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

Study Overview
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Brief Summary
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This is a 12-week study that will test the safety and efficacy of asenapine when used in addition to lithium or valproate for subjects with acute manic or mixed episodes of Bipolar I Disorder.

Official Title
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A Phase 3, Randomized, Placebo-Controlled, Double-Blinded Trial Evaluating the Safety and Efficacy of Asenapine in Subjects Continuing Lithium or Valproic Acid/Divalproex Sodium for the Treatment of an Acute Manic or Mixed Episode

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Asenapine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have bipolar I disorder, current episode manic or mixed Treated with lithium or valproic acid Exclusion Criteria: Have an unstable medical condition Clinically significant laboratory abnormality. Have a primary diagnosis other than bipolar I disorder.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Asenapine<br>Participants received asenapine as a fast-dissolving sublingual (SL) tablet, given twice daily (BID). On Day 1, participants received asenapine 5 mg, BID. On Days 2 to 84, asenapine was dosed flexibly: BID at either 5 or 10 mg. Asenapine doses were up- or down-titrated based on efficacy, safety, and tolerability. | Drug: Asenapine<br>* Asenapine fast dissolving SL tablets 5 and 10 mg; starting dose 5 mg BID on Day 1; 5-10 mg BID after Day 1.<br>* Other names: Org 5222;|
| Placebo Comparator: Placebo<br>Participants received placebo on Days 1-84 as a fast-dissolving SL tablet, BID. | Drug: Placebo<br>* Placebo fast dissolving SL tablets, BID<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing an Adverse Event (AE) | The number of participants experiencing an AE was assessed. An AE is any untoward or unfavorable medical occurrence in a participant, including any abnormal sign, symptom, or disease, temporally associated with the use of the investigational product, whether or not considered related to the investigational product. | Up to Day 114 | 
| Number of Participants Discontinuing Study Treatment Due to an AE | The number of participants discontinuing study treatment due to an AE was assessed. An AE is any untoward or unfavorable medical occurrence in a participant, including any abnormal sign, symptom, or disease, temporally associated with the use of the investigational product, whether or not considered related to the investigational product. | Up to Day 84 | 
| Least Squares Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Score at Day 42 | The least squares mean change from baseline in Y-MRS score at day 42 was assessed. The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 42 | 
| Least Squares Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Score at Day 84 | The least squares mean change from baseline in Y-MRS score at day 84 was assessed. The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 84 | 
| Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Responder Status | The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. At pre-specified time points, the number of participants achieving Y-MRS responder status was assessed, defined as the number of participants with a 50% decrease from baseline in Y-MRS total score. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Up to Day 84 | 
| Number of Participants Achieving Young-Mania Rating Scale (Y-MRS) Remitter Status | The Y-MRS is a clinician-rated instrument used for assessing the symptoms of mania, composed of 11 items. For the 11 items, scores range from 0 (symptoms absent) to, depending on the item, either 4 (7 items) or 8 (4 items). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater symptom severity. At pre-specified time points, the number of participants achieving Y-MRS remitter status was assessed, defined as the number of participants with a Y-MRS total score of 12 or lower. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Up to Day 84 | 
| Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Mania Score at Day 21 | The least squares mean change from baseline in CGI-BP severity of mania score at day 21 was assessed. The CGI-BP severity of mania scale is a clinician-rated scale for assessing the severity of manic symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 21 | 
| Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Mania Score at Day 84 | The least squares mean change from baseline in CGI-BP severity of mania score at day 84 was assessed. The CGI-BP severity of mania scale is a clinician-rated scale for assessing the severity of manic symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 84 | 
| Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Depression Score at Day 21 | The least squares mean change from baseline in CGI-BP severity of depression score at day 21 was assessed. The CGI-BP severity of depression scale is a clinician-rated scale for assessing the severity of depressive symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 21 | 
| Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Depression Score at Day 84 | The least squares mean change from baseline in CGI-BP severity of depression score at day 84 was assessed. The CGI-BP severity of depression scale is a clinician-rated scale for assessing the severity of depressive symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 84 | 
| Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Overall Bipolar Illness Score at Day 21 | The least squares mean change from baseline in CGI-BP severity of severity of overall bipolar illness score at day 21 was assessed. The CGI-BP severity of overall bipolar illness scale is a clinician-rated scale for assessing the severity of overall symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 21 | 
