Early Versus Delayed Switch in Medication in Patients With Major Depressive Disorder

Study Overview
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Brief Summary
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This study investigates two different approaches to the change in antidepressant treatment when an initial treatment is not effective: early intervention or delayed intervention. Two hypothesis will be tested: that time to confirmed response is shorter in the early intervention strategy vs. delayed intervention strategy that the time to confirmed remission is shorter in the early intervention strategy compared to delayed intervention strategy.

Official Title
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Comparison of Two Different Treatment Strategies in Patients With Major Depressive Disorder Not Exhibiting Improvement on Escitalopram Treatment: Early vs. Delayed Intervention Strategy

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Duloxetine Hydrochloride
* Drug: Escitalopram


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female participants of at least 18 years of age who meet criteria for Major Depressive Disorder (MDD), single or recurrent episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV®-TR) disease diagnostic criteria. Participants (receiving or not antidepressant treatment) who, based on investigator criteria, initiate treatment with escitalopram or change their current Alzheimer's Disease (AD) treatment to escitalopram for this current MDD episode, at the initial visit. Must have a baseline score of ≥ 19 on the 17-item Hamilton Depression Rating Scale (HAMD-17) at the initial visit. Must have a baseline score of ≥ 4 in the Clinical Global Impression-Severity Scale (CGI-S) at the initial visit. Have a level of understanding sufficient to provide Informed Consent Document (ICD), and to communicate with the investigators and site personnel. Are judged to be reliable and agree to keep all appointments for clinic visits and procedures required by the protocol. Exclusion Criteria: Have any current primary Axis I disorder other than MDD, including but not limited to dysthymia. Have a diagnosis of dementia, Alzheimer's disease (AD), or organic brain syndrome; or who are cognitively impaired or who have language problems that prevent them from understanding and/or providing valid answers to the rating scale contents. Concomitant participation in other studies with investigational or marketed products. Are not expected to be able to be monitored throughout the entire study period for reasons unrelated to their illness (for instance, change of residence or healthcare center of reference). Are demonstrating a response or demonstrated a response to the AD treatment for the current depression episode previous to baseline visit. Are investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted. Are employed by Lilly or Boehringer Ingelheim (BI) (that is, employees, temporary contract workers, or designees responsible for the conduct of the study). Immediate family of Lilly or BI employees may participate in Lilly or BI-sponsored clinical trials, but are not permitted to participate at a Lilly or BI facility. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted. Women of childbearing potential who are not using a medically accepted means of contraception (for example, intrauterine device, oral contraceptive, contraceptive patch, implant, Depo-Provera [medroxyprogesterone acetate injectable suspension, Pharmacia & Upjohn], or barrier devices) when engaging in sexual intercourse. Women who are pregnant or breast-feeding may not participate in 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. Are judged to be at serious suicidal risk in the opinion of the investigator, and/or if the participant's baseline (Visit 1) HAMD-17 scores on item 3 suicide are 3. Have been treated with a monoamine oxidase inhibitor (MAOI) within 14 days prior to Visit 1 or potential need to use an MAOI during the study or within 5 days after discontinuation of study drug. Require initiation or discontinuation of psychotherapy within 6 weeks prior to enrollment (Visit 1) or at any time during the study. Have any contraindication for the use of duloxetine based on Duloxetine Summary of Product Characteristics (SPC) or any contraindication for the use of escitalopram based on Escitalopram SPC. Have a history of lack of response to duloxetine or escitalopram at a clinically appropriate dose for a minimum of 4 weeks, or have previously completed or withdrawn from this study or any other study investigating duloxetine or escitalopram. Have any previous diagnosis of bipolar disorder, schizophrenia, or other psychotic disorders. Have DSM-IV-defined history of substance abuse or dependence within the past year, excluding nicotine and caffeine. Have serious or unstable cardiovascular, hepatic, renal, respiratory or hematological illness; symptomatic peripheral vascular disease; or other medical (including unstable hypertension and not clinically euthyroid) or psychological conditions that, in the opinion of the investigator, would compromise participation or be likely to require hospitalization during the course of the study. Have had Electroconvulsive Therapy (ECT) or Transcranial Magnetic Stimulation within the past year.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early Intervention<br>Escitalopram 10 milligrams per day for 4 weeks (one 10 milligram [mg]-capsule) followed by Duloxetine flexible dose (60 or 120 mg daily) for 12 weeks. | Drug: Duloxetine Hydrochloride<br>* Flexible dose of 60 or 120 mg daily<br>* Other names: LY248686;Drug: Escitalopram<br>* 10 mg in both Early and Delayed Intervention. Flexible dose of 10 to 20 mg daily in Delayed Intervention.<br>* Other names: Cipralex;|
