A Duloxetine Dosing Strategy Study in Korean Patients With Major Depressive Disorder

Study Overview
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Brief Summary
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The purpose of this study is to assess nausea severity in response to four different drug dosing strategies of Duloxetine (30 mg with food, 60 mg with food, 30 mg without food, and 60 mg without food) in Korean patients with major depressive disorder (MDD).

Official Title
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A Phase 4 Comparison of Duloxetine Dosing Strategies in the Treatment of Korean Patients With Major Depressive Disorder

Conditions
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Major Depressive Disorder (MDD)

Intervention / Treatment
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* Drug: Duloxetine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For females of child-bearing potential test negative for pregnancy at the time of enrollment based on a urine pregnancy test and agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug. 17-item Hamilton Depression Rating Scale (HAMD-17) total score >15 at Screening and Randomization Have signed the informed consent document (ICD) Have a level of understanding sufficient to provide informed consent and to communicate with the investigators and site personnel Are judged to be reliable and agree to keep all appointments for clinic visits, tests, and procedures required by the protocol Patients must meet Diagnostic and Statistical Manual of Mental Disorders-fourth edition-text revision (DSM-IV-TR) criteria for Major Depressive Disorder (MDD). The Mini International Neuropsychiatric Interview (MINI) will be used to establish the diagnosis and exclude other psychiatric illnesses. Exclusion Criteria: 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 any current primary Axis I disorder other than MDD Have any previous diagnosis of bipolar disorder, schizophrenia, or other psychotic disorders Lack of response of the current episode of major depression to two or more adequate courses of antidepressant therapy at clinically appropriate dose for a minimum of 4 weeks or, in the judgment of the investigator, the patient meets criteria for treatment-resistant depression Have a history of a lack of response, at any time, to an adequate trial of duloxetine (defined as treatment with at least 60 mg/day of duloxetine for a minimum of 4 weeks) Presence of an Axis II disorder that, in the judgment of the investigator, would interfere with study compliance DSM-IV-TR-defined history of substance abuse or dependence within the past 6 months, excluding nicotine and caffeine Patients judged to be at serious suicidal risk in the opinion of the investigator and/or score ≥3 on Item 3 (suicide) of the HAMD-17 Serious medical illness or clinically significant laboratory abnormalities that, in the judgment of the investigator, are likely to require intervention/hospitalization/excluded medication during the course of the study Note: Patients with acute liver injury (such as hepatitis) or severe (Child-Pugh Class C) cirrhosis will be excluded Have an acute or chronic medical illness with the main symptoms of nausea or gastrointestinal discomfort or taking any medication known to have major gastric effects that would interfere with nausea ratings. Electroconvulsive therapy (ECT) or Transcranial Magnetic Stimulation (TMS) within the past year Taking any excluded medications within 7 days prior to Randomization. Treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to Randomization or potential need to use a MAOI within 5 days after discontinuation of study drug. Treatment with fluoxetine within 30 days prior to Randomization. Frequent and/or severe allergic reactions with multiple medications or known hypersensitivity to duloxetine. Abnormal thyroid stimulating hormone (TSH) concentration. Note: Participants diagnosed with hyperthyroidism or hypothyroidism who were treated with a stable dose of thyroid supplement for at least the past 3 months, have medically appropriate TSH concentration, and are clinically euthyroid, are allowed to enroll in this study.

