A Study of Patients With Major Depressive Disorder and Residual Apathy

• ClinicalTrials.gov Identifier: NCT00985504
• Recruitment Status: Completed
• First Posted: September 28, 2009
• Results First Posted: October 3, 2011
• Last Update Posted: December 13, 2011
• Sponsor: Eli Lilly and Company
• Collaborator: Boehringer Ingelheim
• Information provided by (Responsible Party): Eli Lilly and Company

Study Description

Brief Summary:

The purpose of this study is to provide a comparison of the apathy, depression, and functional outcomes associated with switching to duloxetine or escitalopram in patients who have previously responded to treatment with a selective serotonin reuptake inhibitor (SSRI) for major depressive disorder and who have residual apathy in the absence of depressed mood.

Condition or disease	Intervention/treatment	Phase
Major Depressive Disorder	Drug: Duloxetine; Drug: Escitalopram	Phase 4

Detailed Description:

Apathy is reported by up to 30% of patients with major depressive disorder (MDD) and is hypothesized to be a treatment emergent adverse effect associated with selective serotonin reuptake inhibitor medication. While there is currently no consistent method for treating apathy among psychiatrists, it has been proposed that switching MDD patients to antidepressant medications containing both serotonin and norepinephrine, such as duloxetine, may reduce the incidence and severity of apathy in these patients.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 483 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 4, 8-week, Double-blind, Randomized Study Comparing Switching to Duloxetine or Escitalopram in Patients With Major Depressive Disorder and Residual Apathy in the Absence of Depressed Mood
• Study Start Date: September 2009
• Actual Primary Completion Date: December 2010
• Actual Study Completion Date: December 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Duloxetine	Drug: Duloxetine; 60-120 milligrams (mg) taken once daily (QD) by mouth (po) for 8 weeks; with option for additional 2 weeks.; Other Names: Cymbalta; LY248686
Active Comparator: Escitalopram	Drug: Escitalopram; 10-20 mg taken QD po for 8 weeks; with option for additional 2 weeks.

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in the Apathy Evaluation Scale - Clinician Rated Version (AES-C) Total Score at Week 8 [ Time Frame: Baseline, 8 weeks ]
   The AES-C is a validated 18-item instrument used to assess cognitive, behavioral, emotional and other symptoms of apathy. Clinicians rate each item based on verbal and nonverbal information provided by the participant. Item scores range from 1 (not at all characteristic) to 4 (a lot characteristic). Total scores range from 18 to 72 where higher derived scores indicate more severe apathy. The Least Squares (LS) Mean Value was calculated from a mixed model repeated measures (MMRM) model with terms of treatment, pooled investigator, visit, treatment*visit, baseline, and baseline*visit.

Secondary Outcome Measures :

1. Change From Baseline in the Apathy Evaluation Scale-Clinician Rated Version (AES-C) Subscale Scores at Week 8 [ Time Frame: Baseline, 8 weeks ]
   AES-C subscales separately assess participants' intensity of cognitive, behavioral, emotional, and other apathy symptoms with individual item scores of 1 (not at all characteristic) to 4 (a lot characteristic). Subtotal score ranges for the subscales are: 8-32 (cognitive), 5-20 (behavioral), 2-8 (emotional), and 3-12 for other (display of personal insight, initiative and motivation). Higher subscale scores indicate greater illness severity. The LS Mean Value was calculated from an MMRM model with terms of treatment, pooled investigator, visit, treatment*visit, baseline, and baseline*visit.
2. Change From Baseline in the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) Total and Individual Item Scores at Week 8 [ Time Frame: Baseline, 8 weeks ]
   RSAT assesses symptoms of apathy or decreased motivation among depressed participants who have achieved symptomatic remission with antidepressant treatment and consists of 6 self-report items assessing energy level, motivation and interest, cognitive functioning, weight gain, sleep and sexual functioning, as well as affect. Each item score ranges from 0 to 4 with total scores ranging from 0 to 28. Higher scores indicate greater disease severity. LS Mean Value was calculated from an MMRM model with terms of treatment, pooled investigator, visit, treatment*visit, baseline, and baseline*visit.
3. Patient's Global Impressions of Improvement Scale (PGI-I) Rating Scale Score at Week 8 [ Time Frame: 8 weeks ]
   The PGI-I is a scale that measures the participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). The LS Mean Value was calculated from an MMRM model with terms of treatment, pooled investigator, visit, and treatment*visit.
4. Change From Baseline in the Clinical Global Impression of Severity (CGI-S) Rating Scale at Week 8 [ Time Frame: Baseline, 8 weeks ]
   The CGI-S 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 patients). The LS Mean Value was calculated from an MMRM model with terms of treatment, pooled investigator, visit, treatment*visit, baseline, and baseline*visit.
5. Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Item 8 (Inability to Feel) at Week 8 [ Time Frame: Baseline, 8 weeks ]
   MADRS is a rating scale for severity of depressive mood symptoms and has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Item 8 assesses the participant's inability to feel. Scores range from 0 (normal interest in surroundings and other people) to 6 (emotional paralysis, inability to feel anger/grief/pleasure). The LS Mean Value was calculated from an MMRM model with terms of treatment, pooled investigator, visit, treatment*visit, baseline, and baseline*visit.
6. Change From Baseline in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) Total and Item Scores at Week 8 [ Time Frame: Baseline, 8 weeks ]
   The MGH-CPFQ is a 7-item participant-rated questionnaire evaluating the participant's cognitive and physical well-being during the past month. The MGH-CPFQ assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item is scored on a 6-point scale ranging from 1 ("greater than normal") to 2 ("normal") to 6 ("totally absent"). Total scores range from 7 to 42. Higher scores indicate greater disease severity. The LS Mean Value was calculated from an analysis of covariance (ANCOVA) model with terms of treatment, pooled investigator, and baseline.
7. Change From Baseline in the Sheehan Disability Scale (SDS) Total and Individual Scores at Week 8 [ Time Frame: Baseline, 8 weeks ]
   The SDS is a participant-rated assessment. Total scores range from 0-30 with higher values indicating greater disruption in the participant's work/social/family life. Items 1-3 assess the effect of the participant's symptoms on work/school schedule, social life/leisure activities, and family life/home responsibilities, respectively. Item scores are 0-10; higher values indicate greater disruption. Number of unproductive days and days lost in past week (symptom related) were reported. LS Mean Value was calculated from an ANCOVA model with terms of treatment, pooled investigator, and baseline.
8. Percentage of Participants Who Relapsed During 8 Weeks [ Time Frame: Baseline through 8 weeks ]
   Relapse is defined as achieving a Montgomery-Asberg Depression Rating Scale (MADRS) total score≥16 at any time after baseline. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
9. Number of Days From Baseline to Relapse as Defined by Montgomery-Asberg Depression Rating Scale (MADRS) Total Score ≥16 During 8 Weeks [ Time Frame: Baseline through 8 weeks ]
   The number of days from baseline to the first relapse is defined as reaching a MADRS Total Score≥16. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Censored participants were included in the Kaplan-Meier analysis, the minimum and maximum time to relapse have been calculated and reported here. Median time to relapse and quartiles could not be computationally calculated using the Kaplan-Meier procedure due to low event rate and high completion rate (censored).
10. Percentage of Participants Who Discontinue Due to Lack of Efficacy During 8 Weeks [ Time Frame: Baseline through 8 weeks ]
    Percentage of participants who discontinue after baseline due to lack of efficacy in the investigator's opinion.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Have received treatment with an SSRI (escitalopram, sertraline, paroxetine, or citalopram) for major depressive disorder
• Females of child-bearing potential to 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
• Apathy Evaluation Scale - Clinician Rated Version (AES-C) total score >30 at screening and randomization.
• Montgomery-Asberg Depression Rating Scale (MADRS) total score ≤15 and Item 1 (apparent sadness) score of <2 at screening and randomization.
• Have a level of understanding sufficient to provide informed consent and to communicate with the investigators, study coordinator, and site personnel.

