A Study in Pediatric Participants With Generalized Anxiety Disorder

Study Overview
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Brief Summary
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The purpose of this study is to find out if duloxetine [30-120 milligrams (mg)] given once a day by mouth for 10 weeks to children and adolescents, is better than placebo when treating Generalized Anxiety Disorder (GAD).

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 Generalized Anxiety Disorder

Conditions
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Anxiety Neuroses, Anxiety States, Neurotic, Neuroses, Anxiety

Intervention / Treatment
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* Drug: Duloxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with GAD on clinical exam 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 GAD as determined by the following: Presence of 4 or more symptoms identified on the generalized anxiety subsection of the Pediatric Anxiety Rating Scale (PARS) symptom checklist at screening and randomization. Two of which are excessive worry and dread or fearful anticipation (nonspecific) PARS severity score of 15 or more at screening and randomization for symptoms identified on the generalized anxiety subsection of PARS symptom checklist at screening and randomization Clinical Global Impressions of Severity (CGI-S) rating of 4 or more at screening and randomization Presence of significant social, academic, and/or familial dysfunction as determined by the Children's Global Assessment Scale (CGAS) score of 60 or less at screening and randomization Female participants must test negative for pregnancy during screening Furthermore, female participants must agree to abstain from sexual activity or to use a reliable method of birth control as determined by the investigator during the study Participant's parent/legal representative and participant, if capable, are judged to be reliable by the investigator to keep all appointments for clinical visits, tests, and procedures required by the protocol Participant's parent/legal representative and participant, if capable, must have a degree of understanding such that they can communicate intelligently with the investigator and study coordinator Participants must be capable of swallowing study drug whole (without opening the capsule, crushing, dissolving, dividing, et cetera) Participants must have venous access sufficient to allow blood sampling and are compliant with blood draws as per the protocol Exclusion Criteria: Current diagnosis of major depressive disorder (MDD) Participants for whom the primary focus of treatment is separation anxiety or social phobia (participants with secondary separation anxiety or social phobia are allowed to participate) Have current primary diagnosis of any DSM-IV-TR Axis I disorder except GAD, or a current secondary DSM-IV-TR Axis 1 disorder that requires any pharmacologic treatment (other than those disorders listed below). Primary is defined as the disorder that is the primary focus of treatment Have a history of DSM-IV-TR-defined substance abuse or dependence within the past year, excluding caffeine and nicotine Have a current or previous diagnosis of bipolar disorder, psychotic depression, schizophrenia or other psychotic disorder, anorexia, bulimia, obsessive compulsive disorder, post-traumatic stress disorder, panic disorder, or pervasive development disorder, as judged by the investigator Have 1 or more first-degree relatives (parents or siblings) with diagnosed bipolar I disorder Have a serious or unstable medical illness, psychological condition, clinically significant laboratory or electrocardiogram (ECG) result, hypersensitivity to duloxetine, or its active ingredients, frequent or severe allergic reactions to multiple medications, uncontrolled narrow-angle glaucoma, acute liver injury (for example, hepatitis) or severe cirrhosis (Child-Pugh Class C), or a history of any seizure disorder (other than febrile seizures) Have a significant suicide attempt within 1 year of screening or are currently at risk of suicide in the opinion of the investigator Have initiated, stopped, or changed the type or intensity of psychotherapy within 6 weeks prior to screening. Participants who require a change to psychotherapy between weeks 1 through 10 will be excluded Have a weight less than 20 kilograms at any time during the screening period Female participants who are pregnant, nursing or have recently given birth

