Efficacy and Safety of Asenapine Treatment for Pediatric Bipolar Disorder (P06107 Has an Extension [P05898; NCT01349907])(P06107)

Study Overview
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Brief Summary
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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. The 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. Trial medication and placebo are provided as identical-looking sublingual tablets; concurrent use of psychotropics is prohibited, except use of short-acting benzodiazepines and psychostimulants approved for the treatment of attention deficit hyperactivity disorder (ADHD). Main treatment effect is measured using Y-MRS and safety is evaluated using the recordings of adverse events, routine blood panels, physical examinations (including vital signs), and electrocardiograms. Participants who complete the double blind trial may be offered to continue (open-label) 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.

Detailed Description
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Participants' Y-MRS total score at baseline will be subtracted from that at the Day 21 visit to determine the amount of change over time with treatment. The responses for the 3 different asenapine doses compared to placebo will be evaluated. The Y-MRS is an 11 item scale: seven items ranked on scale from 0 to 4 and four items ranked 0 to 8 with a range of possible total scores from 0 to 60. Participants' overall score on the CGI-BP at Day 21 will be evaluated to determine the amount of change over time with treatment. The responses for the 3 different asenapine doses compared to placebo will be evaluated. CGI-BP overall score is obtained from a single-item clinician-rated scale used to assess the participant's overall bipolar illness. Scores range from not ill (1) to very severely ill (7). The proportion of participants whose total Y-MRS score is decreased ≥50% from baseline at Day 4, 7, 14 and 21. Results for the 3 different asenapine doses compared to placebo will be evaluated. Participants' mania sub-score from the CGI-BP will be evaluated for each study visit (Days 4, 7, 14 and 21) to determine the amount of change over time with treatment. The responses for the 3 different asenapine doses compared to placebo will be evaluated. Participants' depression sub-score from the CGI-BP will evaluated at each study visit (Days 4, 7, 14 and 21) to determine the amount of change over time with treatment. The responses for the 3 different asenapine doses compared to placebo will be evaluated. Participants' CDRS-R at baseline will be subtracted from those at each study visit at which this rating was measured (Days 7, 14 and 21) to determine the amount of change over time with treatment. The responses for the 3 different asenapine doses compared to placebo will be evaluated. The CDRS-R is a 17-item scale that assesses the presence and severity of depressive symptoms: fourteen items are rated from 1 to 7 and three items are rated from 1 to 5; total scores range from 17 to 113. Participants' CGAS at baseline will be subtracted from that at the Day 21 visit to determine the amount of change over time with treatment. The responses for the 3 different asenapine doses compared to placebo will be evaluated. The CGAS is a 100-point scale, with a possible range of 1 to 100. Normal social functioning is defined as a CGAS total score of ≥70. Participants' PQ-LES-Q total score at baseline will be subtracted from that at the Day 21 visit to determine the amount of change over time with treatment. The responses for the 3 different asenapine doses compared to placebo will be evaluated. The PQ-LES-Q is a 15-item scale, with total score calculated as the sum of the first 14 items, with a range of 14 to 70. Each item is scored by the child from 1 to 5, with higher scores indicative of greater enjoyment and satisfaction. Participants' PQ-LES-Q overall score (i.e. item 15) at baseline will be subtracted from that at the Day 21 visit to determine the amount of change over time with treatment. The responses for the 3 different asenapine doses compared to placebo will be evaluated. The PQ-LES-Q overall score is determined by the answer to item 15 on the questionnaire (range: 1 to 5).

Official Title
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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)

Conditions
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Bipolar Disorder, Pediatric

Intervention / Treatment
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* Drug: asenapine
* Drug: Placebo to match asenapine
* Drug: Rescue medication


