups

Asenapine 5.0 mg BID v Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.135

Method

ANCOVA

Parameter type

Difference in LS Means

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.41

Comparison by Treatment Group

Statistical analysis description

ANCOVA model includes terms of (pooled) site, treatment and baseline.

Comparison groups

Asenapine 10.0 mg BID v Placebo

Number of subjects included in analysis

168

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.044

Method

ANCOVA

Parameter type

Difference in LS Means

Point estimate

0.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.49

Adverse events

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Timeframe for reporting adverse events

Up to 30 days after the last dose of study drug (Up to 51 days)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Placebo

Reporting group description

Participants receive placebo BID for 21 days.

Reporting group title

Asenapine 2.5 mg BID

Reporting group description

Participants receive asenapine 2.5 mg BID for 21 days.

Reporting group title

Asenapine 5.0 mg BID

Reporting group description

Reporting group title

Asenapine 10.0 mg BID

Reporting group description

Serious adverse events	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 101 (2.97%)	0 / 104 (0.00%)	2 / 99 (2.02%)	2 / 99 (2.02%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Psychiatric disorders
Bipolar Disorder
subjects affected / exposed	1 / 101 (0.99%)	0 / 104 (0.00%)	0 / 99 (0.00%)	1 / 99 (1.01%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bipolar I Disorder
subjects affected / exposed	1 / 101 (0.99%)	0 / 104 (0.00%)	1 / 99 (1.01%)	0 / 99 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mania
subjects affected / exposed	0 / 101 (0.00%)	0 / 104 (0.00%)	1 / 99 (1.01%)	0 / 99 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal Behaviour
subjects affected / exposed	1 / 101 (0.99%)	0 / 104 (0.00%)	0 / 99 (0.00%)	0 / 99 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal Ideation
subjects affected / exposed	1 / 101 (0.99%)	0 / 104 (0.00%)	0 / 99 (0.00%)	0 / 99 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide Attempt
subjects affected / exposed	0 / 101 (0.00%)	0 / 104 (0.00%)	0 / 99 (0.00%)	1 / 99 (1.01%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	Asenapine 2.5 mg BID	Asenapine 5.0 mg BID	Asenapine 10.0 mg BID
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 101 (29.70%)	68 / 104 (65.38%)	70 / 99 (70.71%)	72 / 99 (72.73%)
Investigations
Weight Increased
subjects affected / exposed	0 / 101 (0.00%)	6 / 104 (5.77%)	2 / 99 (2.02%)	2 / 99 (2.02%)
occurrences all number	0	6	2	2
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 101 (2.97%)	6 / 104 (5.77%)	10 / 99 (10.10%)	5 / 99 (5.05%)
occurrences all number	4	6	11	5
Dysgeusia
subjects affected / exposed	2 / 101 (1.98%)	4 / 104 (3.85%)	5 / 99 (5.05%)	9 / 99 (9.09%)
occurrences all number	2	4	5	9
Headache
subjects affected / exposed	6 / 101 (5.94%)	8 / 104 (7.69%)	11 / 99 (11.11%)	9 / 99 (9.09%)
occurrences all number	6	11	12	10
Sedation
subjects affected / exposed	5 / 101 (4.95%)	16 / 104 (15.38%)	19 / 99 (19.19%)	18 / 99 (18.18%)
occurrences all number	5	16	19	20
Somnolence
subjects affected / exposed	6 / 101 (5.94%)	34 / 104 (32.69%)	34 / 99 (34.34%)	31 / 99 (31.31%)
occurrences all number	6	39	36	34
General disorders and administration site conditions
Fatigue
subjects affected / exposed	5 / 101 (4.95%)	4 / 104 (3.85%)	8 / 99 (8.08%)	13 / 99 (13.13%)
occurrences all number	5	4	8	13
Gastrointestinal disorders
Abdominal Pain Upper
subjects affected / exposed	6 / 101 (5.94%)	5 / 104 (4.81%)	2 / 99 (2.02%)	3 / 99 (3.03%)
occurrences all number	6	5	2	3
Hypoaesthesia Oral
subjects affected / exposed	2 / 101 (1.98%)	18 / 104 (17.31%)	18 / 99 (18.18%)	20 / 99 (20.20%)
occurrences all number	2	18	19	21
Nausea
subjects affected / exposed	3 / 101 (2.97%)	6 / 104 (5.77%)	6 / 99 (6.06%)	6 / 99 (6.06%)
occurrences all number	3	6	6	7
Paraesthesia Oral
subjects affected / exposed	2 / 101 (1.98%)	9 / 104 (8.65%)	9 / 99 (9.09%)	11 / 99 (11.11%)
occurrences all number	2	9	9	11
Metabolism and nutrition disorders
Increased Appetite
subjects affected / exposed	2 / 101 (1.98%)	10 / 104 (9.62%)	9 / 99 (9.09%)	6 / 99 (6.06%)
occurrences all number	2	10	10	6

