A Study in the Treatment of Children and Adolescents With Major Depressive Disorder

Study Overview
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Brief Summary
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The purpose of this study is to assess whether duloxetine is superior to placebo in the treatment of children and adolescents with major depressive disorder (MDD)

Official Title
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A Double-Blind, Efficacy and Safety Study of Duloxetine Versus Placebo in the Treatment of Children and Adolescents With Major Depressive Disorder

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Placebo
* Drug: fluoxetine
* Drug: duloxetine
* Drug: duloxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatient, diagnosed with major depressive disorder (MDD) as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) and supported by the Mini International Neuropsychiatric Interview for children and adolescents (MINI-KID). Diagnosis of moderate or greater severity of MDD as determined by Children's Depression Rating Scale - Revised (CDRS-R) with a total score greater than or equal to 40 at screen, and randomization and a Clinical Global Impression of Severity (CGI-Severity) rating of greater than or equal to 4 at screen, and randomization. Female patients must test negative for pregnancy during screening. Judged to be reliable by the investigator to keep all appointments for clinical visits, tests, and procedures required by the protocol. Has a degree of understanding such that they can communicate intelligently with the investigator and study coordinator. Capable of swallowing study drug whole. It is anticipated the patients will need to swallow up to 6 capsules per day. Patients must have venous access sufficient to allow blood sampling and are compliant with blood draws as per the protocol. Exclusion Criteria: Children of site personnel directly affiliated with this study and/or their immediate families. Children of Lilly employees or employees of the designated clinical research organization (CRO) assisting with the conduct of the study. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. Have a current or previous diagnosis of bipolar disorder, psychotic depression, schizophrenia or other psychotic disorder, anorexia, bulimia, obsessive compulsive disorder, or pervasive development disorder, as judged by the investigator. Have a history of DSM-IV-TR-defined substance abuse or dependence within the past year, excluding caffeine and nicotine. Have a current primary DSM-IV-TR Axis I disorder other than MDD or a current secondary DSM-IV-TR Axis I disorder that requires any pharmacologic treatment Have 1 or more first-degree relatives with diagnosed bipolar I disorder. Have a significant suicide attempt within 1 year of screening or are currently at risk of suicide in the opinion of the investigator. Have a weight less than 20 kilogram (kg) at screening. Have a lack of response to 2 or more adequate treatment trials of antidepressants at a clinically appropriate dose for a minimum of 4 weeks for the same MDD episode. Have initiated, stopped, or changed the type or intensity of psychotherapy within 6 weeks prior to screening. Have a history of seizure disorder (other than febrile seizures). Have a history of electroconvulsive therapy within 1 year of screening. Have had treatment with a monoamine oxidase inhibitor (MAOI) within 14 days or fluoxetine within 30 days of randomization; or the potential need to use an MAOI during the study or within 5 weeks of discontinuation of study drug. Have previously enrolled, completed, or withdrawn from this study or any other study investigating duloxetine or fluoxetine. Have a positive urine drug screen for any substances of abuse or excluded medication. Are taking any excluded medications that cannot be discontinued by screening. Have known hypersensitivity to duloxetine, fluoxetine, or their inactive ingredients; or have frequent or severe allergic reactions to multiple medications. Have uncontrolled narrow-angle glaucoma. Have acute liver injury or severe cirrhosis. Have a serious or unstable medical illness, psychological condition, or clinically significant laboratory or electrocardiogram (ECG) result that, in the opinion of the investigator, would compromise participation in the study or be likely to lead to hospitalization. Have abnormal thyroid-stimulating hormone concentration. Have initiated or discontinued hormone therapy within the previous 3 months. Female patients who are either pregnant, nursing or have recently given birth. Need to use thioridazine during the study or within 5 weeks after discontinuation of study drug or need to use pimozide during the study.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Capsules identical in appearance, color, taste, and smell to study drug, orally, once daily for 10 weeks (acute treatment phase)<br>|
