Anxiety Neuroses, Anxiety States, Neurotic, Neuroses, Anxiety
Conditions
Brief summary
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).
Interventions
DRUGDuloxetine
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Years to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, 10 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, 10 weeks | 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. |
| Change From Baseline to 10-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale | Baseline, 10 weeks | 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. |
| Remission Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Clinical Global Impressions of Severity (CGI-S) Scale | 10 weeks | 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. |
| Change From Baseline to 10-Week Endpoint in the Children's Global Assessment Scale (CGAS) | Baseline, 10 weeks | 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. |
| 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) | Baseline up to 10 weeks | 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. |
| 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) | Baseline up to 10 weeks | 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. |
| Response Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Pediatric Anxiety Rating Scale (PARS) Severity Score for GAD | Baseline, 10 weeks | 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. |
| 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 | 10 weeks, 28 weeks | 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. |
| Change From 10-Week to 28-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale | 10 weeks, 28 weeks | 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. |
| Change From 10-Week to 28-Week Endpoint in the Children's Global Assessment Scale (CGAS) | 10 weeks, 28 weeks | 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. |
| 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) | 10 weeks up to 28 weeks | 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. |
| 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) | 10 weeks up to 28 weeks | 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. |
| 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 | 10 weeks, 28 weeks | 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. |
Countries
Mexico, South Africa, United States
Participant flow
Pre-assignment details
This study had 4 periods: Screening period (1-week), acute treatment period (10-week, double-blind period with flexible duloxetine dosing), extension treatment (18-week period, of which 16 weeks were open-label treatment with flexible duloxetine dosing), and a taper period (2 weeks recommended at discontinuation from study any point after Week 2).
Participants by arm
| Arm | Count |
|---|---|
| Duloxetine/Duloxetine Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules.
Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period. | 135 |
| Placebo/Duloxetine Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules.
Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period. | 137 |
| Total | 272 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Acute Treatment Period | Adverse Event | 7 | 6 |
| Acute Treatment Period | Lack of Efficacy | 2 | 1 |
| Acute Treatment Period | Lost to Follow-up | 3 | 6 |
| Acute Treatment Period | Parent/caregiver decision | 5 | 7 |
| Acute Treatment Period | Protocol Violation | 5 | 5 |
| Acute Treatment Period | Withdrawal by Subject | 10 | 6 |
| Extension Treatment Period | Adverse Event | 8 | 8 |
| Extension Treatment Period | Lack of Efficacy | 3 | 2 |
| Extension Treatment Period | Lost to Follow-up | 4 | 3 |
| Extension Treatment Period | Parent/Caregiver Decision | 8 | 8 |
| Extension Treatment Period | Protocol Violation | 2 | 2 |
| Extension Treatment Period | Sponsor Decision | 1 | 1 |
| Extension Treatment Period | Withdrawal by Subject | 1 | 3 |
| Taper Period | Adverse Event | 1 | 0 |
| Taper Period | Lost to Follow-up | 2 | 2 |
| Taper Period | Parent/Caregiver Decision | 1 | 1 |
| Taper Period | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Duloxetine/Duloxetine | Placebo/Duloxetine | Total |
|---|---|---|---|
| Age, Customized 12 to 17 years | 73 participants | 71 participants | 144 participants |
| Age, Customized 7 to 11 years | 62 participants | 66 participants | 128 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 37 Participants | 40 Participants | 77 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 88 Participants | 88 Participants | 176 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 9 Participants | 19 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 7 participants | 6 participants | 13 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 9 participants | 10 participants | 19 participants |
| Race/Ethnicity, Customized More than 1 race | 6 participants | 9 participants | 15 participants |
| Race/Ethnicity, Customized White | 112 participants | 111 participants | 223 participants |
| Region of Enrollment Mexico | 26 participants | 26 participants | 52 participants |
| Region of Enrollment South Africa | 11 participants | 12 participants | 23 participants |
| Region of Enrollment United States | 98 participants | 99 participants | 197 participants |
| Sex: Female, Male Female | 70 Participants | 75 Participants | 145 Participants |
| Sex: Female, Male Male | 65 Participants | 62 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 106 / 135 | 90 / 137 | 73 / 104 | 73 / 106 | 12 / 97 | 1 / 7 |
| serious Total, serious adverse events | 1 / 135 | 0 / 137 | 2 / 104 | 2 / 106 | 1 / 97 | 1 / 7 |
Outcome results
Primary
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.
Time frame: Baseline, 10 weeks
Population: Randomized participants with a baseline and at least 1 post-baseline PARS severity score for GAD during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine (Acute Treatment) | 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 | -9.70 units on a scale | Standard Error 0.502 |
| Placebo (Acute Treatment) | 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 | -7.05 units on a scale | Standard Error 0.5 |
p-value: <0.00195% CI: [-4.03, -1.27]Mixed Models Analysis
Secondary
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.
Time frame: 10 weeks, 28 weeks
Population: Randomized participants with a CGAS score during the acute treatment period and at least 1 CGAS score during the extension treatment period \[last observation carried forward (LOCF)\], excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine (Acute Treatment) | Change From 10-Week to 28-Week Endpoint in the Children's Global Assessment Scale (CGAS) | 7.32 units on a scale | Standard Error 1.19 |
| Placebo (Acute Treatment) | Change From 10-Week to 28-Week Endpoint in the Children's Global Assessment Scale (CGAS) | 10.48 units on a scale | Standard Error 1.03 |
Secondary
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.