More information

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Were there any global substantial amendments to the protocol? Yes

16 Jan 2013

Amendment 01: Primary reason for amendment was to incorporate revisions to age range for study entry (lower limit), exclusion criteria and list of closely monitored events. Original base protocol and Amendments 01, 02 and 03 were submitted together to country authority (Russia health ministry) that provided approval.

16 Jan 2013

Amendment 02: Primary reason for amendment was to incorporate revisions to age range for study entry (lower limit), list of treatments allowed as rescue therapy, list of closely monitored events and testing to monitor liver enzymes. Original base protocol and Amendments 01, 02 and 03 were submitted together to country authority (Russia health ministry) that provided approval.

16 Jan 2013

Amendment 03: Primary reason for amendment was to add cognitive testing and additional laboratory tests for hormone levels. Original base protocol and Amendments 01, 02 and 03 were submitted together to country authority (Russia health ministry) that provided approval.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Efficacy and Safety of 3-Week Fixed-Dose Asenapine Treatment in Pediatric Acute Manic or Mixed Episodes Associated with Bipolar I Disorder (Protocol No. P06107)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in Y-MRS Total Score at Day 21

Primary: Change from Baseline in Y-MRS Total Score at Day 21

Secondary: Change from Baseline in CGI-BP Overall Score at Day 21

Secondary: Change from Baseline in CGI-BP Overall Score at Day 21

Secondary: Total Y-MRS 50% Responders at Days 4, 7, 14 and 21

Secondary: Total Y-MRS 50% Responders at Days 4, 7, 14 and 21

Secondary: Change from Baseline in CGI-BP Mania Score at Day 4

Secondary: Change from Baseline in CGI-BP Mania Score at Day 4

Secondary: Change from Baseline in CGI-BP Mania Score at Day 7

Secondary: Change from Baseline in CGI-BP Mania Score at Day 7

Secondary: Change from Baseline in CGI-BP Mania Score at Day 14

Secondary: Change from Baseline in CGI-BP Mania Score at Day 14

Secondary: Change from Baseline in CGI-BP Mania Score at Day 21

Secondary: Change from Baseline in CGI-BP Mania Score at Day 21

Secondary: Change from Baseline in CGI-BP Depression Score at Day 4

Secondary: Change from Baseline in CGI-BP Depression Score at Day 4

Secondary: Change from Baseline in CGI-BP Depression Score at Day 7

Secondary: Change from Baseline in CGI-BP Depression Score at Day 7

Secondary: Change from Baseline in CGI-BP Depression Score at Day 14

Secondary: Change from Baseline in CGI-BP Depression Score at Day 14

Secondary: Change from Baseline in CGI-BP Depression Score at Day 21

Secondary: Change from Baseline in CGI-BP Depression Score at Day 21

Secondary: Change from Baseline in CDRS-R Total Score at Day 7

Secondary: Change from Baseline in CDRS-R Total Score at Day 7

Secondary: Change from Baseline in CDRS-R Total Score at Day 14

Secondary: Change from Baseline in CDRS-R Total Score at Day 14

Secondary: Change from Baseline in CDRS-R Total Score at Day 21

Secondary: Change from Baseline in CDRS-R Total Score at Day 21

Secondary: Change from Baseline in CGAS Score at Day 21

Secondary: Change from Baseline in CGAS Score at Day 21

Secondary: Change from Baseline in PQ-LES-Q Total Score at Day 21

Secondary: Change from Baseline in PQ-LES-Q Total Score at Day 21

Secondary: Change from Baseline in PQ-LES-Q Overall Score (i.e., Item 15) at Day 21

Secondary: Change from Baseline in PQ-LES-Q Overall Score (i.e., Item 15) at Day 21

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Efficacy and Safety of 3-Week Fixed-Dose Asenapine Treatment in Pediatric Acute Manic or Mixed Episodes Associated with Bipolar I Disorder (Protocol No. P06107)