Fixed Dose Efficacy and Safety Study of Asenapine for the Treatment of Schizophrenia in Adolescents (P05896)

Study Overview
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Brief Summary
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This study is designed to evaluate whether asenapine, which is approved by the United States Food and Drug Administration (US FDA) for acute treatment of schizophrenia in adults, is also effective in adolescents with schizophrenia. Participants who qualify for the study will be randomly assigned to receive a fixed dose of asenapine (either 2.5 mg or 5 mg twice daily [BID]) or placebo for 8 weeks. Throughout the study, observations will be made on each participant at various times to assess the efficacy and safety of the study treatment. The primary objective of the trial is to demonstrate significant superiority of at least one asenapine dose to placebo, as measured by the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score at Day 56.

Official Title
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An 8-week, Placebo-controlled, Double-blind, Randomized, Fixed-dose Efficacy and Safety Trial of Asenapine in Adolescent Subjects With Schizophrenia

Conditions
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Schizophrenia, Paranoid, Schizophrenia, Disorganized, Schizophrenia, Undifferentiated

Intervention / Treatment
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* Drug: asenapine 2.5 mg
* Drug: asenapine 5.0 mg
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each participant must have schizophrenia, diagnosed and confirmed by board-eligible or board certified psychiatrists with at least two years of specialization in pediatric/adolescent psychiatric medicine. Each participant must be ≥12 years of age and <18 years of age. Each participant must have a minimum PANSS total score of 80 at Screening and Baseline. Each participant must have a score of at least 4 (moderate) on two or more of the five items in the positive subscale of the PANSS (delusions, conceptual disorganization, hallucinatory behavior, grandiosity, suspiciousness/ persecution) at Screening and Baseline. Each participant must have a CGI-S scale score of ≥4 at Screening and Baseline. Each participant must taper off all prohibited psychotropic medications (including antipsychotics, antidepressants, and mood stabilizers) prior to Baseline. Each participant must agree not to begin formal, structured psychotherapy during the trial. Exclusion Criteria: A participant must not have a diagnosis of schizoaffective disorder; schizophrenia of residual subtype; schizophrenia of catatonic subtype, or schizophrenia with continuous, single episode in partial remission, or single episode in full remission course specifiers. A participant must not have a primary Axis I diagnosis other than schizophrenia and must not have a comorbid Axis I diagnosis that is primarily responsible for current symptoms and functional impairment. A participant must not have a known or suspected diagnosis of mental retardation or organic brain disorder. A participant must not currently (within the past 6 months) meet the Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR^TM) criteria for substance abuse or dependence (excluding nicotine). A participant must not have a diagnosis of psychotic disorder or a behavioral disturbance thought to be substance induced or due to substance abuse. A participant must not be at imminent risk of self-harm or harm to others, in the investigator's opinion based on clinical interview and responses provided on the Columbia Suicide Severity Rating Scale (C-SSRS).

