Illuminate: Lurasidone Pediatric Bipolar Study

• Sponsor: Sunovion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02046369
• Collaborator: (none)
• Enrollment: 350
• Locations: 66
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

A study to evaluate efficacy and safety of flexibly dosed Lurasidone in children and adolescents with bipolar I depression

Condition or Disease	Intervention/Treatment	Phase
Bipolar I Depression	Drug: Lurasidone; Drug: Placebo	Phase 3

Detailed Description

This is a randomized, parallel, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of flexibly dosed lurasidone (20 - 80 mg/day) for 6 weeks compared with placebo in children and adolescent subjects with depression associated with Bipolar I Disorder (bipolar depression).

Study Design

• Study Type: Interventional
• Actual Enrollment: 350 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, 6-Week, Double-blind, Placebo-Controlled, Flexible Dose, Parallel-Group Study to Evaluate the Efficacy and Safety of Lurasidone in Children and Adolescent Subjects With Bipolar I Depression
• Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Oct 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Luradisone Luradisone 20- 80 mg administered once daily	Drug: Lurasidone; Lurasidone flexibly dosed 20-80 mg once daily; Other Names: Latuda
Placebo Comparator: Placebo Placebo administered once daily	Drug: Placebo; Placebo Comparator once daily

Outcome Measures

Primary Outcome Measures

1. Change in the Children's Depression Rating Scale, Revised (CDRS-R) Total Score as Compared to Placebo From Double-Blind Baseline to Week 6 (Day 43) Baseline [baseline, Week 6]

   CDRS-R total score: changes from baseline over time - mixed model for repeated measures. LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures. The CDRS-R total score ranges from 17-113. In general, higher values of CDRS-R total score represent greater severity of illness. The primary efficacy endpoint will be assessed between the placebo and treatment group.

Secondary Outcome Measures

1. Change From Baseline in Pediatric Anxiety Rating Scale (PARS) Score as Compared to Placebo. [baseline and week 6]

   PARS score: changes from baseline over time - mixed model for repeated measures-LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures.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. The PAR total score over all 7 questions ranges in value from 0 to 35.

2. Change From Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Score as Compared to Placebo. [baseline]

   PQ-LES-Q percentage maximum possible score: changes from baseline over time - mixed model for repeated measures LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures

3. Change From Baseline in Clinician-rated Children's Global Assessment Scale (CGAS) Score as Compared to Placebo. [baseline and week 6]

   CGAS Score: changes from baseline over time - mixed model for repeated measures. LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures. LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures

4. Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) Score as Compared to Placebo. [baseline and week 6]

   ADHD-RS total score: changes from baseline over time -ANCOVA-LS Mean and SE for change from baseline are based on ANCOVA. The Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-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.

5. Change From Baseline in Clinical Global Impressions-Bipolar-Severity (CGI-BP-S) Depression Score [baseline and week 6]

   Change from baseline in Clinical Global Impressions-Bipolar-Severity (CGI-BP-S) depression score changes from baseline over time - mixed model for repeated measures. LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures.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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent from parent(s) or legal guardian(s) with sufficient intellectual capacity to understand the study and support subjects' adherence to the study procedures must be obtained for subjects who are not emancipated. If emancipated, subjects must provide written informed consent. In accordance with Institutional Review Board (IRB) requirements, the subject will complete an informed assent prior to study participation.

• Male or female subjects 10 to 17 years of age, inclusive with bipolar I disorder, most recent episode depressed, with or without rapid cycling disease course (≥ 4 episodes of mood disturbance but < 8 episodes in the previous 12 months) and without psychotic features (diagnosed by DSM-V criteria, and confirmation of the bipolar I disorder diagnosis by an adequately trained clinician at the time of screening, by means of the Schedule for Affective Disorders and Schizophrenia for School-age Children [K-SADS-PL]). Note: The current episode of major depression associated with bipolar I disorder must be confirmed by the investigator and noted in the source records.

• Subject has a lifetime history of at least one manic episode. A reliable informant (eg, family member or caregiver) or medical records must be able to confirm this history.

• Subject's current major depressive episode is ≥ 4 weeks and less than 12 months in duration.

• CDRS-R score ≥ 45 at screening and Baseline.

• YMRS score ≤ 15 (with YMRS Item 1 [elevated mood] score ≤ 2) at screening and Baseline.

