Pediatric Open-Label Extension Study

Study Overview
=================
Brief Summary
-----------------
This is an open-label, 104-week, multicenter, extension study designed to evaluate the long-term safety, tolerability and effectiveness of flexibly dosed lurasidone (20, 40, 60 or 80 mg/day) in pediatric subjects who have completed the 6-week treatment period in the preceding studies, D1050301, D1050325, and D1050326

Official Title
-----------------
A 104-Week, Flexible-Dose, Open-Label, Multicenter, Extension Study to Evaluate the Long-Term Safety and Effectiveness of Lurasidone in Pediatric Subjects

Conditions
-----------------
Autism, Schizophrenia, Bipolar Depression

Intervention / Treatment
-----------------
* Drug: Lurasidone 20, 40, 60, 80 mg, flexibly dosed


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent from parent(s) or legal guardian(s) with sufficient intellectual capacity to understand the study and support subjects' participation in the study procedures must be obtained for subjects who are not emancipated. In accordance with Institutional Review Board (IRB) or Independent Ethics Committee (IEC) requirements, the subject will complete an informed assent when developmentally appropriate, to participate in the study before conduct of any study-specific procedures. Subject has completed Study D1050301 (Visit 9) OR Subject has completed Study D1050325 (Visit 9) OR Subject has completed Study D1050326 (Visit 8) Subject is judged by the investigator to be appropriate for participation in a 104-week clinical trial in an outpatient setting involving open-label lurasidone treatment, and is able to comply with the protocol. A reliable informant (eg, parent, legal guardian, or caregiver) must be available to accompany the subject at each visit. For subjects entering from Study D1050325, the reliable caregiver must also oversee the administration of the study drug throughout the study Females who participate in this study: are unable to become pregnant (eg, premenarchal, surgically sterile, etc.) -OR- practices true abstinence (consistent with lifestyle) and must agree to remain abstinent from signing informed consent to at least 7 days after the last dose of study drug has been taken; -OR- are sexually active and willing to use a medically effective method of birth control (eg, male using condom and female using condom, diaphragm, contraceptive sponge, spermicide, contraceptive pill, or intrauterine device) from signing informed consent to at least 7 days after the last dose of study drug has been taken. Males must be willing to remain sexually abstinent (consistent with lifestyle) or use an effective method of birth control (eg, male using condom and female using condom, diaphragm, contraceptive sponge, spermicide, contraceptive pill, or intrauterine device) from signing informed consent to at least 7 days after the last dose of study drug has been taken. Exclusion Criteria: Subject is considered by the investigator to be at imminent risk of suicide. Exhibits evidence of moderate or severe extrapyramidal symptoms, dystonia, tardive dyskinesia, or any other moderate or severe movement disorder. Severity to be determined by the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lurasidone 20, 40, 60, 80 mg, flexibly dosed<br>Lurasidone 20, 40, 60, 80 mg, flexibly dosed, once daily | Drug: Lurasidone 20, 40, 60, 80 mg, flexibly dosed<br>* Lurasidone 20, 40, 60, 80 mg once daily, flexibly dosed<br>* Other names: Latuda;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Adverse Events (AEs), Discontinuations Due to AEs and Serious AEs (SAEs) | The Safety population consists of all subjects who received at least one dose of study drug in this study. | During 104 Weeks (2-years) treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score | Change from Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score for subjects continued from study D1050301. PANSS is comprised of 30 items and 3 subscales (Positive, Negative, General Psychopathology). An anchored Likert scale from 1 - 7, where values of 2 and above indicate the presence of progressively more severe symptoms, is used to score each item. Individual items are then summed to determine scores for the 3 subscales, as well as a total score. PANSS Positive subscale score range: 7-49. PANSS Negative subscale score range: 7-49. PANSS General Psychopathology subscale score range: 16-112. PANSS total score range: 30-210 Higher values of PANSS total score represents greater severity of