Efficacy and Safety of Lurasidone in Children and Adolescents With Bipolar I Depression: A Double-Blind, Placebo-Controlled Study

Accepted Manuscript Efficacy and Safety of Lurasidone in Children and Adolescents With Bipolar I Depression: A Double-Blind, Placebo-Controlled Study Melissa P. DelBello, MD, MS, Robert Goldman, PhD, Debra Phillips, BA, Ling Deng, PhD, Josephine Cucchiaro, PhD, Antony Loebel, MD PII:

S0890-8567(17)31772-0

DOI:

10.1016/j.jaac.2017.10.006

Reference:

JAAC 1983

To appear in:

Journal of the American Academy of Child & Adolescent Psychiatry

Received Date: 3 July 2017 Revised Date:

2 October 2017

Accepted Date: 5 October 2017

Please cite this article as: DelBello MP, Goldman R, Phillips D, Deng L, Cucchiaro J, Loebel A, Efficacy and Safety of Lurasidone in Children and Adolescents With Bipolar I Depression: A Double-Blind, Placebo-Controlled Study, Journal of the American Academy of Child & Adolescent Psychiatry (2017), doi: 10.1016/j.jaac.2017.10.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Efficacy and Safety of Lurasidone in Children and Adolescents With Bipolar I Depression: A Double-Blind, Placebo-Controlled Study RH = Lurasidone for BP Depression in Youth

Josephine Cucchiaro, PhD, Antony Loebel, MD

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Melissa P. DelBello, MD, MS, Robert Goldman, PhD, Debra Phillips, BA, Ling Deng, PhD,

This article is discussed in an editorial by Dr. Jon McClellan on page xx. Accepted October 6, 2017

Dr. DelBello is with the Division of Bipolar Disorders Research, University of Cincinnati

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College of Medicine, Cincinnati, OH. Dr. Goldman is with Sunovion Pharmaceuticals Inc, Marlborough, MA. Drs. Deng, Cucchiaro, Loebel, and Ms. Phillips are with Sunovion

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Pharmaceuticals Inc, Fort Lee, NJ. This work is sponsored by Sunovion Pharmaceuticals Inc. Dr. Deng served as the statistical expert for this research.

The authors wish to thank Edward Schweizer, MD, of Paladin Consulting Group, who provided editorial and medical writing support under the direction of the authors, that was funded by Sunovion Pharmaceuticals.

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Disclosure: Dr. DelBello has received grant or research support from National Institute of Mental Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the PatientCentered Outcomes Research Institute, Supernus, Sunovion, Otsuka, Pfizer, Lundbeck, and Shire. She has served on the advisory board/DSMB of Sunovion, Neuronetics, Akili, Supernus,

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Lundbeck, and Johnson and Johnson. She has served as a consultant to Johnson and Johnson, Takeda, and Sunovion. She has served on the editorial board of Bipolar Disorders (Section

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Editor, Pediatrics) and the Journal of Child and Adolescent Psychopharmacology (Associate Editor, Neuroimaging). She has received honoraria from American Academy of Child and Adolescent Psychiatry Institute presentations. She has served on the speakers’ bureau of Sunovion and Otsuka. She has received travel expenses from Sunovion and Supernus. Drs. Goldman, Deng, Cucchiaro, Loebel, and Ms. Phillips are employees of Sunovion Pharmaceuticals Inc. Correspondence to Melissa P. DelBello, MD, University of Cincinnati College of Medicine, Department of Psychiatry, 231 Bethesda Ave., P.O. Box 670559, Cincinnati, OH 45267; email: [email protected].

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ABSTRACT Objective: To evaluate the efficacy and safety of lurasidone in children and adolescents with bipolar depression.

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Method: Patients 10-17 years with a DSM-5 diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with flexible doses of lurasidone 20-80 mg/day. The

primary endpoint was change from baseline to week 6 in the Children’s Depression Rating

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Scale–Revised (CDRS-R) total score, evaluated by a mixed model repeated measures analysis. Results: A total of 347 patients were randomized and received at least one dose of lurasidone

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(n=175; mean age, 14.2 years; mean dose, 33.6 mg/day) or placebo (n=172; mean age, 14.3 years). At the primary week 6 endpoint, treatment with lurasidone was associated with statistically significant improvement compared with placebo in CDRS-R total score (-21.0 vs. 15.3; P<.0001; effect size, 0.45). Lurasidone was also associated with statistically significant

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improvement in the Clinical Global Impression-Bipolar-Severity (key secondary measure), and measures of anxiety, quality of life, and global functioning. Study completion rates were 92.0% in the lurasidone group, and 89.7% in the placebo group; discontinuation rates due to adverse

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events were the same for both groups (1.7%). The two most common adverse events on lurasidone were nausea and somnolence. Treatment with lurasidone was associated with few

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effects on weight and metabolic parameters. Conclusion: In this placebo-controlled study, monotherapy with lurasidone, in the dose range of 20-80 mg/day, significantly reduced depressive symptoms in children and adolescents with bipolar depression. Lurasidone was well-tolerated, with minimal effects on weight and metabolic parameters. Clinical trial registration information—Lurasidone Pediatric Bipolar Study;

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http://Clinicaltrials.gov/; NCT02046369. Key Words: bipolar depression; second generation antipsychotic; lurasidone INTRODUCTION

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Bipolar disorder (BD) in children and adolescents has an estimated prevalence of

approximately 1.8% (95%-CI, 1.1%-3.0%), with higher estimates reported in studies that

to age 19 occurs in an estimated 50-60% of individuals.2,3

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included broader definitions of bipolarity (e.g., bipolar II).1 Among adults with BD, onset prior

BD in children and adolescents is associated with high rates of recurrence and psychiatric