| Active Comparator: Fluoxetine<br> | Drug: fluoxetine<br>* 20 milligram (mg) orally, once daily for 10 weeks (acute treatment phase) and 20-40 mg orally, once daily for additional 6 months (extension phase)<br>* Other names: Prozac;|
| Experimental: Duloxetine 60 mg<br> | Drug: duloxetine<br>* 60 mg orally, once daily for 10 weeks (acute treatment phase) and 60-120 mg orally, once daily for additional 6 months (extension phase)<br>* Other names: Cymbalta;|
| Experimental: Duloxetine 30 mg<br> | Drug: duloxetine<br>* 30 mg orally, once daily for 10 weeks (acute treatment phase) and 60-120 mg orally, once daily for additional 6 months (extension phase)<br>* Other names: Cymbalta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at Week 10 Endpoint | CDRS-R Total score measure the presence and severity of depression in children. The scale consists of 17 items scored on a 1-to-5- or 1-to-7-point scale. A rating of 1 indicates normal functioning. Total scores range from 17 to 113. In general, scores below 20 indicate an absence of depression, scores of 20 to 30 indicate borderline depression, and scores of 40 to 60 indicate moderate depression. Least Square (LS) means are adjusted for baseline, pooled investigator, age category, visit, treatment, treatment*visit, age category*visit and baseline*visit. | Baseline, Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Week 10 in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at Week 36 Endpoint | CDRS-R Total score measure the presence and severity of depression in children. The scale consists of 17 items scored on a 1-to-5- or 1-to-7-point scale. A rating of 1 indicates normal functioning. Total scores range from 17 to 113. In general, scores below 20 indicate an absence of depression, scores of 20 to 30 indicate borderline depression, and scores of 40 to 60 indicate moderate depression. LS means are adjusted for baseline, pooled investigator, age category, visit, age category*visit and baseline*visit. | Week 10, Week 36 | 
| Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at Week 10 Endpoint | CDRS-R Total score measure the presence and severity of depression in children. The scale consists of 17 items scored on a 1-to-5- or 1-to-7-point scale. A rating of 1 indicates normal functioning. Total scores range from 17 to 113. In general, scores below 20 indicate an absence of depression, scores of 20 to 30 indicate borderline depression, and scores of 40 to 60 indicate moderate depression. Least Square (LS) means are adjusted for baseline, pooled investigator, age category, visit, treatment, treatment*visit, age category*visit and baseline*visit. | Baseline, Week 10 | 
| Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Subscale Score at Week 10 Endpoint | CDRS-R Subscale scores include Mood (Sum of items 8, 11, 14, 15), Somatic (Sum of items 4-7, 16, 17), Subjective (Sum of items 9, 10, 12, 13) and Behavior (Sum of items 1-3). Mood and Subjective subscale scores range from 4 to 28; Somatic subscale scores range from 6 to 36; Behavior subscale scores range from 3 to 21. Higher score indicates greater severity of disease. LS means are adjusted for baseline, pooled investigator, age category, visit, treatment, treatment*visit, age category*visit and baseline*visit. | Baseline, Week 10 | 
| Change From Week 10 in Children's Depression Rating Scale-Revised (CDRS-R) Subscale Score at Week 36 Endpoint | CDRS-R Subscale scores include Mood (Sum of items 8, 11, 14, 15), Somatic (Sum of items 4-7, 16, 17), Subjective (Sum of items 9, 10, 12, 13) and Behavior (Sum of items 1-3). Mood and Subjective subscale scores range from 4 to 28; Somatic subscale scores range from 6 to 36; Behavior subscale scores range from 3 to 21. Higher score indicates greater severity of disease. LS means are adjusted for baseline, pooled investigator, age category, visit, age category*visit and baseline*visit. | Week 10, Week 36 | 