| Experimental: Delayed Intervention<br>Escitalopram 10 mg per day for 4 weeks (one 10 mg-capsule) followed by Escitalopram 10 to 20 mg per day for 4 weeks (one or two 10 mg capsule[s]). Then, non-responders switched to Duloxetine 60 or 120 mg per day for 8 weeks , and responders continued on Escitalopram 10 to 20 mg per day for 8 weeks. | Drug: Duloxetine Hydrochloride<br>* Flexible dose of 60 or 120 mg daily<br>* Other names: LY248686;Drug: Escitalopram<br>* 10 mg in both Early and Delayed Intervention. Flexible dose of 10 to 20 mg daily in Delayed Intervention.<br>* Other names: Cipralex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Confirmed Response by ≥ 50% Change From Baseline Reduction in the Hamilton Depression Rating Scale-17 Items (HAMD-17) | Time to confirmed response is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed response defined as ≥ 50% baseline score reduction on the HAMD-17 for 2 consecutive visits. The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale, e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe). | Week 4 through Week 16 | 
| Estimated Probability of Not Reaching Confirmed Response at 12 Weeks Based on the Survival Function for the Time to Confirmed Response | Survival function is estimating the probability of participants not achieving confirmed response after 12 weeks. Confirmed response is defined as >=50% change from baseline reduction in the Hamilton Depression Rating Scale-17 Items (HAMD-17). The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe). | Week 4 through Week 16 | 
| Time to Confirmed Remission by a Hamilton Depression Rating Scale-17 Items (HAMD-17) Score of ≤ 7 That is Maintained for Two Consecutive Visits | Time to confirmed remission is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed remission defined as a score on the HAMD-17 of ≤ 7 for 2 consecutive visits. The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe). | Week 4 through Week 16 | 
| Estimated Probability of Not Reaching Confirmed Remission at 12 Weeks Based on the Survival Function for the Time to Confirmed Remission | Survival function is estimating the probability of participants not achieving confirmed remission. Confirmed remission is defined as a Hamilton Depression Rating Scale-17 Items (HAMD-17) Score of ≤ 7 that is maintained for two consecutive visits. The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe). | Week 4 through Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Confirmed Response as Defined by ≥ 50% Reduction From Baseline Reduction in the 16-Item Quick Inventory of Depressive Symptomatology Self Report (QIDS16SR) That is Reported for Two Consecutive Visits | Time to confirmed response is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed response. QIDS16SR is a 16-item participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27 with higher scores indicative of greater severity. | Week 4 through Week 16 | 
| Time to Confirmed Remission as Defined by a 16-Item Quick Inventory of Depressive Symptomatology Self Report (QIDS16SR) Score of ≤ 5 That is Maintained for Two Consecutive Visits. | Time to confirmed remission is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed remission. A 16-item participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27 with higher scores indicative of greater severity. | Week 4 through Week 16 | 
| Clinical Global Impressions of Severity (CGI-S) Scale | Measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). | Baseline, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, Week 16 | 
| Visual Analog Scale (VAS) - Overall Pain Severity | VAS for pain consists of 6 questions that assess overall pain, headache, back pain, shoulder pain, pain interference with daily activities, and pain while awake. Participant rates pain on a 10 centimeter (cm) line between two anchors (0= no pain and 10=very severe pain). | Baseline, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, Week 16 | 
| Euro Quality of Life Questionnaire-5 Dimensions (EQ-5D) Scale - Health State Score | The EQ-5D Health State Score is self-rated health on a vertical, visual analogue scale measured in centimeters (cm) and reported as units on a scale. Best imaginable health state = 10 cm and worst imaginable health state = 0 cm. | Baseline, Week 4, Week 8, Week 12, Week 16 | 
| Euro Quality of Life Questionnaire-5 Dimensions (EQ-5D) Scale - United Kingdom (UK) Population Based Index Score | The EQ-5D is a generic, multidimensional, health-related, quality of life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood. A single score between 1 and 3 is generated for each domain. For each participant, the outcome rating on the 5 domains will be mapped to a single index through an algorithm. The index ranges between 0 and 1, with the higher score indicating a better health state perceived by the participant. | Baseline, Week 4, Week 8, Week 12, Week 16 | 
| Sheehan Disability Scale (SDS) Normal Functioning Total Score | The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work/social/family life. Total scores range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. | Baseline, Week 4, Week 8, Week 12, Week 16 | 
| Resource Utilisation - Number of Hours Worked Per Week |  | Baseline, Week 4, Week 8, Week 12, Week 16 | 
| Resource Utilisation - Number of Work Hours Missed in the Last 4 Weeks | Only those participants who missed at least 1 hour of work were included. | Week 4, Week 8, Week 12, Week 16 | 
| Resource Utilisation - Number of Work Hours Missed Due to Depression in the Last 4 Weeks | Only those participants who missed at least 1 hour of work due to depression were included. | Week 4, Week 8, Week 12, Week 16 | 
| Resource Utilisation - Number of Visits to Primary Healthcare Provider Due to Depression in the Last 4 Weeks |  | Week 4, Week 8, Week 12, Week 16 | 
| Resource Utilisation - Number of Visits to Other Specialists Due to Depression in the Last 4 Weeks |  | Week 4, Week 8, Week 12, Week 16 | 
| Resource Utilisation - Has the Participant Been Hospitalized Due to Depression in the Last 4 Weeks - Number of Participants With a Yes Response |  | Week 4, Week 8, Week 12, Week 16 | 
| Number of Participants With Adverse Events (AEs) | The list of AEs is located in the Reported Adverse Event module. | Baseline through Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDD, Major Depressive Disorder, Depression