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comorbidity,4-6 marked impairment in functioning and quality of life,7-9 and increased risk for both suicide attempts10,11 and self-injurious behavior.12 Follow-up studies in youth have reported a median time to recovery from an index bipolar I episode of 78 weeks (averaged across both poles), and median time to a recurrence of 69 weeks, with a depressive episode being the most

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frequent subsequent episode.13

Efficacy in treating manic or mixed mood states in children and adolescent with bipolar disorder has been demonstrated for lithium14 and for several second-generation antipsychotic

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agents (SGAs).15-19 However, few controlled treatment studies of bipolar depression in children and adolescents have been reported. To our knowledge, there have been no controlled studies in

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pediatric populations of mood stabilizers for bipolar depression, and only 3 studies of SGAs have been reported. Two short-term studies of quetiapine failed to demonstrate efficacy,20,21 while one study, of combination olanzapine/fluoxetine (OFC) therapy,22 demonstrated efficacy in youth with bipolar depression. However, treatment with OFC was associated with a high discontinuation rate, and a high proportion of patients (52%) experiencing ≥7% weight gain. Thus, there remains a substantial unmet need for efficacious treatment of bipolar depression in

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children and adolescents with a favorable tolerability and benefit–risk profile, in particular lower cardiometabolic risk.23,24 Lurasidone is an SGA with high affinity for D2, 5-HT2A, and 5-HT7 receptors (Ki=1 nM,

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0.5 nM, and 0.495 nM, respectively).25 In animal models, lurasidone has demonstrated

antidepressant effects that have been shown to be mediated, in part, by antagonist activity at the 5-HT7 receptor.26,27 In two placebo-controlled clinical trials, lurasidone has demonstrated

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efficacy for the treatment of bipolar depression in adults, both as monotherapy and as adjunctive therapy with lithium or valproate.28,29 On the basis of these studies, lurasidone was approved by

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the United States Food and Drug Administration (USFDA) for the treatment of bipolar depression. Lurasidone has also demonstrated efficacy in adult patients with unipolar depression presenting with subthreshold hypomanic symptoms (mixed features).30 With these considerations in mind, this study was designed to evaluate the efficacy and safety of lurasidone for the

METHOD Patients

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treatment of major depressive episode in children and adolescents with BD.

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This international study (clinicaltrials.gov identifier: NCT02046369) enrolled male or female patients, 10 to 17 years, with bipolar I disorder, based on DSM-5 criteria,31 who were

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experiencing a major depressive episode with a duration of 1-12 months, and had a Children’s Depression Rating Scale–Revised (CDRS-R)32 total score ≥45 at screening and baseline. The DSM-5 bipolar I disorder diagnosis was confirmed based on completion of the Schedule for Affective Disorders and Schizophrenia for School-age Children-Present and Lifetime (K-SADSPL)33 interview administered by a trained clinician. Patients with a history of rapid cycling (≥4 but ≤8 mood episodes in the previous 12 months) were eligible for enrollment. A Young Mania

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Rating Scale (YMRS)34 score ≤15 was required for study entry, with a YMRS item 1 (elevated mood) score ≤2 at screening and baseline. Patients were excluded if they met DSM-IV-TR criteria for a current or lifetime diagnosis

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of schizophrenia or any psychotic disorder, substance use disorder within the last 6 months

(except caffeine or tobacco), intellectual disability, or autism spectrum disorder. Patients were also excluded if any clinically significant neurologic, endocrine, or other medical disorder was

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present at screening that might pose a risk to patients participating in the study, or that might confound interpretation of study results. Sex-specific body mass index (BMI)-for-age was

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required to be within the 3rd to 97th percentile on the World Health Organization (WHO) growth charts.35 Patients were excluded if their CDRS-R total score was >85 at screening or baseline, or if CDRS-R total score decreased by ≥25% from the screening to baseline visit. Enrollment was permitted for patients currently being treated in an inpatient, outpatient,

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partial hospital, or therapeutic day program setting. Hospitalization was permitted for up to 14 days, or until discharge was judged to be clinically appropriate. Enrollment was also permitted for patients with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) who were

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receiving a stable regimen of stimulant medication for at least 30 days prior to screening. Sexually active males and females (unless premenarchal or surgically sterile) were required to

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use an effective method of birth control. The study was approved by the institutional review board at each investigational site and

was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and with the ethical principles of the Declaration of Helsinki. Informed assent and consent were obtained from all patients and their legal guardian, respectively, at study entry and before commencement of any study procedures. The study was conducted between March

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2014 and October 2016. Study Design Three-hundred and fifty children and adolescents at 28 sites in the United States (n=153

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patients) and 36 non-US sites (in Bulgaria, Colombia, France, Hungary, Mexico, Philippines, Poland, Russia, South Korea, Ukraine; n=263 patients) were enrolled in this randomized, doubleblind, placebo-controlled, parallel-group, 6-week study. Patients were evaluated for eligibility

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during a screening period of up to 21 days, during which they were tapered off all psychotropic medications (except for permitted concomitant medications). Following the screening period,

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patients who continued to meet entry criteria were randomly assigned, in a 1:1 ratio, either to lurasidone or placebo. Study medication was provided in blister packs as identically matched (in color, shape, size, and packaging) lurasidone 20 mg or 40 mg tablets, or placebo tablets. A central randomization center used a computer-generated list of random numbers to allocate study

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treatments. None of the investigators, study staff, or patients had access to the randomization codes or list during the study. In order to ensure balanced treatment allocation for younger and older patients, and for patients receiving (vs. not receiving) stimulant treatment for ADHD,

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randomization was balanced using permuted blocks with two within-country stratification criteria applied: 1) age group (10-14 vs. 15-17 years old at screening); and 2) stimulant usage

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status. Treatment with lurasidone was initiated at a daily dose of lurasidone 20 mg for 7 days, with flexible dosing, in the range of 20-80 mg/day permitted after 7 days. Participants were instructed to take study treatment once daily in the evening by mouth with food (at least 350 calories), or within 30 minutes after eating. Patients who completed the study were eligible to participate in a separate 104-week, open-label, lurasidone extension study (clinicaltrials.gov identifier: NCT01914393).