illness. | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in PANSS Positive Subscale Score | Change from Baseline in PANSS Positive Subscale Score for subjects continued from study D1050301 The Positive scale contains seven questions to assess delusions, conceptual disorganization, hallucinations behavior, excitement, grandiosity, suspiciousness /persecution, and hostility; Positive subscale (range 7-49) is calculated as sum of Items P1 to P7 in the positive subscale Higher values of PANSS sub-scale scores represent greater severity | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in PANSS Negative Subscale Score | Change from Baseline in PANSS Negative Subscale Score for subjects continued from study D1050301 The Negative scale contains seven questions to assess blunted effect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of motivation, and similar symptoms; Negative subscale (range 7-49) is calculated as sum of Items N1 to N7 in the negative subscale Higher values of PANSS sub-scale scores represent greater severity of illness. | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in PANSS General Psychopathology Subscale Score | Change from Baseline in PANSS General Psychopathology Subscale Score for subjects continued from study D1050301 The General Psychopathology subscale addresses other symptoms such as anxiety, somatic concern, and disorientation; General psychopathology subscale (range 16-112) is calculated as sum of Items G1 to G16 in the general psychopathology subscale Higher values of PANSS sub-scale scores represent greater severity of illness. | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in PANSS Excitability Subscale Score | Change from Baseline in PANSS Excitability Subscale Score for subjects continued from study D1050301 Subscale of Excitability consists of the following four items from the PANSS: excitement, hostility, uncooperativeness, and poor impulse control. The sum of the four items ranges from 4 to 28 Higher values of PANSS sub-scale scores represent greater severity of illness. | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in the Clinical Global Impression -Severity Score | Change from Baseline in the Clinical Global Impression -Severity Score for subjects continued from study D1050301 The CGI-S is a single value, clinician-rated assessment of illness severity, and 7-point scale with range from 1='Normal, not at all ill' to 7='Among the most extremely ill patients'. A higher score is associated with greater illness severity | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Clinician-Rated Children's Global Assessment Score (CGAS) Score | Change from Baseline in Clinician-Rated Children's Global Assessment Score (CGAS) Score for subjects continued from study D1050301 The Children's Global Assessment Scale (CGAS) is a numeric scale (1 through 100) used by mental health clinicians to rate the general functioning of children under the age of 18, where 1 represents the most impaired functioning and 100, superior functioning. Each decile (e.g., 1-10, 11-20) has a descriptive header (e.g., Moderate impairment in functioning in most domains) and examples of behaviors and types of environmental accommodations that might be seen at that level of functioning. Scores above 70 on the CGAS indicate functioning within the range of typically developing children of the same age as the child being rated while scores below 60 indicate a definite clinical case | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Percentage Maximum Possible Score | Change from Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Percentage Maximum Possible Score for subjects continued from study D1050301 The Pediatric Q-LES-Q is a 15-item self-report measure of the degree of enjoyment and satisfaction in various areas of daily living, based on the content of the Short From of the Q-LES-Q. Each item is rated on a 5-point scale, ranging from 1 (very poor) to 5 (very good). The first 14 items are the same as the General Activities section of the regular Q-LES-Q form and are used to compute the raw score. The PQ-LES-Q-SF percentage maximum possible score is calculated as follows: % Max = 100 × (Raw Score - Minimum Score) / (Maximum Score - Minimum Score), where the Minimum Score equals 14 and the Maximum Score equals 70, and the % maximum possible score can range from 0% to 100%. Higher scores indicate better quality of life. | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Aberrant Behavior Checklist (ABC) Irritability