Ages Eligible for Study
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Minimum Age: 12 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 BID<br>Participants receive active asenapine 2.5 mg tablets sublingually BID for 8 weeks. | Drug: asenapine 2.5 mg<br>* asenapine 2.5 mg tablets for sublingual administration<br>* Other names: Saphris®, SCH 900274, Org 5222;|
| Experimental: Asenapine 5.0 mg BID<br>Participants receive active asenapine 2.5 mg tablets sublingually 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 active asenapine 5.0 mg tablets sublingually BID for the remainder of the 8-week treatment period. | Drug: asenapine 2.5 mg<br>* asenapine 2.5 mg tablets for sublingual administration<br>* Other names: Saphris®, SCH 900274, Org 5222;Drug: asenapine 5.0 mg<br>* asenapine 5.0 mg tablets for sublingual administration<br>* Other names: Saphris®, SCH 900274, Org 5222;|
| Placebo Comparator: Placebo<br>Participants receive placebo asenapine tablets sublingually BID for 8 weeks. | Drug: placebo<br>* asenapine-matched placebo tablets for sublingual administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Day 56 | The PANSS is a 30-item clinician-rated instrument for assessing the symptoms of schizophrenia. It consists of 3 subscales: positive subscale (7 items), negative subscale (7 items), and general psychopathology subscale (16 items). Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS total score for each participant was calculated as the sum of the rating assigned to each of the 30 PANSS items, and ranged from 30 to 210 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at Day 56 | Change from baseline in CGI-S score at Day 56 is the Key Secondary Outcome Measure. CGI-S is a 7-point scale for assessing the global severity of the participant's illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Change From Baseline in PANSS Positive Subscale Score at Day 56 | This measure reports results for the 7 items of the positive subscale of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS positive subscale score for each participant was calculated as the sum of the rating assigned to each of the 7 subscale items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Change From Baseline in PANSS Negative Subscale Score at Day 56 | This measure reports results for the 7 items of the negative subscale of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS negative subscale score for each participant was calculated as the sum of the rating assigned to each of the 7 subscale items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Change From Baseline in PANSS Positive and Negative Subscale Scores Combined at Day 56 | This measure reports results for the combined positive subscale (7 items) and negative subscale (7 items) of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each of the total 14 items in the combined positive and negative subscales, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS positive and negative subscale scores combined for each participant was calculated as the sum of the rating assigned to each of the 14 combined subscale items, and ranged from 14 to 98 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Change From Baseline in PANSS General Psychopathology Subscale Score at Day 56 | This measure reports results for the 16 items of the general psychopathology subscale of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS general psychopathology subscale score for each participant was calculated as the sum of the rating assigned to each of the 16 subscale items, and ranged from 16 to 112 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Change From Baseline in PANSS Marder Positive Symptoms Factor Score at Day 56 | This measure reports results for the 8 items of the Marder positive symptoms factor of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. Marder factors are a modified grouping of the 30 PANSS items (Marder et al. J Clin Psychiatry 1997;58(12):538-46). Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder positive symptoms factor score for each participant was calculated as the sum of the rating assigned to each of the 8 applicable Marder factor items, and ranged from 8 to 56 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Change From Baseline in PANSS Marder Negative Symptoms Factor Score at Day 56 | This measure reports results for the 7 items of the Marder negative symptoms factor of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. Marder factors are a modified grouping of the 30 PANSS items. Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder negative symptoms factor score for each participant was calculated as the sum of the rating assigned to each of the 7 applicable Marder factor items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Change From Baseline in PANSS Marder Disorganized Thoughts Factor Score at Day 56 | This measure reports results for the 7 items of the Marder disorganized thoughts factor of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder disorganized thoughts factor score for each participant was calculated as the sum of the rating assigned to each of the 7 applicable Marder factor items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Change From Baseline in PANSS Marder Hostility/Excitement Factor Score at Day 56 | This measure reports results for the 4 items of the Marder hostility/excitement factor of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder hostility/excitement factor score for each participant was calculated as the sum of the rating assigned to each of the 4 applicable Marder factor items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Change From Baseline in PANSS Marder Anxiety/Depression Factor Score at Day 56 | This measure reports results for the 4 items of the Marder anxiety/depression factor of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder anxiety/depression factor score for each participant was calculated as the sum of the rating assigned to each of the 4 applicable Marder factor items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. | Baseline and Day 56 | 
| Total PANSS 30% Responders | A Total PANSS 30% responder was defined as a participant who had a reduction from baseline of at least 30% in the PANSS Total score at the last available assessment of the study for that participant (i.e., endpoint). The PANSS is a 30-item clinician-rated instrument for assessing the symptoms of schizophrenia. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The Total score is the sum of the ratings for the individual items, and ranged from 30 to 210 with a higher score indicating greater severity of symptoms. | Baseline up to Day 56 | 
| Kaplan-Meier Estimate of Cumulative Percentage of Participants With Total PANSS 30% Response at End of Study | A total PANSS 30% response was defined as a reduction from baseline of at least 30% in the PANSS Total score. The PANSS is a 30-item clinician-rated instrument for assessing the symptoms of schizophrenia. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The Total score is the sum of the ratings for the individual items, and ranged from 30 to 210 with a higher score indicating greater severity of symptoms. The Kaplan-Meier estimate reports the cumulative percentage of participants with total PANSS 30% response from first drug intake up to approximately Day 59. | Baseline up to approximately Day 59 | 
| Clinical Global Impression of Improvement (CGI-I) Score at Day 56 | CGI-I is a 7-point scale for assessing the global improvement of the participant's illness relative to baseline, with ratings from 1=very much improved to 7=very much worse. | Baseline and Day 56 | 
| CGI-I Responders | A CGI-I responder was defined as a participant who had a CGI-I score of 1 (very much improved) or 2 (much improved) at the last available assessment of the study for that participant (i.e., endpoint). CGI-I is a 7-point scale for assessing the global improvement of the participant's illness relative to baseline, with ratings from 1=very much improved to 7=very much worse. | Baseline up to Day 56 | 
| Kaplan-Meier Estimate of Cumulative Percentage of Participants With CGI-I Response at End of Study | CGI-I response was defined as the occurrence of a CGI-I score of 1 (very much improved) or 2 (much improved). CGI-I is a 7-point scale for assessing the global improvement of the participant's illness relative to baseline, with ratings from 1=very much improved to 7=very much worse. The Kaplan-Meier estimate reports the cumulative percentage of participants with CGI-I response from first drug intake up to approximately Day 58. | Baseline up to approximately Day 58 | 
| Change From Baseline in Children's Global Assessment Scale (CGAS) Score at Day 56 | 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 56; improvement in functioning is represented by positive values. | Baseline and Day 56 | 
| Change From Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Total Score at Day 56 | 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 56; improvement in quality of life is represented by positive values. This analysis used a last-observation-carried-forward (LOCF) approach; if no Day 56 value was available for a participant, the last available assessment prior to the Day 56 assessment was used. | Baseline and Day 56 | 
| Change From Baseline in PQ-LES-Q Overall Score (i.e., Item 15) at Day 56 | 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 56; improvement in quality of life is represented by positive values. This analysis used an LOCF approach; if no Day 56 value was available for a participant, the last available assessment prior to the Day 56 assessment was used. | Baseline and Day 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asenapine, adolescents, schizophrenia, phase IIIb, placebo-controlled