Exclusion Criteria:

• Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device
• Have previously completed or withdrawn from this study or any other study investigating duloxetine.
• Have had previous lack of response to an adequate trial of duloxetine within the past 12 months or escitalopram at any time.
• Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), diagnosis of mania, bipolar disorder, treatment resistant depression or psychosis; or current suicide risk
• Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision(DSM-IV-TR),substance abuse or dependence within the 6 months
• Presence of an Axis II disorder
• Monoamine oxidase inhibitor (MAOI) treatment within 14 days prior to randomization or the potential need to use an MAOI during the study
• Positive urine drug screen for any substance of abuse or excluded medication.
• Are pregnant or breast-feeding.
• Serious medical illness, requires hospitalization during the study
• Have uncontrolled narrow-angle glaucoma.
• Have acute liver injury or severe cirrhosis
• Abnormal thyroid stimulating hormone (TSH) concentration
• Amphetamines, dopaminergic medications or modafinil within 14 days prior to randomization or potential need to use such medications during the study or within 14 days of discontinuation of study drug.

Contacts and Locations

Locations

Australia, Queensland

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Everton Park, Queensland, Australia, 4053

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Spring Hill, Queensland, Australia, 4000

Australia, South Australia

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Glenside, South Australia, Australia, 5065

Australia, Victoria

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Dandenong, Victoria, Australia, 3175

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Frankston, Victoria, Australia, VIC 3199

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Prahran, Victoria, Australia, 3181

Canada, Manitoba

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Winnipeg, Manitoba, Canada, R3P 0N5

Mexico

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Durango, Mexico, 34270

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Frac. Hacienda De Las Cruces, Mexico, 82110

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Mexico City, Mexico, 06700

Russian Federation

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Moscow, Russian Federation, 115522

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Saint Petersburg, Russian Federation, 192019

Taiwan

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Douliou City, Taiwan, 640

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Kao Hsiung, Taiwan, 802

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Tao-Yuan, Taiwan, 333

Sponsors and Collaborators

Eli Lilly and Company

Boehringer Ingelheim

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

More Information

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00985504
• Other Study ID Numbers: 13018; F1J-CR-HMGM ( Other Identifier: Eli Lilly and Company )
• First Posted: September 28, 2009
• Results First Posted: October 3, 2011
• Last Update Posted: December 13, 2011
• Last Verified: August 2011

Keywords provided by Eli Lilly and Company:

Major Depressive Disorder; Apathy; Duloxetine Hydrochloride; SSRI; Escitalopram

Additional relevant MeSH terms:

Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Pathologic Processes; Mood Disorders; Mental Disorders; Behavioral Symptoms; Duloxetine Hydrochloride; Citalopram; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Serotonin Agents; Physiological Effects of Drugs; Antidepressive Agents, Second-Generation; Antidepressive Agents; Psychotropic Drugs; Peripheral Nervous System Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Analgesics; Sensory System Agents; Dopamine Agents