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants who (or whose parent/legal representative) are able to give written informed consent. Participants must be 10 years of age or older and 17 years of age or younger at the time of treatment assignment (randomization). Participants must have a diagnosis of bipolar I disorder, confirmed by structured interview at screening. Participants must not be pregnant or lactating, and those who are sexually active or become sexually active during the trial, and of child-bearing potential, must be using a medically accepted form of birth control. Participants will be required to have stopped taking certain psycho-active medications prior to baseline. Participants must have a caregiver, or other responsible person living with them who agrees to provide support to the participant to ensure study and procedure compliance. Exclusion criteria: Diagnosis of bipolar II disorder, or other form of bipolar or psychotic disorder. Known or suspected mental retardation. Substance abuse, or dependence, within the past 6 months. There is risk of self-harm or harm to others. There is a history of tardive dyskinesia or dystonia. Pregnancy or lactation during the study. History of seizure disorder. Participation in any other clinical trial at the same time. A family member who is part of the study staff or is directly involved with the study. Other medical conditions determined by the study staff to possibly interfere with the study safety and efficacy evaluations.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 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 2.5 mg twice daily (BID)<br>Participants receive asenapine 2.5 mg BID for 21 days. | Drug: asenapine<br>* Asenapine tablets, administered sublingually twice daily at one of three dose levels (2.5 mg, 5.0 mg, or 10.0 mg)<br>* Other names: SCH 900274, Saphris;Drug: Rescue medication<br>* 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.<br>|
| Experimental: Asenapine 5.0 mg BID<br>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. | Drug: asenapine<br>* Asenapine tablets, administered sublingually twice daily at one of three dose levels (2.5 mg, 5.0 mg, or 10.0 mg)<br>* Other names: SCH 900274, Saphris;Drug: Rescue medication<br>* 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.<br>|
| Experimental: Asenapine 10.0 mg BID<br>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. | Drug: asenapine<br>* Asenapine tablets, administered sublingually twice daily at one of three dose levels (2.5 mg, 5.0 mg, or 10.0 mg)<br>* Other names: SCH 900274, Saphris;Drug: Rescue medication<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Participants receive placebo BID for 21 days. | Drug: Placebo to match asenapine<br>* Placebo tablets to match asenapine tablets, administered sublingually twice daily<br>Drug: Rescue medication<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Y-MRS Total Score at Day 21 | The Y-MRS is an 11-item clinician-rated instrument for assessing the severity of manic episodes. A severity rating is assigned to each of the 11 items (Elevated mood, Increased motor activity-energy, Sexual interest, Sleep, Irritability, Speech, Language-thought disorder, Thought content, Disruptive-aggressive behavior, Appearance, Insight), based on the participant's subjective report of his or her condition over the previous 48 hours and the clinician's observations during the interview, with the emphasis on the latter. Seven of the 11 items are rated on a scale of 0-4 and 4 of the items 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. | Baseline and Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinical Global Impression Scale for Use in Bipolar Disorder (CGI-BP) Overall Score at Day 21 | 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. | Baseline and Day 21 | 
| Total Y-MRS 50% Responders at Days 4, 7, 14 and 21 | A total Y-MRS 50% responder was defined as a participant who had a reduction from baseline to the identified study visit of at least 50% in the Y-MRS total score. The Y-MRS is an 11-item clinician-rated instrument for assessing the severity of manic episodes. A severity rating is assigned to each of the 11 items, based on the participant's subjective report of his or her condition over the previous 48 hours and the clinician's observations during the interview, with the emphasis on the latter. 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. This analysis used a Last-Observation-Carried-Forward (LOCF) approach; 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. | Baseline and Days 4, 7, 14 and 21 | 
| Change From Baseline in CGI-BP Mania Score at Day 4 | 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. | Baseline and Day 4 | 
| Change From Baseline in CGI-BP Mania Score at Day 7 | 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. | Baseline and Day 7 | 
| Change From Baseline in CGI-BP Mania Score at Day 14 | 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. | Baseline and Day 14 | 
| Change From Baseline in CGI-BP Mania Score at Day 21 | 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. | Baseline and Day 21 | 
| Change From Baseline in CGI-BP Depression Score at Day 4 | 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. | Baseline and Day 4 | 
| Change From Baseline in CGI-BP Depression Score at Day 7 | 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. | Baseline and Day 7 | 
| Change From Baseline in CGI-BP Depression Score at Day 14 | 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. | Baseline and Day 14 | 
| Change From Baseline in CGI-BP Depression Score at Day 21 | 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. | Baseline and Day 21 | 
| Change From Baseline in Children's Depression Rating Scale, Revised (CDRS-R) Total Score at Day 7 | 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. | Baseline and Day 7 | 
| Change From Baseline in CDRS-R Total Score at Day 14 | 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. | Baseline and Day 14 | 
| Change From Baseline in CDRS-R Total Score at Day 21 | 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. | Baseline and Day 21 | 
| Change From Baseline in Children's Global Assessment Scale (CGAS) Score at Day 21 | 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. | Baseline and Day 21 | 
| Change From Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Total Score at Day 21 | 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 with respect to the previous week on a scale of 1=very poor to 5=very good. Items 1-14 assess specific areas (e.g., your health, your mood or feelings); Item 15 is a global assessment of overall quality of life. The PQ-LES-Q total score for each participant was calculated as the sum of the rating assigned to each of the first 14 items, and ranged from 14 to 70 with a higher score indicating better quality of life. The reported measure is the change from baseline at Day 21; improvement in quality of life 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. | Baseline and Day 21 | 
| Change From Baseline in PQ-LES-Q Overall Score (i.e., Item 15) at Day 21 | 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 with respect to the previous week on a scale of 1=very poor to 5=very good. Items 1-14 assess specific areas (e.g., your health, your mood or feelings); Item 15 is a global assessment of overall 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. The reported measure is the change from baseline at Day 21; improvement in quality of life 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. | Baseline and Day 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bi-polar I disorder, antipsychotic, serotonin, dopamine, noradrenalin, histamine, pediatric