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Concomitant Medications Anticholinergic therapy was permitted for the as-needed treatment of extrapyramidal symptoms (EPS; benztropine ≤ 6 mg/d, biperiden ≤ 16 mg/day, trihexyphenidyl ≤ 15 mg/day, or

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diphenhydramine ≤ 100 mg/day). Treatment of akathisia with propranolol (≤ 120 mg/day, as needed) was permitted. Concomitant use of benzodiazepines was permitted (≤ 6 mg/day of

lorazepam equivalents). Temazepam (≤ 30 mg/day), diphenhydramine (≤ 100 mg/day), and

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melatonin (≤ 5 mg/day) were permitted at bedtime for insomnia, as needed. Efficacy Assessments

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The primary efficacy measure was mean change from baseline to week 6 in the CDRS-R total score.32 The CDRS-R is a 17-item semi-structured, clinician-rated instrument that assesses the severity of depression-related symptoms. The key secondary efficacy endpoint (corrected for multiplicity) was mean change from baseline to week 6 in the Clinical Global Impression-

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Bipolar-Severity (CGI-BP-S) assessment, which rates depression severity on a 7-point scale.36 Additional secondary efficacy assessments included the Pediatric Anxiety Rating Scale (PARS),37 the Children’s Global Assessment Scale (CGAS),38 the Pediatric Quality of Life

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Enjoyment and Satisfaction Questionnaire (PQ-LES-Q),39 and the AttentionDeficit/Hyperactivity Disorder Rating Scale (ADHD-RS).40,41 Prior to study initiation,

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investigators completed a rater training program that included didactic instruction and assessment of interviewing skills, qualification in use of study efficacy assessments, and demonstration of inter-rater reliability. Treatment response was defined as ≥50% reduction from baseline to week 6 (endpoint) in

CDRS-R total score (after subtracting 17 points from the total score to adjust for the scale range). Remission was defined by the following composite criteria at week 6 (endpoint): a CDRS-R total

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score ≤28, a YMRS total score ≤8, and a CGI-BP-S depression score ≤3. Safety and Tolerability Evaluations Safety and tolerability assessments included incidence and severity of adverse events; the

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Simpson-Angus Rating Scale (SARS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BARS) to evaluate movement disorders; physical examination and vital signs (including weight and height), laboratory tests, and a 12-lead electrocardiogram

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(ECG). The Young Mania Rating Scale (YMRS)34 was used to evaluate treatment-emergent symptoms of mania. Treatment-emergent mania was defined, a priori, as a YMRS score of ≥20

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on 2 consecutive visits, or at the final assessment; or an adverse event of mania or hypomania. Suicidal ideation and behavior were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS).42 To provide a more sensitive measure of treatment-emergent mania, the same composite criteria were used, but with the YMRS score reduced to ≥15 on 2 consecutive visits,

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or at the final assessment.

The Cogstate Brief Battery43 was included to assess the potential for impairment in cognitive function during study treatment. Cogstate domains that were included were processing

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speed (detection task), attention/vigilance (identification task), visual learning (one card learning task, accuracy), and working memory (one back task, speed). A Cogstate composite score was

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calculated as the average of the standardized z-scores for the individual domains, with z-scores for each domain representing the standard deviation units above or below the age-adjusted normative mean score. Statistical Analysis

The safety population included all patients who were randomized and received at least one dose of study medication. The intent-to-treat population (ITT) consisted of randomized

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patients who received at least one dose of study medication and had at least one post-baseline CDRS-R or CGI-S assessment. The primary (CDRS-R), key secondary (CGI-BP-S depression score) and other secondary (PARS, CGAS, PQ-LES-Q, ADHD-RS) efficacy endpoints were

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assessed using a mixed model for repeated measures (MMRM) analysis that included fixed

effects for treatment, visit (as a categorical variable), pooled country, age stratum (10-14 vs. 1517 years), CDRS-R total score at baseline, and treatment-by-visit interaction. An unstructured

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covariance model was fitted using restricted maximum likelihood estimation. In the analysis of

control overall Type I error at 5%.

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the CDRS-R and the CGI-BP-S depression scores, a sequential testing procedure was used to

Treatment interaction effects for clinical subgroups (e.g., sex, race) were evaluated based on an analysis of covariance (ANCOVA). No adjustments for multiplicity were made, except for analysis of the CDRS-R and CGI-BP-S.

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Descriptive statistics were used for safety variables, including adverse events, vital signs, and laboratory results. MMRM analysis was used to evaluate change from baseline in the YMRS score, and in body weight and age- and sex-adjusted BMI expressed as a standardized z-score.35

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Changes from baseline in the Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale scores were analyzed using ANCOVA with terms for

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treatment, pooled country, and age group, and baseline score as a covariate. Change from baseline in the Cogstate Brief Battery composite score was analyzed using an ANCOVA with the same covariate terms.

Between-group effect size was calculated as the absolute value of least squares (LS)

mean difference divided by the model estimate of the pooled SD, obtained from the square root of the diagonal element, associated with that week, from the covariance matrix. The number

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needed to treat (NNT) to achieve response (based on prespecified CDRS-R response and remission criteria) was calculated by assessing the reciprocal of the difference in responder rates in the lurasidone and placebo groups; the number needed to harm (NNH) for selected adverse

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events was calculated by assessing the reciprocal of the difference in adverse effect rates for the lurasidone and placebo groups.