| Change From Baseline in Clinical Global Impressions of Severity (CGI-Severity) Scale at Week 10 Endpoint | CGI-Severity evaluates the severity of illness at the time of assessment. The score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). LS means are adjusted for baseline, pooled investigator, age category, visit, treatment, treatment*visit, age category*visit and baseline*visit. | Baseline, Week 10 | 
| Change From Week 10 in Clinical Global Impressions of Severity (CGI-Severity) Scale at Week 36 Endpoint | CGI-Severity evaluates the severity of illness at the time of assessment. The score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). LS means are adjusted for baseline, pooled investigator, age category, visit, age category*visit and baseline*visit. | Week 10, Week 36 | 
| Number of Participants With Suicidal Ideation or Suicidal Behavior Baseline Through Week 10 | Columbia Suicide Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior: a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation: a yes answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Treatment Emergent Suicidal Ideation is worsening or new occurrence of events during treatment compared to lead-in baseline (Week -1 to 0). | Baseline through Week 10 | 
| Number of Participants With Suicidal Ideation or Suicidal Behavior Week 10 Through Week 36 | Columbia Suicide Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior: a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation: a yes answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Treatment Emergent Suicidal Ideation is worsening or new occurrence of events during treatment compared to lead-in baseline (Week 7-10). | Week 10 through Week 36 | 
| Number of Participants With Potentially Clinically Significant Hepatic Laboratory Results Any Time Baseline Through Week 10 | Total number of participants with any abnormal post-baseline value, based on all values at scheduled and unscheduled visits. Potentially clinically significant hepatic laboratory results at any time are defined as alanine transaminase (ALT) ≥3 x upper limit of normal (ULN), ALT ≥5 x ULN and ALT ≥10 x ULN, as well as ALT ≥3 x ULN and Total Bilirubin ≥2 x ULN. | Baseline through Week 10 | 
| Number of Participants With Potentially Clinically Significant Hepatic Laboratory Results Any Time Week 10 Through Week 36 | Total number of participants with any abnormal post-baseline value, based on all values at scheduled and unscheduled visits. Potentially clinically significant hepatic laboratory results at any time are defined as ALT ≥3 x ULN, ALT ≥5 x ULN and ALT ≥10 x ULN, as well as ALT≥3 x ULN and Total Bilirubin ≥2 x ULN. | Week 10 through Week 36 | 
| Percentage of Participants With Potentially Clinically Significant (PCS) Changes in Systolic Blood Pressure (BP), Diastolic BP, Pulse, and Weight Any Time Baseline Through Week 10 | PCS increase in systolic and diastolic BP was defined as increase of ≥5 millimeter mercury (mm Hg) from baseline (BL) high value to a value above the 95th percentile at post-BL; PCS increase of pulse was defined as >140 and increase of ≥15 from BL high value for age 7-11 and >120 and increase of ≥15 from BL high value for age 12-17; PCS decrease of pulse was defined as <60 and a decrease of ≥25 from BL low value for age 7-11 and <50 and a decrease of ≥15 from BL low value for age 12-17; PCS decrease of weight was defined as decrease of at least 3.5% from BL low value. | Baseline through Week 10 | 
| Percentage of Participants With Potentially Clinically Significant (PCS) Changes in Systolic Blood Pressure (BP), Diastolic BP, Pulse, and Weight Any Time Week 10 Through Week 36 | PCS increase in systolic and diastolic BP was defined as increase of ≥5 mm Hg from baseline (BL) high value to a value above the 95th percentile at post-BL; PCS increase of pulse was defined as >140 and increase of ≥15 from BL high value for age 7-11 and >120 and increase of ≥15 from BL high value for age 12-17; PCS decrease of pulse was defined as <60 and a decrease of ≥25 from BL low value for age 7-11 and <50 and a decrease of ≥15 from BL low value for age 12-17; PCS decrease of weight was defined as decrease of at least 3.5% from BL low value. | Week 10 through Week 36 |