Subscale Score | Change from Baseline in ABC Irritability Subscale Score for subjects continued from study D1050325 The Aberrant Behavior Checklist (ABC) contains 58 items resolve into five subscales: (1) irritability and agitation (15 items), (2) lethargy and social withdrawal (16 items), (3) stereotypic behavior (7 items), (4) hyperactivity and noncompliance (16 items), and (5) inappropriate speech (4 items). Each item is rated for severity on a 4-point Likert scale ranging from 0 (not at all a problem) to 3 (the problem is severe in degree). Irritability Subscale Score is calculated as summing of items 2, 4, 8, 10, 14, 19, 25, 29, 34, 36, 41, 47, 50, 52, and 57; as a result, ABC irritability subscale score ranges from 0 to 45. In general, higher values of ABC subscale scores represent greater severity of illness. If one or more items are missing, no imputation was performed and the scores of the subscales that include these items was left missing | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Aberrant Behavior Checklist (ABC) Lethargy and Social Withdrawal Subscale Score | Change from Baseline in ABC Lethargy and Social Withdrawal Subscale Score for subjects continued from study D1050325 The ABC contains 58 items resolve into five subscales: (1) irritability and agitation (15 items), (2) lethargy and social withdrawal (16 items), (3) stereotypic behavior (7 items), (4) hyperactivity and noncompliance (16 items), and (5) inappropriate speech (4 items). Each item is rated for severity on a 4-point Likert scale ranging from 0 (not at all a problem) to 3 (the problem is severe in degree). Lethargy and Social Withdrawal Subscale Score is calculated as summing of items 3, 5, 12, 16, 20, 23, 26, 30, 32, 37, 40, 42, 43, 53, 55, and 58. ABC Lethargy and Social Withdrawal Subscale Score ranges from 0 to 48. In general, higher values of ABC subscale scores represent greater severity of illness. If one or more items are missing, no imputation was performed and the scores of the subscales that include these items was left missing | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Aberrant Behavior Checklist (ABC) Stereotypic Behavior Subscale Score | Change from Baseline in ABC Stereotypic Behavior Subscale Score for subjects continued from study D1050325. The ABC contains 58 items resolve into five subscales: (1) irritability and agitation (15 items), (2) lethargy and social withdrawal (16 items), (3) stereotypic behavior (7 items), (4) hyperactivity and noncompliance (16 items), and (5) inappropriate speech (4 items). Stereotypic behavior Subscale Score is calculated as summing of 6, 11, 17, 27, 35, 45, and 49 items . ABC Stereotypic behavior Subscale Score ranges from 0 to 21. Each item is rated for severity on a 4-point Likert scale ranging from 0 (not at all a problem) to 3 (the problem is severe in degree). To score the ABC, the individual items for each subscale are simply summed to their respective totals. It is inappropriate to compute a total aberrant score, based on a summation of all 58 items, as the subscales are largely independent. In general, higher values of ABC subscale scores represent greater severity | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Aberrant Behavior Checklist (ABC) Hyperactivity and Noncompliance Subscale Score | Change from Baseline in ABC Hyperactivity and Noncompliance Subscale Score for subjects continued from study D1050325 The ABC contains 58 items resolve into five subscales: (1) irritability and agitation (15 items), (2) lethargy and social withdrawal (16 items), (3) stereotypic behavior (7 items), (4) hyperactivity and noncompliance (16 items), and (5) inappropriate speech (4 items). Each item is rated for severity on a 4-point Likert scale ranging from 0 (not at all a problem) to 3 (the problem is severe in degree). Hyperactivity and noncompliance Subscale Score is calculated as summing of 1, 7, 13, 15, 18, 21, 24, 28, 31, 38, 39, 44, 48, 51, 54, and 56 items. ABC hyperactivity and noncompliance Subscale Score ranges from 0 to 48. In general, higher values of ABC subscale scores represent greater severity of illness. If one or more items are missing, no imputation was performed and the scores of the subscales that include these items was left missing | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Aberrant Behavior Checklist (ABC) Inappropriate Speech Subscale Score | Change from Baseline in ABC Inappropriate Speech Subscale Score for subjects continued from study D1050325 The ABC contains 58 