The sample size for this study was determined by two-sample t-test using nQuery

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Advisor (Version 7.0) software, and was powered at 85% to reject the null hypothesis of no difference in the CDRS-R total score for lurasidone versus placebo (based on a mean change-

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from-baseline difference score of 5 points on the CDRS-R for lurasidone versus placebo, and a common standard deviation of 14.2 points). The estimated sample size of 170 patients per treatment arm included an additional 25 patients per arm based on an expected attrition rate of 15%.

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RESULTS

Patients and disposition. A total of 450 patients were screened, of whom 347 (lurasidone, 175; placebo, 172) were randomly assigned to 6 weeks of double-blind treatment

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and received at least one dose of study treatment (safety population; Figure 1); and 343 patients (lurasidone, 173; placebo, 170) also had at least one post-baseline CDRS-R assessment, and

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comprised the ITT population. Baseline demographic and clinical characteristics were comparable for the two treatment groups (Table 1). Prior treatment (in the 90 days prior to screening) with the following antipsychotic medications were reported by at least 2% of patients: risperidone (14.7%), quetiapine (10.4%), and aripiprazole (10.1%). The study completion rates for the lurasidone and placebo groups were 92.0% and 89.7%, respectively (Figure 1). Study medication and concomitant medication. The mean daily dose of lurasidone

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during the study was 31.5 mg/d in the 10-14-year-old age group, and 33.8 mg/d in the 15-17year-old age group, and 32.5 mg/d in the combined age groups. The modal daily dose of

60 mg in 12.8% of patients, and 80 mg in 8.7% of patients.

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lurasidone (combined age groups) was 20 mg in 52.3% of patients, 40 mg in 26.2% of patients,

In the safety population, as-needed treatment with a benzodiazepine occurred in 12.6% of patients in the lurasidone group and 8.1% of patients in the placebo group. As-needed treatment

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with a sedative-hypnotic medication was reported by 10.9% of patients in the lurasidone group and 12.8% of patients in the placebo group. A small number of patients on lurasidone (n=10) and

diagnosis of ADHD (Table 1).

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placebo (n=21) were being treated concurrently with a central nervous system stimulant for a

Efficacy. The least squares mean change from baseline to week 6 in CDRS-R total score (primary endpoint) was significantly greater in the lurasidone group compared with the placebo

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group (-21.0 vs. -15.3; P<.0001; effect size, 0.45; Table 2). Similarly, change from baseline to week 6 on the CGI-BP-S depression severity score (key secondary endpoint) was significantly greater in the lurasidone group compared with the placebo group (-1.49 vs. -1.05; P<.0001; effect

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size, 0.44). On both measures of treatment effect, significant differences compared with placebo were observed starting at week 2 that were maintained at all subsequent study visits (Figure 2).

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A significant treatment-by-age stratum interaction (10-14 vs. 15-17 years) was observed

on the CDRS-R total score (P<.05), but not on the CGI-BP-S depression score (not significant [ns]). On the CDRS-R, the least squares (LS) mean (95% CI) lurasidone versus placebo difference score at week 6 was -1.8 (-5.6, 2.0) for the 10-14 years age group, and -8.6 (-12.4, 4.8) for the 15-17 years age group. The smaller mean (SE) difference score in the 10-14 (vs. 1517) age group was partly contributed by greater mean improvement in the CDRS-R total at week

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6 in the placebo group for the younger age group (-17.3 [1.5] vs -14.7 [1.6]), resulting in a smaller and non-significant week 6 lurasidone effect size (0.29 vs. 0.61). On the CGI-BP-S depression scale, the LS mean (95%-CI) lurasidone versus placebo difference score at week 6

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was -0.3 (-0.6, 0.0) for the 10-14 years age group, and -0.5 (-0.8, -0.2) for the 15-17 years age group.

Response and remission rates. The percent of participants meeting a priori response

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criteria was significantly greater in the lurasidone group compared with the placebo group at week 6 (59.5% vs. 36.5%; P<.0001; NNT=5; last observation carried forward [LOCF]). The

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percent of patients achieving remission, based on a priori composite criteria, was not significantly different between the lurasidone and placebo group at week 6 (26.0% vs. 18.8%; P=.082; NNT=14; LOCF).

Secondary efficacy measures. Treatment with lurasidone was associated with

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significantly greater improvement at week 6 compared with placebo on secondary efficacy measures, including measures of anxiety (PARS), global functioning (CGAS), and quality of life (PQ-LES-Q; Table 2). In the lurasidone group, the mean CGAS score at LOCF endpoint was

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62.4 (a score >60 represents “generally functioning pretty well, with some difficulty in a single

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In the total sample, mean (SD) ADHD-RS scores at baseline were similar for lurasidone

(11.8 [10.8]) and placebo (12.3 [11.6]). Least squares mean change in the ADHD-RS total score at week 6 was not significantly different for lurasidone vs. placebo (-2.8 vs. -2.1; effect size, 0.09).

Treatment response in clinical subgroups. No statistically significant treatment interactions by sex, race, country (US vs non-US), rapid-cycling status, or stimulant use for

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ADHD were observed for either the CDRS-R total or CGI-BP-S depression scores based on ANCOVA analyses. Adverse events. At least one treatment-emergent adverse event was reported by 64.0%

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of patients in the lurasidone group and 51.7% in the placebo group. The percent of patients

reporting at least one adverse event in the lurasidone group vs. placebo group was 71.1% vs. 51.4% in patients 10–12 years old, and 62.0% vs. 51.9% in patients 13-17 years old.