• Within 3rd to 97th percentile for gender specific BMI-for-age growth charts from the World Health Organization (WHO) growth charts

• In good physical health on the basis of medical history, physical examination, and laboratory screening.

• 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.

• In the judgment of the investigator, the subject is able to swallow the size and number of study drug tablets specified per protocol

• Willing and able to adhere to protocol-specified meal requirements during dosing.

• Subjects may have a lifetime diagnosis of ADHD. If a subject is taking psychostimulants for ADHD, they must have been on a stable treatment regimen of these medication(s) for 30 days prior to screening and the treatment regimen is expected to remain stable throughout the study. This must be confirmed by the investigator and noted in the source records.

Exclusion Criteria:

• Has an Axis I or Axis II (DSM-IV or any DSM-5) diagnosis other than bipolar I disorder that has been the primary focus of treatment within 3 months of screening.

• Subject has been hospitalized for a bipolar manic or mixed episode within the 30 days prior to randomization.

• Has a history or current diagnosis of intellectual disability, autism spectrum disorder, neuroleptic malignant syndrome, or any neurologic disorder, or severe head trauma.

• Lifetime history of human immunodeficiency virus (HIV) positive or acquired immune deficiency syndrome (AIDS), or history of Hepatitis B or C.

• Any of the following:

• Documented history of chromosomal disorder with developmental impairment (ie, trisomy chromosome 21; 22q11 deletion syndrome).

• Evidence of any chronic organic disease of the CNS such as tumors, inflammation, active seizure disorder, vascular disorder, potential CNS related disorders that might occur in childhood - eg, Duchenne muscular dystrophy, myasthenia gravis, or other neurologic or serious neuromuscular disorders. In addition, subjects must not have a history of persistent neurological symptoms attributable to serious head injury. Past history of febrile seizure, drug-induced seizure, or alcohol withdrawal seizure is not exclusionary.

• CDRS-R total score > 85 at screening or Baseline

• Demonstrates a decrease (improvement) of ≥ 25% in the CDRS-R adjusted total score between Screening and Baseline visits, or the CDRS-R is below 45 at Baseline.

• 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.

• Lifetime history of electroconvulsive therapy (ECT).

• Resistant to antipsychotic treatment based on at least two prior adequate trials (ie, adequate dose and duration) of an antipsychotic agent within the current episode of depression, or subject has a history of non-response to an adequate (6-week) trial of three or more antidepressants (with or without mood stabilizers) during the current episode.

• Clinically significant neurological, metabolic (including Type 1 diabetes), hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, carcinoma, and/or urological disorder that would pose a risk to the subjects if they were to participate in the study or that might confound the results of the study.

• Has a history of malignancy < 5 years prior to signing the informed consent.

• Clinically significant finding(s) on physical examination determined by the investigator to pose a health concern to the subject while on study.

• Clinically relevant abnormal laboratory values or abnormal vital sign values/findings.

• A history or presence of abnormal ECG, which in the investigator's opinion is clinically significant. Abnormal screening ECGs will be centrally over-read, and eligibility will be determined based on the over-read.

• Presence or history (within the last year) of a medical or surgical condition (eg, gastrointestinal disease) that might interfere with the absorption, metabolism, or excretion of orally administered lurasidone.

• Clinically significant substance abuse disorder (with the exception of caffeine or tobacco) based on DSM-5 criteria within the last 6 months prior to screening.

• Positive test results at screening or Baseline for:

1. Urine drugs of abuse (including amphetamines/methamphetamines, barbiturates, benzodiazepines, cocaine, opioids, phencyclidine, and cannabinoids). A positive test for amphetamines/methamphetamines, barbiturates, opioids, or benzodiazepines may not result in exclusion of subjects if the investigator determines that the positive test is as a result of taking prescription medicine(s) as prescribed. In the event a subject tests positive for cannabinoids (tetrahydrocannabinol), the investigator will evaluate the subject's ability to abstain from prohibited substances during the study. If in the investigator's clinical judgment the subject will abstain, the subject may be enrolled after consultation with the Medical Monitor.

2. Pregnancy test.

• Females who are pregnant, lactating, or likely to become pregnant during the study.

• Participated in another interventional clinical trial or receiving an investigational product within 30 days prior to screening.

• Donation of whole blood within 60 days prior to randomization.

• Known history or presence of clinically significant intolerance to any antipsychotic medications including but not limited to angioedema, serotonin or neuroleptic malignant syndromes.