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 |
| --- | --- |
| Experimental: Duloxetine<br>30-120 mg flexible dosing once daily for 10 weeks. At the end of the 10 week blinded treatment period, participants may participate in an 18 week extension | Drug: Duloxetine<br>* Administered orally<br>* Other names: LY248686;|
| Placebo Comparator: Placebo<br>Administered once daily for 10 weeks. At the end of the 10 week blinded treatment period, placebo participants receive duloxetine in the 18 week extension | Drug: Duloxetine<br>* Administered orally<br>* Other names: LY248686;Drug: Placebo<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 10-Week Endpoint in the Pediatric Anxiety Rating Scale (PARS) Severity Score Evaluated for Symptoms Identified on the Generalized Anxiety Subsection of the PARS Symptom Checklist | PARS severity score for GAD was assessed for all symptoms identified in the generalized anxiety section of the PARS symptom checklist. PARS severity score for GAD was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity scores for GAD ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for baseline, pooled investigator, age category, visit, treatment, treatment*visit, age category*visit, and baseline*visit. | Baseline, 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Pediatric Anxiety Rating Scale (PARS) Severity Score for GAD | Response rate was defined as the percentage of participants having a 50% improvement from baseline to endpoint on the PARS severity score for GAD. PARS severity score for GAD was assessed for all symptoms identified in the generalized anxiety section of the PARS symptom checklist. PARS severity score for GAD was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity scores for GAD ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. | Baseline, 10 weeks | 
| Change From Baseline to 10-Week Endpoint on the Pediatric Anxiety Rating Scale (PARS) Severity Total Score Evaluated for All Symptoms Identified on the PARS Symptom Checklist Symptoms | PARS severity total score was assessed for all symptoms identified on the PARS symptom checklist. PARS severity total score was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity total scores ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for treatment, pooled investigator, visit, baseline, age category, treatment*visit, baseline*visit, and age category*visit. | Baseline, 10 weeks | 
| Change From Baseline to 10-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale | The CGI-S scale evaluated the severity of illness at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill). Higher scores indicated a greater severity of illness. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for treatment, pooled investigator, visit, baseline, age category, treatment*visit, baseline*visit, and age category*visit. | Baseline, 10 weeks | 
| Remission Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Clinical Global Impressions of Severity (CGI-S) Scale | Remission rate was defined as the percentage of participants having a CGI-S score ≤2 at endpoint. The CGI-S scale evaluated the severity of illness at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill). Higher scores indicated a greater severity of illness. | 10 weeks | 
| Change From Baseline to 10-Week Endpoint in the Children's Global Assessment Scale (CGAS) | The CGAS was a clinician-rated assessment of general functioning. CGAS raw scores ranged from 1 (greatest impairment) to 100 (superior functioning). Lower scores indicated a lower level of functioning and greater impairment. Least squares (LS) mean from an analysis of covariance (ANCOVA) was adjusted for treatment, pooled investigator, baseline, and age category. | Baseline, 10 weeks | 
| Percentage of Participants During the 10-Week Period With Treatment-Emergent (New or Worsening) Suicidal Ideation as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) | The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation: a yes answer to any 1 of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Results reported as percentage of participants with treatment-emergent (new or worsening) suicidal ideation from baseline=(number of participants with changes compared to baseline/total number of participants at risk)*100. | Baseline up to 10 weeks | 
| Percentage of Participants During the 10-Week Period With Treatment-Emergent (New or Worsening) Suicidal Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) | The C-SSRS captured 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. Reported as percentage of participants with treatment-emergent (new or worsening) suicidal behavior from baseline=(number of participants with changes compared to baseline/total number of participants at risk)*100. | Baseline up to 10 weeks | 
| Change From 10-Week to 28-Week Endpoint in the Pediatric Anxiety Rating Scale (PARS) Severity Score Evaluated for Symptoms Identified on the Generalized Anxiety Subsection of the PARS Symptom Checklist | PARS severity score for GAD was assessed for all symptoms identified in the generalized anxiety section of the PARS symptom checklist. PARS severity score for GAD was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity scores for GAD ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for pooled investigator, visit, baseline, age category, baseline*visit, and age category*visit within reporting groups. | 10 weeks, 28 weeks | 
| Change From 10-Week to 28-Week Endpoint on the Pediatric Anxiety Rating Scale (PARS) Severity Total Score Evaluated for All Symptoms Identified on the PARS Symptom Checklist Symptoms | PARS severity total score was assessed for all symptoms identified on the PARS symptom checklist. PARS severity total score was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity total scores ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for pooled investigator, visit, baseline, age category, baseline*visit, and age category*visit within reporting groups. | 10 weeks, 28 weeks | 
| Change From 10-Week to 28-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale | The CGI-S scale evaluated the severity of mental illness at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill). Higher scores indicated a greater severity of illness. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for pooled investigator, visit, baseline, age category, baseline*visit, and age category*visit within reporting groups. | 10 weeks, 28 weeks | 
| Change From 10-Week to 28-Week Endpoint in the Children's Global Assessment Scale (CGAS) | The CGAS was a clinician-rated assessment of general functioning. CGAS raw scores ranged from 1 (greatest impairment) to 100 (superior functioning). Lower scores indicated a lower level of functioning and greater impairment. Least squares (LS) mean from an analysis of covariance (ANCOVA) was adjusted for pooled investigator, baseline, and age category within reporting groups. | 10 weeks, 28 weeks | 
| Percentage of Participants During the 18-Week Extension Period With Treatment-Emergent (New or Worsening) Suicidal Ideation as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) | The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation: a yes answer to any 1 of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Results reported as percentage of participants with treatment-emergent (new or worsening) suicidal ideation from baseline=(number of participants with changes compared to baseline/total number of participants at risk)*100. | 10 weeks up to 28 weeks | 
| Percentage of Participants During the 18-Week Extension Period With Treatment-Emergent (New or Worsening) Suicidal Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) | The C-SSRS captured 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. Reported as percentage of participants with treatment-emergent (new or worsening) suicidal behavior from baseline=(number of participants with changes compared to baseline/total number of participants at risk)*100. | 10 weeks up to 28 weeks |