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Duloxetine 60 mg with food<br>Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks | Drug: Duloxetine hydrochloride<br>* po, QD<br>* Other names: LY248686;|
| Experimental: Duloxetine 60 mg without food<br>Duloxetine 60 mg capsule po QD without food for 8 weeks | Drug: Duloxetine hydrochloride<br>* po, QD<br>* Other names: LY248686;|
| Experimental: Duloxetine 30 mg with food<br>Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks | Drug: Duloxetine hydrochloride<br>* po, QD<br>* Other names: LY248686;|
| Experimental: Duloxetine 30 mg without food<br>Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks | Drug: Duloxetine hydrochloride<br>* po, QD<br>* Other names: LY248686;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Maximum Nausea Severity, Association for Methodology and Documentation in Psychiatry (AMDP-5) Adverse Event (AE) Scale Item 112 (Nausea) | AMDP-5 AE scale Item 112 (nausea) measured nausea severity during treatment (Week 0-8). The scores ranged from 0-3: 0=Not present; 1=Mild; 2=Moderate; 3=Severe. | 1 week and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to 8-Week Endpoint in Association for Methodology and Documentation in Psychiatry (AMDP-5) Adverse Event (AE) Scale Item 112 (Nausea) | Scores for AE scale Item 112 (nausea) of AMDP-5 (Week 0-8) ranged from 0-3: 0=Not present; 1=Mild; 2=Moderate; 3=Severe. Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix. | Baseline, 8 weeks | 
| Mean Change From Baseline to 1-Week and 8-Week Endpoints in Association for Methodology and Documentation in Psychiatry (AMDP-5) Measure: Gastric Events Score | Gastric events scores (average of Item 112 [nausea] + Item 113 [vomiting]) of AMDP-5 (Week 0-8) ranged from 0-3: 0=Not present; 1=Mild; 2=Moderate; 3=Severe. Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix. | Baseline, 1 week and 8 weeks | 
| Mean Change From Baseline to 1-Week and 8-Week Endpoints in Association for Methodology and Documentation in Psychiatry (AMDP-5) Measure: Common Adverse Events (AEs) Score | AMDP-5 common AEs score was used to create a composite measure of AEs from previous duloxetine studies (incidence >5% and 2X placebo rate). The common AEs total score was the sum of the following 8 AMDP-5 items: 1) Mean of Item 112 (nausea) + 113 (vomiting); 2) Item 111 (dry mouth); 3) Item 115 (constipation); 4) Mean of Items 101-104 (insomnia); Item 122 (increased perspiration); 8) Item 106 (decreased appetite). Score was based on a 5-point scale: 1=absent, 2=mild, 3=moderate, 4=severe, 5=extremely severe; Higher score=worse severity. | Baseline, 1 week, 8 weeks | 
| Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Total Score | The HAMD-17 total score ranged from 0 (not at all depressed)-52 (severely depressed). Least squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariance matrix. | Baseline, 1 week, 8 weeks | 
| Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Maier Subscale | The HAMD-17 Maier subscale (Items 1, 2, 7, 8, 9, 10 of HAMD-17 questionnaire) represented the core symptoms of depression. Total subscale scores ranged from 0 (normal)-24 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix. | Baseline, 1 week, 8 weeks | 
| Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Core Mood Subscale | The HAMD-17 Core Mood subscale (Items 1, 2, 3, 7, 8 of HAMD-17 questionnaire) represented the core symptoms of depression. Total subscale scores ranged from 0 (normal)-20 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix. | Baseline, 1 week, 8 weeks | 
| Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Anxiety/Somatization Subscale | The HAMD-17 Anxiety/Somatization subscale (Items 10, 11, 12, 13, 15, 17 of HAMD-17 questionnaire) evaluated the severity of psychic and somatic manifestations of anxiety and agitation. Total subscale scores ranged from 0 (normal)-18 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix. | Baseline, 1 week, 8 weeks | 
| Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Retardation/Somatization Subscale | The HAMD-17 Retardation/Somatization subscale (Items 1, 7, 8, 14 of HAMD-17 questionnaire) evaluated dysfunction in mood, work, sexual activity, and overall motor retardation. Total subscale scores ranged from 0 (normal)-14 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix. | Baseline, 1 week, 8 weeks | 
| Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Sleep Subscale | The HAMD-17 Sleep subscale (Items 4, 5, 6 of HAMD-17 questionnaire) evaluated initial, middle, and late insomnia. Total subscale scores ranged from 0 (no difficulty)-6 (difficulty). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix. | Baseline, 1 week, 8 weeks | 
| Mean Change From Baseline to 1-Week and 8-Week Endpoints in Clinical Global Impressions of Severity (CGI-S) | The CGI-S Rating Scale was a 7-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; or 7=extremely ill. Least squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariance matrix. | Baseline, 1 week, 8 weeks | 
| Patient Global Impression of Improvement (PGI-I) at 1 Week and 8 Weeks | The PGI-I Rating Scale was a 7-point scale: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. Least squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction and an unstructured covariance matrix. | 1 week, 8 weeks | 
| Time to Onset of Nausea | Events of nausea were taken from the adverse event (AE) data. Participants were censored based on the following rules: 1=study discontinuation date if the participant discontinues the study; 2=study lost to follow-up date if the participant drops out of the study. | Baseline to onset of nausea (Baseline up to 8 weeks) | 
| Time to Resolve Nausea | Events of nausea were taken from the adverse event (AE) data. Participants were censored based on the following rules: 1=study discontinuation date if the participant discontinues the study; 2=study lost to follow-up date if the participant drops out of the study. | Nausea onset up to nausea resolve (Baseline up to 8 weeks) | 
| Percentage of Participants Achieving Response | Response was defined as ≥50% decrease from baseline on the 17-item Hamilton Depression Rating Scale (HAMD-17) total score. HAMD-17 total scores ranged from 0 (not at all depressed)-52 (severely depressed). | Baseline up to 8 weeks | 
| Percentage of Patients Achieving Remission | Remission was defined as 17-item Hamilton Depression Rating Scale (HAMD-17) total score ≤7. HAMD-17 total scores ranged from 0 (not at all depressed)-52 (severely depressed). | Baseline up to 8 weeks |