• Clinically relevant history of drug hypersensitivity to lurasidone or any components in the formulation.

• Use of concomitant medications that consistently prolong the QT/QTc interval within 28 days prior to randomization.

• Received depot neuroleptics unless the last injection was at least 1 month or 1 treatment cycle prior to screening, whichever is longer.

• Received treatment with antidepressants, atomoxetine or alpha 2 agonists (eg, guanfacine) within 3 days prior to randomization, fluoxetine hydrochloride within 21 days of randomization, monoamine oxidase (MAO) inhibitor within 28 days of randomization, or clozapine within 120 days of randomization.

• Use of all psychotropic medications prior to randomization with the exception of those medications explicitly permitted within 3 days prior to randomization (7 days prior to randomization for aripiprazole).

• Has a prolactin concentration ≥ 100 ng/mL at screening, or has a history of pituitary adenoma.

• At screening or Baseline the subject answers "yes" to "Suicidal Ideation" Items 4 or 5 on the C-SSRS or has a score of 7 on item 13, Suicidal Ideation, on the CDRS-R.

• Subject is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property during the study. Subject has a history of one or more serious suicide attempts (based on the investigator's judgment) in the 3 months prior to screening. Subjects determined to be at risk of suicide or injury, as assessed by the investigator at screening, will be referred for further psychiatric evaluation.

• Adhering to a special diet for the 28 days prior to drug administration (eg, liquid, protein, raw food diet).

• Subject is planning to move during the study, is chronically homeless, or is unable to attend all planned study visits. The Medical Monitor will be consulted for individual cases, as needed.

• Subject with newly diagnosed Type 2 diabetes during screening or subject is on injectable medication for the treatment of Type 2 diabetes. A subject with Type 2 diabetes is eligible for study inclusion if considered clinically stable, which is defined as:

• Random (non-fasting) screening glucose is < 200 mg/dl (11.1 mmol/L); and If ≥ 200 mg/dL (11.1 mmol/L) must be retested in a fasted state. Retested fasted value cannot be ≥ 126 mg/dL.

• HbA1c ≤ 6.5%; and

• If a subject is currently being treated with oral anti-diabetic medication(s), the dose must have been stable for at least 4 weeks prior to screening. Such medication may be adjusted or discontinued during the study, as clinically indicated.

• Subject has required hospitalization for diabetes or related complications in the past 12 months.

• The use of concomitant medications that are potent inducers or inhibitors of the cytochrome P450 (CYP) 3A4 enzyme system during the trial (from signing informed consent until follow-up).

