A Randomized, Placebo-Controlled, Double-Blind Study of LY2216684 Flexible-Dose 12 mg to 18 mg Once Daily and LY2216684 Fixed-Dose 6 mg Once Daily as Adjunctive Treatment for Patients With Major Depressive Disorder Who Are Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment
Overview
- Phase
- Phase 3
- Intervention
- LY2216684
- Conditions
- Major Depressive Disorder (MDD)
- Sponsor
- Eli Lilly and Company
- Enrollment
- 1480
- Locations
- 1
- Primary Endpoint
- Change From Randomization to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
The purpose of this study is to assess if LY2216684 (flexible dose of 12 to 18 milligrams [mg] or fixed dose of 6 mg once daily) is superior to placebo once daily in the adjunctive treatment of participants with Major Depressive Disorder (MDD) who were identified as partial responders to an adequate course of treatment with a selective serotonin reuptake inhibitor (SSRI) during an 8-week, double-blind, acute adjunctive treatment phase.
Detailed Description
Following the Confirmation (CF) Phase, participants were randomized to adjunctive LY2216684 or adjunctive placebo if they had \<25% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score over the past 3 weeks and a current MADRS total score ≥14. Participants who did not meet criteria received adjunctive placebo to preserve the blind.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Clinical diagnosis of Major Depressive Disorder (MDD)
- •Using a reliable method of birth control
- •Are taking a selective serotonin reuptake inhibitor (SSRI) approved for MDD treatment within the participant's country and the SSRI prescribed, including dose, should be consistent with labeling guidelines within the participating country
- •Have a partial response to SSRI treatment
- •Meet inclusion scores on pre-defined psychiatric scales to assess diagnosis of depression, disease severity, and response to SSRI treatment
- •Reliable and able to keep all scheduled appointments
Exclusion Criteria
- •Presence of another primary psychiatric illness:
- •Have had or currently have any additional ongoing Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) Axis 1 condition other than major depression within 1 year of screening
- •Have had any anxiety disorder that was considered a primary diagnosis within the past year (including panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and social phobia, but excluding specific phobias)
- •Have a current or previous diagnosis of a bipolar disorder, schizophrenia, or other psychotic disorder
- •Have a history of substance abuse and/or dependence within the past 1 year (drug categories defined by DSM-IV-TR), not including caffeine and nicotine
- •Have an Axis II disorder that, in the judgment of the investigator, would interfere with compliance with protocol
- •Have any diagnosed medical condition that could be exacerbated by noradrenergic agents, including unstable hypertension, unstable heart disease, tachycardia, tachyarrhythmia, narrow-angle glaucoma, and history of urinary hesitation or retention
- •Use of excluded concomitant or psychotropic medication other than SSRI
- •Have initiated or discontinued hormone therapy within the previous 3 months of prior to enrollment
- •History of treatment-resistant depression as shown by lack of response of the current depressive episode to 2 or more adequate courses of antidepressant therapy at a clinically appropriate dose for at least 4 weeks, or in the judgment of the investigator, the participant has treatment-resistant depression
Arms & Interventions
12 or 18 mg flexible dose LY2216684 + SSRI
LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Prior to entering the Adjunctive Treatment (AT) Phase, participants completed a 3-week Confirmation (CF) Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to a 12 or 18 mg flexible dose of LY2216684. During the AT Phase, participants first received 6 mg LY2216684 QD for 3 days, followed by 12 mg QD for the next 11 days. Then, based on efficacy and tolerability, dosage could be increased to 18 mg QD over the next 6 weeks. Participants on 18 mg QD could have had their dose decreased back to 12 mg QD. Participants who completed the AT Phase or discontinued early had the option to enter the Discontinuation (DC) Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.
Intervention: LY2216684
12 or 18 mg flexible dose LY2216684 + SSRI
LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Prior to entering the Adjunctive Treatment (AT) Phase, participants completed a 3-week Confirmation (CF) Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to a 12 or 18 mg flexible dose of LY2216684. During the AT Phase, participants first received 6 mg LY2216684 QD for 3 days, followed by 12 mg QD for the next 11 days. Then, based on efficacy and tolerability, dosage could be increased to 18 mg QD over the next 6 weeks. Participants on 18 mg QD could have had their dose decreased back to 12 mg QD. Participants who completed the AT Phase or discontinued early had the option to enter the Discontinuation (DC) Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.