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The most frequent adverse events on lurasidone were nausea and somnolence (Table 3). The number of patients who discontinued the study due to an adverse event was low in both the

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lurasidone and placebo groups (n=3 in both groups).

Serious adverse events. Serious adverse events occurred in 2 patients in the lurasidone group (fractured humerus; worsening of BD) and 4 patients in the placebo group (worsening of BD; increased depression severity; psychotic disorder; spontaneous abortion). No deaths

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occurred in either treatment group.

Suicidal ideation or behavior. Suicidal ideation, as an adverse event, was reported by none of the patients in the lurasidone group, and by one patient in the placebo group. On the C-

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SSRS, one patient in the lurasidone group reported “active suicidal ideation” but “without intent to act”; in the placebo group, three patients reported “active suicidal ideation” but “without intent

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to act”; and one patient reported active suicidal ideation “with some intent to act.” No suicidal behavior was reported on the C-SSRS in either treatment group. Treatment-emergent mania. The percentage of participants who met a priori criteria

for treatment-emergent mania (defined by a YMRS score of ≥20 on 2 consecutive visits, or at the final assessment; or an adverse event of mania or hypomania) was comparable in the lurasidone and placebo groups (1.7% vs. 2.3%). In a post hoc analysis using a YMRS score ≥15 at any

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study visit, the proportion of patients who met criteria for treatment-emergent mania was higher than in the prespecified analysis, but comparable in the lurasidone and placebo groups (6.9% vs. 7.0%).

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On the YMRS, least squares mean (SE) change from baseline to week 6 was significantly greater in the lurasidone group compared with the placebo group (-2.0 [0.3] vs. -1.1 [0.3]; p<.05; effect size, 0.20).

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Akathisia and EPS. The incidence of akathisia was 2.9% in the lurasidone group and 3.5% in the placebo group. The incidence of extrapyramidal symptom-related adverse events

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(excluding akathisia) was 2.3% in the lurasidone group and 1.7% in the placebo group (Table 3). The proportion of patients who received treatment with anticholinergic medications for acute extrapyramidal symptoms was 1.2% in the lurasidone group and 0.6% in the placebo group. LS mean changes from baseline to endpoint in the lurasidone group vs. the placebo group were

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small and not clinically meaningful for the Barnes Akathisia Rating Scale (0.10 vs. 0.14), the Abnormal Involuntary Movement Scale (0.02 vs. 0.00), and the Simpson-Angus Scale (0.02 vs. 0.02).

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Cogstate Battery. At baseline, using a z-score metric (representing standard deviations below the expected mean score in this age group), cognition was impaired in the lurasidone and

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placebo groups on the Cogstate composite score (-0.79 and -1.04), processing speed domain score (-1.1 vs. -1.5), attention/vigilance domain score (-1.3 vs. -1.6), visual learning domain score (-0.3 and -0.2), and working memory domain score (-0.4 and -0.6). The LS mean baseline to endpoint change in z-scores, for lurasidone vs. placebo, were as follows (with positive scores indicating improvement): for the Cogstate composite score (+0.03 vs. -0.13; n.s.), processing speed (detection task; -0.10 vs. -0.44; P<.05), attention/vigilance (identification task; +0.09 vs. -

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0.22; P<.05), visual learning (one card learning task, accuracy; -0.06 vs. +0.04; n.s.), and working memory (one back task, speed; +0.03 vs. +0.06; n.s.). Weight and BMI. LS mean change at week 6 in body weight was similar for the

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lurasidone and placebo groups (+0.74 vs. +0.44 kg), and a similar percent of patients on

lurasidone vs. placebo had ≥7% weight gain (4.0% vs. 5.3%; Table 3). In addition, the mean change from baseline in BMI percentiles (based on WHO growth charts), and change in the

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standardized BMI z-scores, was similar the lurasidone group compared with the placebo group (Table 3).

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Laboratory and ECG. There were no clinically meaningful differences between lurasidone and placebo groups in change in lipid, glucose, and prolactin levels (Table 3). No participant reported treatment-emergent adverse events potentially related to elevated prolactin (e.g., galactorrhea). The mean change in QTcF interval (Fridericia’s correction for heart rate),

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from baseline to endpoint, was -0.7 msec for the lurasidone group and +0.2 msec for the placebo group. No participant in either treatment group had a QTcF ≥460 msec or a post-baseline change in QTcF ≥60 msec.

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DISCUSSION

In this randomized, double-blind, placebo-controlled study of children and adolescents

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with bipolar I depression, lurasidone (20-80 mg/d, flexibly-dosed) was associated with statistically significant and clinically meaningful improvement in depressive symptoms as assessed by the CDRS-R and CGI-BP-S (primary and key secondary measures) at the week 6 study endpoint. Significant separation from placebo was seen in the lurasidone group starting from week 2 through endpoint on both the CDRS-R and CGI-BP-S. Similar treatment effect size for lurasidone was found in this study on the primary CDRS-R assessment compared to that

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observed in the previously reported adult monotherapy study (0.45 vs. 0.51, respectively).28 Lurasidone also demonstrated significant improvement on validated measures of anxiety (PARS), quality of life (PQ-LES-Q), and global function (CGAS), although caution is warranted

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due to the lack of multiplicity correction for these secondary efficacy assessments. In addition to significantly higher responder rates in patients treated with lurasidone vs placebo (NNT=5), the clinical relevance of improvement in the lurasidone group is underscored by the observed change

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in mean CGAS score from <50 at baseline (moderate-to-severe impairment in functioning) to >60 at study endpoint (“generally functioning pretty well”). The consistency of improvement