• Clinically significant orthostatic hypotension (ie, a drop in systolic blood pressure of 20 mmHg or more and/or drop in diastolic blood pressure of 10 mmHg or more within 4 minutes of standing up).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Harmonex Neuroscience Research	Dothan	Alabama	United States	36303
2	ProScience Research Group	Culver City	California	United States	90230
3	Hartford Hospital	Hartford	Connecticut	United States	06106
4	Sarkis Clinical Trials - Parent	Gainesville	Florida	United States	32607
5	APG Research, LLC	Orlando	Florida	United States	32803
6	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30308
7	Attalla Consultants, LLC	Smyrna	Georgia	United States	30080
8	Capstone Clinical Research, Inc.	Libertyville	Illinois	United States	60048
9	Psychiatric Associates	Overland Park	Kansas	United States	66211
10	Lake Charles Clinical Trials, LLC	Lake Charles	Louisiana	United States	70629
11	Kennedy Krieger Institute	Baltimore	Maryland	United States	21205
12	Neurobehavioral Medicine Group, PLLC	Bloomfield Hills	Michigan	United States	48302
13	St. Charles Psychiatric Associates	Saint Charles	Missouri	United States	63301
14	Jersey Shore University Medical Center	Neptune	New Jersey	United States	07753
15	North Shore/Long Island Jewish PRIME	Glen Oaks	New York	United States	11004
16	Bioscience Research, LLC	Mount Kisco	New York	United States	10549
17	Finger Lakes Clinical Research	Rochester	New York	United States	14618
18	Richmond Behavioral Associates	Staten Island	New York	United States	10312
19	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219-0516
20	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
21	Cutting Edge Research of Enid	Oklahoma City	Oklahoma	United States	73116
22	Research Strategies of Memphis, LLC	Memphis	Tennessee	United States	38119
23	BioBehavioral Research of Austin	Austin	Texas	United States	78759
24	Pillar Clinical Research, LLC	Dallas	Texas	United States	75228
25	Family Psychiatry of The Woodlands, P.A.	The Woodlands	Texas	United States	77381
26	Ericksen Research & Development, LLC	Clinton	Utah	United States	84015
27	Aspen Clinical Research	Orem	Utah	United States	84058
28	University of Virginia	Charlottesville	Virginia	United States	22903
29	Clinical Research Partners, LLC	Petersburg	Virginia	United States	23805
30	Pacific Institute Of Medical Sciences	Bothell	Washington	United States	98011
31	MHC - Ruse, EOOD	Ruse		Bulgaria	7003
32	MHAT-Targovishte, AD	Targovishte		Bulgaria	7700
33	DCC "Mladost M" - Varna, OOD	Varna		Bulgaria	9020
34	Centro de Investigaciones y Proyectos en Neurociencias CIPNA	Barranquilla		Colombia
35	Centro de Investigaciones del Sistema Nervioso Limitada - Grupo CISNE Ltda	Bogota		Colombia	00000
36	Hôpitaux Pédiatriques de Nice CHU-Lenval	Nice	Alpes Maritimes	France	06200
37	CHU Nantes - Hôpital Mère-Enfant	Nantes Cedex 1		France	44093
38	Vadaskert Alapitvany a Gyermekek Lelki Egeszsegeert	Budapest		Hungary	1021
39	Bekes Megyei Pandy Kalman Korhaz	Gyula		Hungary	5700
40	Chonbuk National University Hospital	Jeonju	Jeollabuk-do	Korea, Republic of	561-712
41	Chonnam National University Hospital	Gwangju	Jeollanam-do	Korea, Republic of	501-757
42	Inha University Hospital	Incheon		Korea, Republic of	400-711
43	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of	463-707
44	Seoul National University Hospital	Seoul		Korea, Republic of	110774
45	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	120-752
46	Accelerium S. de R.L. de C.V.	Monterrey	Nuevo León	Mexico	64000
47	Centro para el Desarrollo de la Medicina y de Asistencia Medica Especializada S.C.	Culiacan		Mexico	80020
48	Instituto de Investigaciones Aplicadas a la Neurociencia A.C.	Durango		Mexico	34000
49	Instituto de Informacion de Investigacion en Salud Mental	Monterrey		Mexico	64710
50	Consultorio Especializado Psiquiatría Infantil y Adolescentes	San Luis Potosí		Mexico	78200
51	West Visayas State University Medical Center	Iloilo City		Philippines	5000
52	National Center for Mental Health	Mandaluyong City		Philippines	1553
53	Veterans Memorial Medical Center	Quezon City		Philippines	1101
54	NZOZ Poradnia Zdrowia Psychicznego	Kobierzyce		Poland	55-040
55	Wojewodzki Szpital Zespolony im. L. Rydygiera w Toruniu	Torun		Poland	87-100
56	Instytut Psychiatrii i Neurologii	Warsawa		Poland	02-957
57	INSPIRA Clinical Research	San Juan		Puerto Rico	00918
58	RPsH #3 Сhildren Dept SHEI Ivano-Frankivsk SMU	Ivano Frankivsk		Ukraine	76014
59	SI Institute of Neurology, Psychiatry and Narcology of NAMSU	Kharkiv		Ukraine	61068
60	SI Institute of Children and Adolescents Healthcare of NAMSU	Kharkiv		Ukraine	61153
61	CI Kherson Regional Psychiatric Hospital of Kherson RC	Kherson		Ukraine	73488
62	CI Lviv Regional Clinical Psychiatric Hospital	Lviv		Ukraine	79021
63	CI Odesa Regional Medical Center of Mental Health	Odesa		Ukraine	65006
64	O.F. Maltcev Poltava RCPsH Children Dept Ukrainian Medical Stomatological Academy	Poltava		Ukraine	36006
65	Ternopil RCCPH Dept of Psychiatry #9 (adolescent)& #8 (pediatric) Ternopil I.Ya. Gorbachevskyi SMU	Ternopil		Ukraine	46020
66	Chair of Psychiatry and Narcology, Vinnytsia National Medical University, O.I. Yushchenko Regional Psychoneurological Hospital	Vinnytsia		Ukraine	21005