Time frame: 10 weeks, 28 weeks
Population: Randomized participants with a PARS severity score for GAD during the acute treatment period and at least 1 PARS severity score for GAD during the extension treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine (Acute Treatment) | 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 | -3.33 units on a scale | Standard Error 0.352 |
| Placebo (Acute Treatment) | 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 | -5.15 units on a scale | Standard Error 0.452 |
Secondary
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.
Time frame: 10 weeks, 28 weeks
Population: Randomized participants with a CGI-S score during the acute treatment period and at least 1 CGI-S score during the extension treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine (Acute Treatment) | Change From 10-Week to 28-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale | -0.76 units on a scale | Standard Error 0.093 |
| Placebo (Acute Treatment) | Change From 10-Week to 28-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale | -1.17 units on a scale | Standard Error 0.088 |
Secondary
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.
Time frame: 10 weeks, 28 weeks
Population: Randomized participants with a PARS severity total score during the acute treatment period and at least 1 PARS severity total score during the extension treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine (Acute Treatment) | 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 | -3.32 units on a scale | Standard Error 0.357 |
| Placebo (Acute Treatment) | 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 | -5.26 units on a scale | Standard Error 0.432 |
Secondary
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.
Time frame: Baseline, 10 weeks
Population: Randomized participants with a baseline and at least 1 post-baseline \[last observation carried forward (LOCF)\] CGAS score during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine (Acute Treatment) | Change From Baseline to 10-Week Endpoint in the Children's Global Assessment Scale (CGAS) | 17.14 units on a scale | Standard Error 1.232 |
| Placebo (Acute Treatment) | Change From Baseline to 10-Week Endpoint in the Children's Global Assessment Scale (CGAS) | 12.16 units on a scale | Standard Error 1.219 |
Secondary
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.
Time frame: Baseline, 10 weeks
Population: Randomized participants with a baseline and at least 1 post-baseline CGI-S score during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine (Acute Treatment) | Change From Baseline to 10-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale | -1.93 units on a scale | Standard Error 0.114 |
| Placebo (Acute Treatment) | Change From Baseline to 10-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale | -1.38 units on a scale | Standard Error 0.113 |
Secondary
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.
Time frame: Baseline, 10 weeks
Population: Randomized participants with a baseline and at least 1 post-baseline PARS severity total score during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine (Acute Treatment) | 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 | -9.15 units on a scale | Standard Error 0.479 |
| Placebo (Acute Treatment) | 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 | -6.36 units on a scale | Standard Error 0.477 |
Secondary
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.
Time frame: Baseline up to 10 weeks
Population: Randomized participants with a baseline and at least 1 post-baseline C-SSRS suicidal behavior score during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine (Acute Treatment) | 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) | 0.0 percentage of participants |
| Placebo (Acute Treatment) | 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) | 0.0 percentage of participants |
Secondary
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.
Time frame: Baseline up to 10 weeks
Population: Randomized participants with a baseline and at least 1 post-baseline C-SSRS suicidal ideation score during the acute treatment period, whose baseline maximum C-SSRS suicidal ideation score was \<5. Nine (9) participants from 1 site with major quality issues were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine (Acute Treatment) | 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) | 5.9 percentage of participants |
| Placebo (Acute Treatment) | 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) | 5.2 percentage of participants |
Secondary
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.
Time frame: 10 weeks up to 28 weeks
Population: Randomized participants with a C-SSRS suicidal behavior score at the last 2 visits in the acute treatment period and at least 1 C-SSRS suicidal behavior score during the extension treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine (Acute Treatment) | 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) | 0 percentage of participants |
| Placebo (Acute Treatment) | 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) | 2 percentage of participants |
Secondary
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.
Time frame: 10 weeks up to 28 weeks
Population: Randomized participants with a C-SSRS suicidal ideation score \<5 at the last 2 visits in the acute treatment period and at least 1 C-SSRS suicidal ideation score during the extension treatment period. Nine (9) participants from 1 site with major quality issues were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine (Acute Treatment) | 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) | 3 percentage of participants |
| Placebo (Acute Treatment) | 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) | 3 percentage of participants |
Secondary
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.
Time frame: 10 weeks
Population: Randomized participants with at least 1 post-baseline CGI-S score \[last observation carried forward (LOCF)\] during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine (Acute Treatment) | Remission Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Clinical Global Impressions of Severity (CGI-S) Scale | 45 percentage of participants |
| Placebo (Acute Treatment) | Remission Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Clinical Global Impressions of Severity (CGI-S) Scale | 30 percentage of participants |
Secondary
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.
Time frame: Baseline, 10 weeks
Population: Randomized participants with a baseline and at least 1 post-baseline PARS severity score for GAD \[last observation carried forward (LOCF)\] during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Duloxetine (Acute Treatment) | Response Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Pediatric Anxiety Rating Scale (PARS) Severity Score for GAD | 51 percentage of participants | 4.8 |
| Placebo (Acute Treatment) | Response Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Pediatric Anxiety Rating Scale (PARS) Severity Score for GAD | 37 percentage of participants | 4.8 |