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across primary, key secondary, and all other secondary efficacy measures further substantiates the overall effectiveness of lurasidone in this pediatric population with bipolar depression. Treatment of bipolar depression in children and adolescents remains a major unmet medical need. The last comprehensive practice guideline for the treatment of pediatric BD,46

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published over a decade ago, noted the lack of prospective studies in children and adolescents with acute bipolar depression and the resultant inability to develop a treatment algorithm. Since then, two double-blind, placebo-controlled, monotherapy studies of quetiapine in pediatric

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bipolar depression (utilizing extended20 and immediate21 release formulations) failed to demonstrate significant antidepressant efficacy. In contrast, olanzapine/fluoxetine (OFC)

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combination therapy demonstrated significant efficacy in an 8-week bipolar depression trial in children and adolescents.22 The antidepressant effect of lurasidone in this study was comparable to results reported in the 8-week OFC trial,22 both in terms of CDRS-R improvement (effect size 0.45 vs. 0.46), and responder rates (NNT, 5 vs. 6). However, treatment with OFC was associated with relatively high discontinuation rates, both overall (31.8%) and due to adverse events (14.1%). Treatment with OFC was also associated with a mean weight gain of 4.4 kg (vs. 0.5 kg

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on placebo), and a high proportion of patients (52%) experienced clinically significant (≥7%) weight gain on OFC compared with placebo (4%).22 No differences in efficacy, assessed by the CDRS-R, were observed for lurasidone based

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on sex, race, or history of rapid cycling. However, effect sizes were notably larger for older (ages 15-17) compared with younger (ages 10-14) patients (0.61 vs. 0.19). This was accounted for, in part, by greater improvement on placebo in the CDRS-R score at week 6 in the younger (vs.

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older) age group (-17.0 vs. -14.3). This finding is consistent with previous reports of higher placebo response rates among younger patients in pediatric trials of standard antidepressants.44,45

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Notably, the placebo response rate in the study (36.5%) was lower than rates reported in 3 previous studies of atypical antipsychotic therapy for children and adolescents with bipolar depression (55-67%).22-24 While the reasons for the lower placebo response rate in the current study are unknown, it is possible that various factors may have contributed to the lower rate,

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including the 6-week duration of the current study (vs. 8 weeks for prior quetiapine and OFC studies), limiting entry to patients with bipolar I disorder in the current study (the quetiapine XR study20 included both bipolar I and II disorder patients), and between-study differences in

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country and site selection, as well as rater training and monitoring. Discontinuation rates on lurasidone were low in the current study, both overall (8.0%),

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and due to adverse events (1.7%). Treatment with lurasidone had few effects on weight (mean change vs. placebo, +0.7 vs. +0.4 kg; 4% of patients on lurasidone and 3% on placebo had ≥7% gain) or metabolic parameters. These safety findings are consistent with the metabolic profile of lurasidone reported in previous short- and long-term trials in adults with both BD and schizophrenia,48-52 and in adolescents with schizophrenia.53 Reduction in rates of overweight and obesity as well as metabolic dysfunction associated with atypical antipsychotic treatment is an

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important goal for children and adolescents with bipolar illness in view of the resulting adverse short- and long-term health consequences.23,25,54,55 Treatment with lurasidone in the current study was associated with notably low rates of

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akathisia and extrapyramidal symptoms, with only a small percentage of patients receiving

anticholinergic medications for acute EPS (1.2% vs. 0.6%). Small increases in prolactin were observed, but prolactin-related adverse events were not observed. No changes in QTc interval

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were observed in association with lurasidone treatment in this study.

When compared to placebo, treatment with lurasidone was not associated with treatment-

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emergent suicidal ideation or behavior, or treatment-emergent mania. These and other safety findings require further investigation and confirmation in longer-term studies. The effect of lurasidone on cognition was assessed as a safety endpoint in the current study by administration of a modified Cogstate battery at baseline and 6-week endpoint. At

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baseline, there was notable impairment in cognitive function, with the standardized Cogstate composite score averaging approximately one standard deviation below the age-adjusted normative mean level of cognitive performance. Six weeks of treatment with lurasidone was

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associated with no deleterious effects on learning, memory, or attention as measured by Cogstate domain scores. On the two Cogstate domains with the greatest level of baseline impairment

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(processing speed, detection task; attention/vigilance, identification task), z-scores at endpoint were significantly improved in the lurasidone group compared with placebo. These cognitive findings are consistent with results from a previous trial of lurasidone in adolescents with schizophrenia,53 and suggest that short-term treatment with lurasidone is not associated with impairment in cognition in pediatric populations. Several study limitations should be noted. The safety and effectiveness of lurasidone in

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the long-term treatment of children and adolescents with BD requires further study. Because the study excluded patients with clinically significant psychiatric and/or medical comorbidity (with the exception of ADHD), generalizability of the current findings to patients in the community

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with comorbidity is uncertain. In addition, since study entry was limited to patients with bipolar I disorder, and patients with a current depressive episode with a duration of less than one year, further investigation in patients with bipolar II disorder, and greater depression chronicity, is

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warranted. The maximum approved dose for lurasidone in adults with bipolar depression is 120 mg/day; doses higher than 80 mg/day in children and adolescents with bipolar depression have

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not been studied.

In summary, in this placebo-controlled study, lurasidone monotherapy, in the dose range of 20-80 mg/day, significantly reduced depressive symptoms, and improved overall illness severity, as well as measures of anxiety, quality of life, and global functioning, in children and

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adolescents with bipolar depression. Lurasidone was well tolerated, with minimal effects on weight and metabolic parameters. REFERENCES

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28. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry 2014;171:160-168. 29. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or

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31. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th

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33. Kaufman J, Birmaher B, Brent D, et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36:980-988.