Sponsors and Collaborators

• Sunovion

Investigators

• Study Director: Medical Director, MD, Sunovion

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sunovion
• ClinicalTrials.gov Identifier: NCT02046369
• Other Study ID Numbers: D1050326; 2013-004903-37
• First Posted: Jan 27, 2014
• Last Update Posted: Dec 20, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by Sunovion: Lurasidone, Latuda, Bipolar Depression
• Additional relevant MeSH terms: Depression; Depressive Disorder; Lurasidone Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Luradisone	Placebo
Arm/Group Description	Luradisone 20- 80 mg administered once daily Lurasidone: Lurasidone flexibly dosed 20-80 mg once daily	Placebo administered once daily Placebo: Placebo Comparator once daily
Period Title: Overall Study
STARTED	176	174
COMPLETED	162	156
NOT COMPLETED	14	18

Baseline Characteristics

Arm/Group Title	Luradisone	Placebo	Total
Arm/Group Description	Luradisone 20- 80 mg administered once daily Lurasidone: Lurasidone flexibly dosed 20-80 mg once daily	Placebo administered once daily Placebo: Placebo Comparator once daily	Total of all reporting groups
Overall Participants	175	172	347
Age (Count of Participants)
<=18 years	175 100%	172 100%	347 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.2 (2.18)	14.3 (2.01)	14.2 (2.11)
Sex: Female, Male (Count of Participants)
Female	87 49.7%	83 48.3%	170 49%
Male	88 50.3%	89 51.7%	177 51%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	175 100%	172 100%	347 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 1.1%	0 0%	2 0.6%
Asian	7 4%	4 2.3%	11 3.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	16 9.1%	20 11.6%	36 10.4%
White	135 77.1%	125 72.7%	260 74.9%
More than one race	15 8.6%	23 13.4%	38 11%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Colombia	7 4%	7 4.1%	14 4%
South Korea	4 2.3%	3 1.7%	7 2%
Hungary	5 2.9%	5 2.9%	10 2.9%
United States	75 42.9%	75 43.6%	150 43.2%
Philippines	2 1.1%	0 0%	2 0.6%
Ukraine	33 18.9%	33 19.2%	66 19%
Poland	2 1.1%	3 1.7%	5 1.4%
Mexico	16 9.1%	17 9.9%	33 9.5%
Bulgaria	9 5.1%	8 4.7%	17 4.9%
France	1 0.6%	0 0%	1 0.3%
Russia	21 12%	21 12.2%	42 12.1%
Psychiatric History (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.44 (2.790)	12.17 (2.680)	12.30 (2.735)
Bipolar I disorder history (Count of Participants)
Without rapid cycling (0-3 cycles past 12 months	149 85.1%	147 85.5%	296 85.3%
Without rapid cycling(4-7 cycles past 12 months	26 14.9%	24 14%	50 14.4%
With 8 or more cycles within past 12 months	0 0%	1 0.6%	1 0.3%

Outcome Measures

1. Primary Outcome

Title	Change in the Children's Depression Rating Scale, Revised (CDRS-R) Total Score as Compared to Placebo From Double-Blind Baseline to Week 6 (Day 43) Baseline
Description	CDRS-R total score: changes from baseline over time - mixed model for repeated measures. LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures. The CDRS-R total score ranges from 17-113. In general, higher values of CDRS-R total score represent greater severity of illness. The primary efficacy endpoint will be assessed between the placebo and treatment group.
Time Frame	baseline, Week 6

Outcome Measure Data

Analysis Population Description

The ITT population includes all randomized subjects who received at least one dose of study medication and had at least one post-baseline assessment in any efficacy variable