Intervention: Placebo
12 or 18 mg flexible dose LY2216684 + SSRI
LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Prior to entering the Adjunctive Treatment (AT) Phase, participants completed a 3-week Confirmation (CF) Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to a 12 or 18 mg flexible dose of LY2216684. During the AT Phase, participants first received 6 mg LY2216684 QD for 3 days, followed by 12 mg QD for the next 11 days. Then, based on efficacy and tolerability, dosage could be increased to 18 mg QD over the next 6 weeks. Participants on 18 mg QD could have had their dose decreased back to 12 mg QD. Participants who completed the AT Phase or discontinued early had the option to enter the Discontinuation (DC) Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.
Intervention: SSRI
6 mg fixed dose LY2216684 + SSRI
LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI Prior to entering the AT Phase, participants completed a 3-week CF Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to 6 mg fixed dose of LY2216684. During the AT Phase, participants received a 6 mg fixed dose of LY2216684 adjunctive to their SSRI for 8 weeks. Participants who completed the AT Phase or discontinued early had the option to enter the DC Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.
Intervention: LY2216684
6 mg fixed dose LY2216684 + SSRI
LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI Prior to entering the AT Phase, participants completed a 3-week CF Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to 6 mg fixed dose of LY2216684. During the AT Phase, participants received a 6 mg fixed dose of LY2216684 adjunctive to their SSRI for 8 weeks. Participants who completed the AT Phase or discontinued early had the option to enter the DC Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.
Intervention: Placebo
6 mg fixed dose LY2216684 + SSRI
LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI Prior to entering the AT Phase, participants completed a 3-week CF Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to 6 mg fixed dose of LY2216684. During the AT Phase, participants received a 6 mg fixed dose of LY2216684 adjunctive to their SSRI for 8 weeks. Participants who completed the AT Phase or discontinued early had the option to enter the DC Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.
Intervention: SSRI
Placebo + SSRI
Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI Prior to entering the AT Phase, participants completed a 3-week CF Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to placebo. During the AT Phase, participants received placebo (administered orally, QD) adjunctive to their SSRI for 8 weeks. Participants who completed the AT Phase or discontinued early had the option to enter the DC Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.
Intervention: Placebo
Placebo + SSRI
Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI Prior to entering the AT Phase, participants completed a 3-week CF Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to placebo. During the AT Phase, participants received placebo (administered orally, QD) adjunctive to their SSRI for 8 weeks. Participants who completed the AT Phase or discontinued early had the option to enter the DC Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.
Intervention: SSRI
Outcomes
Primary Outcomes
Change From Randomization to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
Time Frame: Randomization, 8 weeks
The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness \[apparent\], sadness \[reported\], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
Secondary Outcomes
- Percentage of Participants Achieving a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of Less Than or Equal to 10 up to Week 8(Randomization up to 8 weeks)
- Percentage of Participants Achieving a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of Less Than or Equal 10 for at Least 2 Consecutive Measurements, Including the Participant's Last Measurement(Randomization up to 8 weeks)
- Change From Randomization to Week 8 in the Fatigue Associated With Depression (FAsD) Impact Subscale Score(Randomization, 8 weeks)
- Percentage of Participants With Treatment-emergent (TE) Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)(Randomization through 8 weeks)
- Change From Randomization to Week 8 in the Sheehan Disability Scale (SDS) Global Functional Impairment Score(Randomization, 8 weeks)
- Change From Randomization to Week 8 in the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)(Randomization, 8 weeks)
- Pharmacokinetics: Plasma Concentrations of LY2216684(Pre-randomization, 1 week, 4 weeks, and 8 weeks)
- Change From Randomization to Week 8 in the Hospital and Anxiety and Depression Scale (HADS) Anxiety Subscale Score(Randomization, 8 weeks)
- Percentage of Participants Who Have a Greater Than or Equal to 50 Percent Improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization up to Week 8(Randomization up to 8 weeks)
- Change From Randomization to Week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) Individual Items(Randomization, 8 weeks)
- Change From Randomization to Week 8 in Clinical Global Impressions of Severity (CGI-S)(Randomization, 8 weeks)
- Change From Randomization to Week 8 in The Fatigue Associated With Depression (FAsD) Average Score and Experience Subscale Score(Randomization, 8 weeks)
- Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Items(Randomization, 8 weeks)
- Change From Randomization to Week 8 in the EuroQol Questionnaire-5 Dimension (EQ-5D)(Randomization, 8 weeks)
- Change From Randomization to Week 8 in Blood Pressure(Randomization, 8 weeks)
- Change From Randomization to Week 8 in the Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score(Randomization, 8 weeks)
- Change From Randomization to Week 8 in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)(Randomization, 8 weeks)
- Change From Randomization to Week 8 in the Arizona Sexual Experiences (ASEX) Scale(Randomization, 8 weeks)
- Change From Randomization to Week 8 in Pulse Rate(Randomization, 8 weeks)