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34. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-435. 35. de Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ.

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39. Endicott J, Nee J, Yang R, Wohlberg C. Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q): reliability and validity. J Am Acad Child Adolesc Psychiatry. 2006;45:401-7. 40. Faries DE, Yalcin I, Harder D, Heiligenstein JH. Validation of the ADHD Rating Scale as a

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43. Maruff P, Thomas E, Cysique L, et al. Validity of the CogState brief battery: relationship to standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia, and AIDS dementia complex. Arch Clin Neuropsychol. 2009;24:165-178. 44. Wagner KD, Ambrosini P, Rynn M, et al. Sertraline pediatric depression study group. Efficacy of sertraline in the treatment of children and adolescents with major depressive

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47. Frías Á, Palma C, Farriols N. Comorbidity in pediatric bipolar disorder: prevalence, clinical impact, etiology and treatment. J Affect Disord. 2015;174:378-89. 48. Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract. 2011;65:189-210. 49. Correll CU, Cucchiaro J, Silva R, Hsu J, Pikalov A, Loebel A. Long-term safety and effectiveness of lurasidone in schizophrenia: a 22-month, open-label extension study. CNS Spectr. 2016;21:393-402.

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50. Citrome L, Weiden PJ, McEvoy JP, et al. Effectiveness of lurasidone in schizophrenia or schizoaffective patients switched from other antipsychotics: a 6-month, open-label, extension study. CNS Spectr. 2014;19:330-9. 51. Ketter TA, Sarma K, Silva R, Kroger H, Cucchiaro J, Loebel A. Lurasidone in the long-term

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52. Pikalov A, Tsai J, Mao Y, Silva R, Cucchiaro J, Loebel A. Long-term use of lurasidone in patients with bipolar disorder: safety and effectiveness over 2 years of treatment. Int J

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in adolescents with schizophrenia: a 6-week, randomized, placebo-controlled study. J Child Adolesc Psychopharmacol 2017 May 5. doi: 10.1089/cap.2016.0189. [Epub ahead of print]. 54. Steinberger J, Daniels SR. Obesity, insulin resistance, diabetes, and cardiovascular risk in children. Circulation. 2003;107:1448-1453.

55. Goldstein BI, Carnethon MR, Matthews KA, et al. Major depressive disorder and bipolar disorder predispose youth to accelerated atherosclerosis and early cardiovascular disease: a

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scientific statement from the American Heart Association. Circulation. 2015;132:965-86.

Figure 1. Patient disposition. Note: safety population received at least one dose of study medication (lurasidone, n = 175, placebo, n = 172). Intent-to-treat population received at least

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one dose of study medication and completed one post-baseline Children’s Depression Rating Scale, Revised (CDRS-R) assessment (lurasidone, n = 173, placebo, n = 170).

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Figure 2. Least squares mean change from baseline in primary (Children’s Depression Rating Scale, Revised [CDRS-R]) and key secondary (Clinical Global Impression-Bipolar-Severity [CGI-BP-S]) efficacy measures (mixed model for repeated measures analysis of intent-to-treat population). Note: A) CDRS-R total score; B) CGI-BP-S score. LS = least squares.

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Table 1. Baseline Patient Characteristics (Intent-to-Treat [ITT] Population) Lurasidone, 20-80 mg/d Characteristic (n=173)

Placebo (n=170)

%

n

%

88

50.9

87

51.2

White

134

77.5

Black/African-American

15

8.7

Asian

7

4.0

Other

17

9.7

Male

125

73.5

18

10.6

4

2.3

23

13.4

74

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Race

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n

42.8

73

42.9

99

57.2

97

57.1

90 86

51.1 48.9

89 85

51.1 48.9

44

25.4

49

28.8

25

14.5

29

17.1

10

10.3

21

12.2

Mean

SD

Mean

SD

14.2

2.2

14.3

2.0

12.4

2.8

12.2

2.7

Duration of BD, years

2.2

2.0

2.6

1.9

Duration of current depression, wks

12.0

8.6

12.5

9.6

CDRS-R total score

59.2

8.2

58.6

8.3

CGI-BP-S depression score

4.6

0.6

4.5

0.6

Young Mania Rating Scale

5.5

3.9

5.1

3.2

Pediatric Anxiety Rating Scale

7.1

6.5

8.7

7.3

Children’s Global Assessment Scale

48.8

8.7

49.5

7.0

Pediatric Q-LES-Q

49.6

9.1

49.7

9.0

32

Ethnicity: Hispanic/Latino United States (US) Non-US Age group at Screening 10-14 years old 15-17 years old

ADHD diagnosis

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Patients with ≥1 hospitalization for bipolar depression ADHD treated with stimulants Age, years

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Baseline scores

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Age at onset of BD, years

33

19.2

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Region

18.3

Note: ADHD = attention-deficit/hyperactivity disorder; BD = bipolar disorder; CDRS-R = Childhood Depression Rating Scale-Revised; CGI-BP-S = Clinical Global Impression-Bipolar-Severity; Q-LES-Q = Quality of Life, Enjoyment, and Satisfaction Questionnaire. 1

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Table 2. Efficacy Endpoints: Change at Week 6 (Intent-to-Treat [ITT] Population; Mixed Model for Repeated Measures [MMRM] Analysis) Placebo

(n=173)

(n=170)

59.2 (8.24)

58.6 (8)

LS mean change (SE)

-21.0 (1.06)

-15.3 (1.08)

CGI-BP-S Depression Score Baseline mean (SD)

4.6 (0.65)

LS mean change (SE)

-1.49 (0.085)

Children’s Global Assessment Scale Baseline mean (SD) LS mean change (SE) Pediatric Q-LES-Q Baseline mean (SD) LS mean change (SE)