items resolve into five subscales: (1) irritability and agitation (15 items), (2) lethargy and social withdrawal (16 items), (3) stereotypic behavior (7 items), (4) hyperactivity and noncompliance (16 items), and (5) inappropriate speech (4 items). Each item is rated for severity on a 4-point Likert scale ranging from 0 (not at all a problem) to 3 (the problem is severe in degree). Inappropriate speech Subscale Score is calculated as summing of 9, 22, 33, and 46 items. ABC inappropriate speech Subscale Score ranges from 0 to 12. In general, higher values of ABC subscale scores represent greater severity of illness. If one or more items are missing, no imputation was performed and the scores of the subscales that include these items was left missing | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Clinical Global Impression (CGI) - Severity Score | Change from Baseline in Clinical Global Impression (CGI) - Severity Score for subjects continued from study D1050325 The CGI-S is a single value, clinician-rated assessment of illness severity, and 7-point scale with range from 1='Normal, not at all ill' to 7='Among the most extremely ill patients'. A higher score is associated with greater illness severity | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Children's Yale-Brown Obsessive Compulsive Score (CY-BOCS) | Change from Baseline in CY-BOCS for subjects continued from study D1050325 CY-BOCS used in the study is a modification of the Yale-Brown Obsessive Compulsive Scale and contains total 7 items for compulsion. Obsessions section was removed as it is difficult to obtain valid information given typical language/cognitive delays in the population. Each item of the compulsive scale ranges from 0 to 4. At this time, item 1b (compulsion-free interval) and item 6 (peculiarity of the behavior) are not being used in the scoring. Item 7 is a rating for reliability, ranging from 0 (excellent) to 3 (poor). It reflects the interview's judgment regarding the confidence in the data collected hence it is not counted in the CY-BOCS total score. The CY-BOCS compulsion total score is the sums of item 1-5. As a result, the CY-BOCS compulsion total score may range from 0 to 20. In general, higher values of CY-BOCS scores represent greater severity of illness | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Caregiver Strain Questionnaire (CGSQ) Global Strain Score | Change from Baseline in Caregiver Strain Questionnaire (CGSQ) Global Strain Score for subjects continued from study D1050325 The CGSQ is comprised of total 21 items. Each item is rated on a 5-point Likert-type scale (1 (not at all a problem) to 5 (very much a problem)) and is grouped into three subscales: objective strain, subjective externalized strain, and subjective internalized strain. The 3 subscale scores are calculated as the averages of the corresponding individual items, which range in severity from 1 to 5. Higher scores on each of these subscale scales indicate greater strain. A global strain score is calculated by summing the three subscales (i.e., objective strain, subjective externalized strain, and subjective internalized strain) to provide an indication of the total impact of the special demands on the family. Global strain scores range from 3 to 15. As with the individual subscales, higher scores indicate greater strain | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Children's Depression Rating Scale, Revised (CDRS-R) Total Score | Change from Baseline in CDRS-R Total Score for subjects continued from study D1050326 CDRS-R is a semi-structured, clinician-rated instrument designed for use with children and adolescents between the ages of 6 17 years. It contains 17 ordinally-scaled items that evaluate the presence and severity of symptoms commonly associated with depression in childhood. The CDRS-R is administered separately to the patient and to the caregiver; among 17 items, 14 items are based on separate interviews with child and parent, 3 items are based solely on the rater's observation of child (ie, no questions).The 14 items are rated on a 1 (no psychopathology) to 7 (most psychopathology) scale, where a rating of 3 represents mild psychopathology. The 3 items (sleep disturbance, appetite disturbance, listless speech) are rated on a 1 (no pathology) to 5 (most pathology) scale. The CDRS-R total score ranges from 17-113. In general, higher values of CDRS-R total score represent greater severity of illness | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Clinical