| Least Squares Mean Change From Baseline in Clinical Global Impressions for Use in Bipolar Disorder (CGI-BP) Severity of Overall Bipolar Illness Score at Day 84 | The least squares mean change from baseline in CGI-BP severity of severity of overall bipolar illness score at day 84 was assessed. The CGI-BP severity of overall bipolar illness scale is a clinician-rated scale for assessing the severity of overall symptoms of bipolar disorder, with scores ranging from 1 (normal) to 7 (very severely ill). Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 84 | 
| Least Squares Mean Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Score at Day 21 | The least squares mean change from baseline in MADRS score at day 21 was assessed. The MARDS is a clinician-rated scale for assessing the severity of symptoms of depression, composed of 10 items. For the 10 items, scores range from 0 (symptoms absent) to 6 (severe). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater severity of depression. Further, decreases in depression severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 21 | 
| Least Squares Mean Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Score at Day 84 | The least squares mean change from baseline in MADRS score at day 84 was assessed. The MARDS is a clinician-rated scale for assessing the severity of symptoms of depression, composed of 10 items. For the 10 items, scores range from 0 (symptoms absent) to 6 (severe). Scores for individual items add to a total score (range: 0-60), with higher scores indicating greater severity of depression. Further, decreases in depression severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 84 | 
| Least Squares Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Score at Day 21 | The least squares mean change from baseline in PANSS score at day 21 was assessed. The PANSS assesses the severity of schizophrenia symptoms through a clinician-rated inventory of 30 items organized in 3 subscales: 1) positive subscale (7 items); 2) negative subscale (7 items); and 3) general psychopathology subscale (16 items). For each item, symptoms are scored from 1 (absent) to 7 (extreme) and add to a total PANSS score (range: 30-210). Higher scores reflect more severe symptoms of schizophrenia. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 21 | 
| Least Squares Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Score at Day 84 | The least squares mean change from baseline in PANSS score at day 84 was assessed. The PANSS assesses the severity of schizophrenia symptoms through a clinician-rated inventory of 30 items organized in 3 subscales: 1) positive subscale (7 items); 2) negative subscale (7 items); and 3) general psychopathology subscale (16 items). For each item, symptoms are scored from 1 (absent) to 7 (extreme) and add to a total PANSS score (range: 30-210). Higher scores reflect more severe symptoms of schizophrenia. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 84 | 
| Least Squares Mean Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Score at Day 21 | The least squares mean change from baseline in HAM-A score at day 21 was assessed. The HAM-A is a clinician-rated instrument for assessing anxiety symptoms, composed of 14 items. For the 14 items, scores range from 0 (not present) to 4 (severe). Scores for individual items add to a total score (range: 0-56), with higher scores indicating greater severity of anxiety. Further, decreases in anxiety severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 21 | 
| Least Squares Mean Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Score at Day 84 | The least squares mean change from baseline in HAM-A score at day 84 was assessed. The HAM-A is a clinician-rated instrument for assessing anxiety symptoms, composed of 14 items. For the 14 items, scores range from 0 (not present) to 4 (severe). Scores for individual items add to a total score (range: 0-56), with higher scores indicating greater severity of anxiety. Further, decreases in anxiety severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 84 | 
| Least Squares Mean Change From Baseline in InterSePT Scale for Suicidal Thinking - Modified Version (ISST-Modified) Score at Day 21 | The least squares mean change from baseline in ISST-Modified score at day 21 was assessed. The ISST-Modified is a clinician-rated scale for rating suicidality, composed of 12 items (score range: 0-2). Scores for the 12 items add to a total ISST-Modified score (range: 0-24), with higher scores indicating increased severity of suicidal thinking. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 21 | 
| Least Squares Mean Change From Baseline in InterSePT Scale for Suicidal Thinking - Modified Version (ISST-Modified) Score at Day 84 | The least squares mean change from baseline in ISST-Modified score at day 84 was assessed. The ISST-Modified is a clinician-rated scale for rating suicidality, composed of 12 items (score range: 0-2). Scores for the 12 items add to a total ISST-Modified score (range: 0-24), with higher scores indicating increased severity of suicidal thinking. Further, decreases in symptom severity over time would be reflected by negative changes from baseline. For evaluation of this endpoint, a LOCF analysis was used; baseline values are not eligible to be carried forward to missing post-baseline assessments. | Baseline and Day 84 | 
| Mean Change From Baseline (CFB) at Day 21 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery | Nine neurocognitive tests with higher scores indicating better performance: Verbal Memory test: recognize/remember/retrieve words (range 0-60) Visual Memory test: recognize/remember/retrieve geometric figures (range 0-60) Speed of Processing: recognize/process information. No min./max. score. Normative average (NA); correct answers: 65.1, avg. errors: 1.37 Social Acuity/Perception of Emotions test: perceive/respond to emotional cues. Min. score: -64/Max. score: 16 Reasoning: reason/respond to non-verbal, visual-abstract stimuli; scores range: -15 to 15 Executive Function: recognize rules/categories/decision making. No min./max. score. NA correct answers: 55.01/avg. errors: 5.28 Working Memory/Continuous Performance Task (CPT): perceive/attend to symbols. Min. score: -45/Max. score: 15 Sustained Attention: direct/focus on specific stimuli: Max. score (raw score); 45; Min. score: -170 Composite Memory: working+verbal+visual memory, Range 0-135. | Baseline and Day 21 | 