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-3.4 (0.44)

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LS mean change (SE)

10.9 (7.7)

P-value (Effect Size)

-5.7 (-8.4, -3.0)

<.0001 (0.45)

-0.44 (-0.66, -0.22)

<.0001 (0.44)

-1.1 (-2.2, -0.1)

<.0001 (0.44)

4.7 (2.4, 7.0)

<.035 (0.23)

3.9 (1.2, 6.5)

<.01 (0.32)

4.5 (0.57)

-1.05 (0.087) 11.5 (7.6)

-2.3 (0.45)

48.8 (8.73)

49.5 (6.99)

+14.0 (0.96)

+9.3 (0.99)

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Pediatric Anxiety Rating Scale Baseline mean (SD)

49.6 (8.9)

49.7 (8.5)

+11.8 (1.1)

+7.9 (1.1)

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CDRS-R Total Score Baseline mean (SD)

Treatment Difference (95% CI)

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Lurasidone, 20-80 mg/d

Note: CGI-BP-S = Clinical Global Impression-Bipolar Version, Severity; LS = least squares; Q-LES-Q = quality of life, enjoyment, and satisfaction.

2

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Table 3. Safety and Tolerability Parameters (Safety Population) Adverse Eventsa

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Placebo (n=172) n (%) 89 (51.7) 10 (5.8) 10 (5.8) 3 (1.7) 6 (3.5) 8 (4.7) 4 (2.3) 4 (2.3) 4 (2.3) 4 (2.3) 3 (1.7) 2 (1.2) 3 (1.7) 3 (1.7) 3 (1.7) 1 (0.6)

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Lurasidone, 20-80 mg/d (n=175) n (%) NNH 112 (64.0) 9 At least one event 28 (16.0) 10 Nausea Somnolence b 20 (11.4) 18 12 (6.9) 20 Weight increased 11 (6.3) 36 Vomiting 10 (5.7) 100 Dizziness 9 (5.1) 36 Insomnia 7 (4.0) 59 Decreased appetite 6 (3.4) 91 Abdominal pain, upper 6 (3.4) 91 Fatigue 5 (2.9) 84 Diarrhea 5 (2.9) 59 Abdominal pain 4 (2.3) >100 Extrapyramidal symptoms c 4 (2.3) >100 Abnormal dreams 4 (2.3) >100 Oropharyngeal pain 4 (2.3) 59 Influenza Change From Baseline to Week 6 in Weight and BMI Lurasidone 20-80 mg/d

LS Mean (SE) change ≥7% weight gain BMI, kg/m2

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Baseline mean (percentile) LS Mean change

n=157 57.02

+0.74 (0.15)

+0.44 (0.15)

4.0%

5.3%

n=162 21.52 (64.3%) +0.20

n=157 21.40 (61.6%) +0.12

d

+0.57

+0.46

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Mean z-score change

n=162 56.58

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Weight, kg Baseline mean

Placebo

3

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Median Change From Baseline in Laboratory Parameters at Week 6 (LOCF Endpoint)e

LDL cholesterol, mg/dL Baseline mean (SD)

n=163 160.7 (31.3)

n=155 159.8 (35.4)

-7.0 (-10.0, -1.0) n=162 88.3 (27.7)

Median change (95%-CI) HDL cholesterol, mg/dL Baseline mean (SD)

-5.0 (-8.0, -1.0) n=162 53.5 (13.8)

Median change (95%-CI)

n=163 101.1 (57.5)

-3.0 (-5.0, 0.0) n=155 87.5 (29.8)

-2.0 (-3.0, 2.0) n=153 53.4 (14.9)

-2.0 (-3.0, 0.0)

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Triglycerides, mg/dL Baseline mean (SD)

-1.0 (-2.0, 1.0)

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Median change (95%-CI)

Placebo

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Total cholesterol, mg/dL Baseline mean (SD)

Lurasidone 29-80 mg/d

n=155 95.0 (49.4)

-7.0 (-13.0, -2.0)

+3.0 (-2.0, 9.0)

n=145 90.0 (9.9) 0.0 (-1.0, 2.0)

n=145 90.3 (9.2) 0.0 (-2.0, 2.0)

n=166 5.2 (0.3)

n=158 5.2 (0.3)

Median change (95%-CI)

0.0 (-0.1, 0.0)

0.0 (-0.1, 0.0)

Prolactin, Male, ng/mL Baseline mean (SD) Median change (95%-CI)

n=82 7.9 (6.4) +0.8 (0.0, 1.8)

n=79 7.2 (5.2) +0.5 (-0.2, 0.9)

n=83 16.3 (25.4)

n=78 12.3 (11.0)

+2.5 (0.1, 4.1)

+0.6 (-0.2, 1.6)

Median change (95%-CI)

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HbA1c, % Baseline mean (SD)

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Glucose, fasting, mg/dL Baseline mean (SD) Median change (95%-CI)

Prolactin, Females, ng/mL Baseline mean (SD)

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Median change (95%-CI)

Note: BMI = body mass index; HbA1c = glycosylated hemoglobin; LOCF = last observation carried forward; NNH = number needed to harm. a Incidence ≥2% on lurasidone and lurasidone > placebo. b Somnolence: hypersomnia, sedation, somnolence, hypersomnolence. c Non-akathisia extrapyramidal symptoms: Parkinsonism, dystonia, salivary hypersecretion, psychomotor hyperactivity, tardive dyskinesia (n=1 on placebo; none on lurasidone). d Age- and gender-specific z-scores and percentiles are obtained by using World Health Organization Growth Charts.37 e Fasting values are reported for glucose; both confirmed and non-confirmed fasting values are reported for the other metabolic parameters. 4

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B

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A