Arm/Group Title	Luradisone	Placebo
Arm/Group Description	Luradisone 20- 80 mg administered once daily Lurasidone: Lurasidone flexibly dosed 20-80 mg once daily	Placebo administered once daily Placebo: Placebo Comparator once daily
Measure Participants	173	170
baseline	59.2 (8.24)	58.6 (8.26)
week 6	-21.0 (1.06)	-15.3 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luradisone, Placebo
	Comments	A mean difference in change from Baseline in CDRS-R total score of 5.0 units was assumed for the lurasidone 20-80 mg/day arm over the placebo arm, and a common standard deviation of 14.2 units (effect size=0.35), a sample size of 145 subjects per treatment arm was calculated to yield a power of 85%. With an expected attrition rate of 15%, approximately 170 subjects per treatment arm (340 in total) were to be randomized in a 1:1 ratio .
	Type of Statistical Test	Superiority
	Comments	The primary efficacy endpoint (the change from baseline in CDRS-R total score at Week 6)will be analyzed using a likelihood-based mixed model for repeated measures (MMRM).The response (dependent) variable is the change from baseline in CDRS-R total score assessed weekly (Weeks 1 to 6).The MMRM model includes fixed effects terms for treatment, visit (as a categorical variable), pooled country, age stratum (stratification factor, CDRS-R total score at baseline, and treatment-by-visit interaction.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	LS mean differnece (SE)
	Comments
Method of Estimation	Estimation Parameter	LS mean differnce (SE)
	Estimated Value	-5.7
	Confidence Interval	(2-Sided) 95%; -8.4 to -3.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.39
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Pediatric Anxiety Rating Scale (PARS) Score as Compared to Placebo.
Description	PARS score: changes from baseline over time - mixed model for repeated measures-LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures.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. The PAR total score over all 7 questions ranges in value from 0 to 35.
Time Frame	baseline and week 6

Outcome Measure Data

Analysis Population Description

The ITT population included all randomized subjects who received at least one dose of study medication and had at least one post-baseline assessment in any efficacy variable

Arm/Group Title	Luradisone	Placebo
Arm/Group Description	Luradisone 20- 80 mg administered once daily Lurasidone: Lurasidone flexibly dosed 20-80 mg once daily	Placebo administered once daily Placebo: Placebo Comparator once daily
Measure Participants	173	170
baseline	10.9 (7.72)	11.5 (7.60)
week 6	-3.4 (0.44)	-2.3 (0.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luradisone, Placebo
	Comments	LS mean difference, and the associated 95% CI and p-value for change from baseline are based on Mixed Model for Repeated Measures (MMRM).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0385
	Comments
	Method	LS mean differnece (SE)
	Comments
Method of Estimation	Estimation Parameter	LS mean differnce (SE)
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -2.2 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.54
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Score as Compared to Placebo.
Description	PQ-LES-Q percentage maximum possible score: changes from baseline over time - mixed model for repeated measures LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

the ITT population included all randomized subjects who received at least one dose of study medication and had at least one post-baseline assessment on any efficacy variable

Arm/Group Title	Luradisone	Placebo
Arm/Group Description	Luradisone 20- 80 mg administered once daily Lurasidone: Lurasidone flexibly dosed 20-80 mg once daily	Placebo administered once daily Placebo: Placebo Comparator once daily
Measure Participants	173	169
baseline	49.6 (15.49)	49.7 (17.31)
week 6	11.8 (1.10)	7.9 (1.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luradisone, Placebo
	Comments	LS mean difference, and the associated 95% CI and p-value for change from baseline are based on Mixed Model for Repeated Measures (MMRM).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0044
	Comments
	Method	LS mean differnece (SE)
	Comments
Method of Estimation	Estimation Parameter	LS mean differnce (SE)
	Estimated Value	3.9
	Confidence Interval	(2-Sided) 95%; 1.2 to 6.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.35
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Clinician-rated Children's Global Assessment Scale (CGAS) Score as Compared to Placebo.
Description	CGAS Score: changes from baseline over time - mixed model for repeated measures. LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures. LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures
Time Frame	baseline and week 6

Outcome Measure Data

Analysis Population Description

the ITT population included all randomized subjects who received at least one dose of study medication and had at least one post-baseline assessment in any efficacy variable

Arm/Group Title	Luradisone	Placebo
Arm/Group Description	Luradisone 20- 80 mg administered once daily Lurasidone: Lurasidone flexibly dosed 20-80 mg once daily	Placebo administered once daily Placebo: Placebo Comparator once daily
Measure Participants	173	170
baseline	48.8 (8.73)	49.5 (6.99)
week 6	14.0 (0.96)	9.3 (0.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luradisone, Placebo
	Comments	LS mean difference, and the associated 95% CI and p-value for change from baseline are based on Mixed Model for Repeated Measures (MMRM).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	LS mean differnece (SE)
	Comments
Method of Estimation	Estimation Parameter	LS mean differnce (SE)
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; 2.4 to 7.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.19
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) Score as Compared to Placebo.
Description	ADHD-RS total score: changes from baseline over time -ANCOVA-LS Mean and SE for change from baseline are based on ANCOVA. The Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-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.
Time Frame	baseline and week 6

Outcome Measure Data

Analysis Population Description

The ITT population included all randomized subjects who received at least one dose of study medication and had at least one post-baseline assessment in any efficacy variable