| Mean Change From Baseline (CFB) at Day 84 in Neurocognitive Function as Determined by Central Nervous System Vital Signs (CNS-VS) Test Battery | Nine neurocognitive tests with higher scores indicating better performance: Verbal Memory test: recognize/remember/retrieve words (range 0-60) Visual Memory test: recognize/remember/retrieve geometric figures (range 0-60) Speed of Processing: recognize/process information. No min./max. score. Normative average (NA); correct answers: 65.1, avg. errors: 1.37 Social Acuity/Perception of Emotions test: perceive/respond to emotional cues. Min. score: -64/Max. score: 16 Reasoning: reason/respond to non-verbal, visual-abstract stimuli; scores range: -15 to 15 Executive Function: recognize rules/categories/decision making. No min./max. score. NA correct answers: 55.01/avg. errors: 5.28 Working Memory/Continuous Performance Task (CPT): perceive/attend to symbols. Min. score: -45/Max. score: 15 Sustained Attention: direct/focus on specific stimuli: Max. score (raw score); 45; Min. score: -170 Composite Memory: working+verbal+visual memory, Range 0-135. | Baseline and Day 84 | 
| Percentage of Participants Determined to be Ready to Discharge at Day 84 (Kaplan-Meier Estimation) | The percentage of participants determined to be ready to discharge at day 84 was estimated (Kaplan-Meier), using the readiness to discharge questionnaire (RDQ). The RDQ is clinician-rated scale to assess readiness for discharge, composed of 7 items. Of the 7 items, only the first 5 items were utilized: Not actively suicidal/homicidal; Adequate control over aggression and impulsivity; Able to carry out basic activities of daily life; Able to take medicine independently; and Delusions and hallucinations do not significantly interfere with functioning. For the 5 items, the clinician provided a response (Strongly Disagree; Disagree; Agree; or Strongly Agree) at each pre-specified visit. The first visit at which the responses to the first 5 items on the RDQ are Strongly Agree or Agree, was defined as the point a participant was ready to discharge. | Day 84 | 
| Least Squares Mean Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), General Activities Subscale Score at Day 21 | The least squares mean change from baseline in Q-LES-Q score at day 21 was assessed. The Q-LES-Q is a participant-completed questionnaire to assess general satisfaction with activities such as physical health, mood, work, household tasks, social and family relationships, leisure activities, and overall satisfaction, composed of 16 items. For each of the 16 items, scores range from 0 (very poor) to 5 (very good), with scores for all items adding to a total score (range: 0-80); higher scores indicate better quality of life. Further, decreases in quality of life are reflected by a negative change from baseline. | Baseline and Day 21 | 
| Least Squares Mean Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), General Activities Subscale Score at Day 84 | The least squares mean change from baseline in Q-LES-Q score at day 84 was assessed. The Q-LES-Q is a participant-completed questionnaire to assess general satisfaction with activities such as physical health, mood, work, household tasks, social and family relationships, leisure activities, and overall satisfaction, composed of 16 items. For each of the 16 items, scores range from 0 (very poor) to 5 (very good), with scores for all items adding to a total score (range: 0-80); higher scores indicate better quality of life. Further, decreases in quality of life are reflected by a negative change from baseline. | Baseline and Day 84 | 
| Least Squares Mean Change From Baseline at Day 21 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) | Least squares mean change from baseline at day 21 in quality of life was assessed, as determined by SF-36v2. The SF-36v2 is a self-administered questionnaire, measuring 8 domains: Physical Functioning (PF); Role-Physical (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role-Emotional (RE); and Mental Health (MH). These 8 concepts are further organized into a Physical Component Summary (PCS; composite of PF, RP, BP, and GH) and a Mental Component Summary (MCS; composite of VT, SF, RE, and MH). The SF-36v2 domains and composite summaries were scored using a norm-based scoring approach, yielding a mean of 50 and standard deviation of 10 based on the norms from the 1998 SF-36 United States general population norms. For the PCS and MCS, scores range from 0 to 100, with higher scores indicating better quality of life. Further, decreases in quality of life (by PCS and MCS) are reflected by a negative change from baseline. | Baseline and Day 21 | 
| Least Squares Mean Change From Baseline at Day 84 in Quality of Life as Determined by Short Form-36 Version 2 (SF-36v2) | Least squares mean change from baseline at day 84 in quality of life was assessed, as determined by SF-36v2. The SF-36v2 is a self-administered questionnaire, measuring 8 domains: Physical Functioning (PF); Role-Physical (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role-Emotional (RE); and Mental Health (MH). These 8 concepts are further organized into a Physical Component Summary (PCS; composite of PF, RP, BP, and GH) and a Mental Component Summary (MCS; composite of VT, SF, RE, and MH). The SF-36v2 domains and composite summaries were scored using a norm-based scoring approach, yielding a mean of 50 and standard deviation of 10 based on the norms from the 1998 SF-36 United States general population norms. For the PCS and MCS, scores range from 0 to 100, with higher scores indicating better quality of life. Further, decreases in quality of life (by PCS and MCS) are reflected by a negative change from baseline. | Baseline and Day 21 |