Global Impression Bipolar Version (CGI-BP-S) Depression Score | Change from Baseline in Clinical Global Impression Bipolar Version (CGI-BP-S) Depression Score for subjects continued from study D1050326 The CGI-BP-S is a three-question clinician-rated assessment of the subject's current illness state (depression, mania, and overall) using a 7-point scale (1(normal, not ill) to 7 (very severely ill)) for each question, where a higher score is associated with greater illness severity. | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Clinician-rated Children's Global Assessment Scale (CGAS) Score | Change from Baseline in Clinician-rated Children's Global Assessment Scale (CGAS) Score for subjects continued from study D1050326 The Children's Global Assessment Scale (CGAS) is a numeric scale (1 through 100) used by mental health clinicians to rate the general functioning of children under the age of 18, where 1 represents the most impaired functioning and 100, superior functioning. Each decile (e.g., 1-10, 11-20) has a descriptive header (e.g., Moderate impairment in functioning in most domains) and examples of behaviors and types of environmental accommodations that might be seen at that level of functioning. Scores above 70 on the CGAS indicate functioning within the range of typically developing children of the same age as the child being rated while scores below 60 indicate a definite clinical case | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Percentage Maximum Possible Score | Change from Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Percentage Maximum Possible Score for subjects continued from study D1050326 The Pediatric Q-LES-Q is a 15-item self-report measure of the degree of enjoyment and satisfaction in various areas of daily living, based on the content of the Short From of the Q-LES-Q. Each item is rated on a 5-point scale, ranging from 1 (very poor) to 5 (very good). The first 14 items are the same as the General Activities section of the regular Q-LES-Q form and are used to compute the raw score. The PQ-LES-Q-SF percentage maximum possible score is calculated as follows: % Max = 100 × (Raw Score - Minimum Score) / (Maximum Score - Minimum Score), where the Minimum Score equals 14 and the Maximum Score equals 70, and the % maximum possible score can range from 0% to 100%. Higher scores indicate better quality of life. | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Pediatric Anxiety Rating Scale (PAR) Total Score | Change from Baseline in PAR Total Score for subjects continued from study D1050326 The PARS is a clinician-rated instrument for assessing over time the severity of anxiety symptoms associated with common DSM-IV anxiety disorders in children ages 6 17 years. The PARS is administered separately to the subject and to the caregiver. The instrument has 2 sections. The first section includes a 50-item symptom checklist, which the clinician rates as present or absent during the past week. The second section is comprised of 7 severity impairment items reflecting the severity/impairment of all symptoms endorsed in Section 1 of the PARS (during the past week). Each question is answered on a 0-5 Likert scale (0 for none, and 1-5 for minimal to extreme) with alternative responses of 8=Not Applicable and 9=Does Not Know. Scores of 8 or 9 are not counted in the summation as per the PARS instructions. The PARS total score over all 7 questions ranges in value from 0 to 35.A higher PARS total score | Open-Label Baseline, Week 28, Week 52, and Week 104 | 
| Change From Baseline in Attention-Deficity/Hyperactivity Disorder Rating Scale (ADHD-RS) Total Score | Change from Baseline in Attention-Deficity/Hyperactivity Disorder Rating Scale (ADHD-RS) Total Score for subjects continued from study D1050326 The ADHD-RS IV is a validated scale that measures the behaviors of children with ADHD. The ADHD-RS IV consists of 18 items reflecting current symptomatology of ADHD based on DSM-IV-TR criteria. Each item is scored from a range of 0 (no symptoms) to 3 (severe symptoms) with total scores ranging from 0 to 54. The 18 items may be grouped into two sub-scales: hyperactivity/impulsivity (even number items 2 through 18) and inattentiveness (odd number items 1 through 17), ranging from 0 to 27. A higher ADHD-RS total score and sub-scales scores are associated with greater illness severity | Open-Label Baseline, Week 28, Week 52, and Week 104 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Schizophrenia, Autism, Lurasidone, Latuda