Arm/Group Title	Luradisone	Placebo
Arm/Group Description	Luradisone 20- 80 mg administered once daily Lurasidone: Lurasidone flexibly dosed 20-80 mg once daily	Placebo administered once daily Placebo: Placebo Comparator once daily
Measure Participants	173	167
baseline	11.8 (10.85)	12.3 (11.62)
week 6	-2.6 (7.26)	-2.0 (7.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luradisone, Placebo
	Comments	LS mean difference, and the associated 95% CI and p-value for change from baseline are based on Mixed Model for Repeated Measures (MMRM).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3715
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean differnce (SE)
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -2.2 to 0.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.77
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Clinical Global Impressions-Bipolar-Severity (CGI-BP-S) Depression Score
Description	Change from baseline in Clinical Global Impressions-Bipolar-Severity (CGI-BP-S) depression score changes from baseline over time - mixed model for repeated measures. LS Mean and SE for change from baseline are based on Mixed Model for Repeated Measures.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.
Time Frame	baseline and week 6

Outcome Measure Data

Analysis Population Description

the ITT population included all randomized subjects who received at least one dose of study medication and had at least one post-baseline assessment in any efficacy variable

Arm/Group Title	Luradisone	Placebo
Arm/Group Description	Luradisone 20- 80 mg administered once daily Lurasidone: Lurasidone flexibly dosed 20-80 mg once daily	Placebo administered once daily Placebo: Placebo Comparator once daily
Measure Participants	173	170
baseline	4.6 (0.65)	4.5 (0.57)
week 6	-1.49 (0.085)	-1.05 (0.087)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luradisone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	LS mean difference, and the associated 95% CI and p-value for change from baseline are based on Mixed Model for Repeated Measures (MMRM).
	Method	LS mean differnece (SE)
	Comments
Method of Estimation	Estimation Parameter	LS mean differnce (SE)
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.66 to -0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.112
	Estimation Comments

Adverse Events

Time Frame	Through study completion. Treatment emergent adverse event (TEAE) is defined as an AE with a start date on or after the date of first does through 7 days after study drug discontinuation (14 days for serious adverse events and deaths) for subjects who complete the double blind study but do not enter the extension study or early discontinue during the double blind study), or through the last study day of the double blind period for subjects continuing into the extension study
Adverse Event Reporting Description	number of participants at risk is equal to the number of patients in the safety population (172 in placebo and 175 in lurasidone)
Arm/Group Title	Luradisone		Placebo
Arm/Group Description	Luradisone 20- 80 mg administered once daily Lurasidone: Lurasidone flexibly dosed 20-80 mg once daily		Placebo administered once daily Placebo: Placebo Comparator once daily
All Cause Mortality
	Luradisone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Luradisone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/175 (1.1%)		4/172 (2.3%)
Injury, poisoning and procedural complications
humerus fracture	1/175 (0.6%)	1	0/172 (0%)	0
Pregnancy, puerperium and perinatal conditions
abortion spontaneous	0/175 (0%)	0	1/172 (0.6%)	1
Psychiatric disorders
Bipolar I disorder	1/175 (0.6%)	1	1/172 (0.6%)	1
depression	0/175 (0%)	0	1/172 (0.6%)	1
psychotic disorder	0/175 (0%)	0	1/172 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Luradisone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/175 (64%)		75/172 (43.6%)
Gastrointestinal disorders
nausea	28/175 (16%)	35	10/172 (5.8%)	13
vomiting	11/175 (6.3%)	15	6/172 (3.5%)	8
Infections and infestations
nasopharyngitis	7/175 (4%)	7	10/172 (5.8%)	10
Investigations
weight increased	12/175 (6.9%)	12	3/172 (1.7%)	3
Nervous system disorders
headache	25/175 (14.3%)	30	26/172 (15.1%)	38
somnolence	16/175 (9.1%)	20	8/172 (4.7%)	9
dizziness	10/175 (5.7%)	12	8/172 (4.7%)	8
Psychiatric disorders
insomnia	9/175 (5.1%)	9	4/172 (2.3%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In the event the Study is part of a multi-center study, the first publication of the results of the Study shall be made in conjunction with the results of other participating study sites as a multi-center publication; provided however, if a multi-center publication is not forthcoming within twenty-four (24) months following completion of the Study at all sites, Institution and Investigator shall be free to publish.