Major Depressive Disorder (MDD)Phase 3NCT01187407

A Study of Flexible or Fixed Dose LY2216684 as Adjunctive Treatment for Participants With Major Depressive Disorder Who Have Had a Partial Response to Selective Serotonin Reuptake Inhibitor (SSRI) Treatment

A Phase 3 study testing LY2216684 and SSRI in people with Major Depressive Disorder (MDD), run by Eli Lilly and Company at 54 sites in 7 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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… Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Major Depressive Disorder (MDD)
What is being tested?: LY2216684 and SSRI
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 1,480 participants
Where: 54 sitesin 7 countries
Study dates: Mar 2011to Aug 2013
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

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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
Have a lifetime history of vagal nerve stimulation (VNS) transcranial magnetic stimulation (TMS), or psychosurgery
Have received electroconvulsive therapy (ECT) in the past year
Enrollment in a clinical study for an investigational drug
Serious or unstable medical condition
History of seizure disorders
Have initiated psychotherapy, change in intensity of psychotherapy or other nondrug therapies (such as acupuncture or hypnosis) within 6 weeks prior to enrollment or any time during the study
Participants who, in the opinion of the investigator, are judged to be at serious risk for harm to self or others

Trial locations and contacts

54 sites in 7 countries.

Country

City, postcode or hospital

54 sites in 7 countries

United States28 sites

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Atlanta, Georgia, 30308
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Baltimore, Maryland, 21285
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Beachwood, Ohio, 44122
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Birmingham, Alabama, 35216
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Brooklyn, New York, 11235
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Chino, California, 91710
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Clearwater, Florida, 33761
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Colorado Springs, Colorado, 80907
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Coral Gables, Florida, 33145
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Flowood, Mississippi, 39232
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Fort Lauderdale, Florida, 33319
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Glendale, California, 91204
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Haverhill, Massachusetts, 01830
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Hoffman Estates, Illinois, 60169
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Houston, Texas, 77096
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Imperial, California, 92251
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Indianapolis, Indiana, 46260
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National City, California, 91950
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New York, New York, 10021
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O'Fallon, Missouri, 63368
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Oklahoma City, Oklahoma, 73103
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Philadelphia, Pennsylvania, 19107
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Phoenix, Arizona, 85032
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Prairie Village, Kansas, 66206
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Sherman Oaks, California, 91403
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Tampa, Florida, 33613
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Weymouth, Massachusetts, 02190
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Wichita, Kansas, 67205

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Czechia7 sites

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Hořovice, 268 31
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Hostivice, 25201
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Kladno, 27201
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Olomouc, 77900
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Prague, 100 00
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Strakonice, 38601
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Ústí nad Labem, 400001

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Japan6 sites

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Chiba, 270-0014
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Fukuoka, 810-0035
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Fukushima, 961-0021
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Hyōgo, 661-0002
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Kanagawa, 247-0056
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Tokyo, 100-0006

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Finland5 sites

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Helsinki, 00100
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Joensuu, 80100
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Kuopio, 70110
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Tampere, 33200
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Turku, 20100

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Slovakia5 sites

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Bratislava, 85101
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Košice, 04001
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Michalovce, SK-071 01
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Rimavská Sobota, 97901
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Rožňava, 04801

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Croatia2 sites

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Rab, 51280
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Zagreb, 10090

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Puerto Rico1 site

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San Juan, 00918

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About this study

Official title: 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

Read the 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.

Conditions: Major Depressive Disorder (MDD)
Being tested: LY2216684, Placebo, SSRI
Medical subject headings: Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

LY2216684Drug
Also called Edivoxetine
PlaceboDrug
SSRIDrug
Also called selective serotonin reuptake inhibitor
Participants should have been on their SSRI for at least 6 weeks prior and were to continue on their stable dose throughout the study

Study groups in NCT01187407
Study group	Role	What they receive
12 or 18 mg flexible dose LY2216684 + SSRI	Experimental	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. Receives: Drug: LY2216684; Drug: Placebo; Drug: SSRI
6 mg fixed dose LY2216684 + SSRI	Experimental	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. Receives: Drug: LY2216684; Drug: Placebo; Drug: SSRI
Placebo + SSRI	Placebo comparator	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. Receives: Drug: Placebo; Drug: SSRI

What is being measured

The primary outcome is the main question the study is designed to answer.

Change From Randomization to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
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.
Measured: Randomization, 8 weeks

Secondary outcomes (19)

Change From Randomization to Week 8 in the Sheehan Disability Scale (SDS) Global Functional Impairment Score
The SDS was completed by the participant and used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. The Global Functional Impairment Score is the sum of the 3 items, and scores ranged from 0 to 30 with higher values indicating greater disruption in the participant's work life (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). 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.
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in the Fatigue Associated With Depression (FAsD) Impact Subscale Score
The FAsD is a participant-rated scale with a total of 13 items. Six of the 13 items ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Seven of the 13 items ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The impact subscale score was derived by taking the mean of Items 7 through 13 (applicable items only). Item 12 applied only to participants with a spouse or significant other and Item 13 applied to participants who had a job or who went to school. The FAsD impact subscale score ranges from 1 to 5. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.
Measured: Randomization, 8 weeks
Percentage of Participants Achieving a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of Less Than or Equal to 10 up to Week 8
A MADRS total score of less than or equal to 10 was defined as remission criteria. 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). Percentage of participants was calculated by dividing the number of participants who meet criteria for remission by the total number of participants analyzed, multiplied by 100%.
Measured: 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
A MADRS total score of less than or equal to 10 for at least 2 consecutive measurements, including the participant's last measurement was defined as remission criteria at last 2 consecutive visits. 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). Percentage of participants was calculated by dividing the number of participants who meet criteria for remission at last 2 consecutive visits by the total number of participants analyzed, multiplied by 100%.
Measured: Randomization up to 8 weeks
Change From Randomization to Week 8 in the Hospital and Anxiety and Depression Scale (HADS) Anxiety Subscale Score
The HADS is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item was rated on a 4-point scale (0 to 3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8 to 10 represent 'borderline' and scores of 0 to 7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.
Measured: 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
A greater than or equal to 50 percent improvement (that is, a decrease from baseline) in the MADRS total score was defined as response criteria. 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). Percentage of participants was calculated by dividing the number of participants meeting response criteria at last visit by the total number of participants analyzed, multiplied by 100%.
Measured: Randomization up to 8 weeks
Change From Randomization to Week 8 in the Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score
The HADS is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item was rated on a 4-point scale (0 to 3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8 to 10 represent 'borderline' and scores of 0 to 7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) Individual Items
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 item score, treatment-by-visit and baseline item score-by-visit.
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in Clinical Global Impressions of Severity (CGI-S)
CGI-S measures severity of depression at the time of assessment compared with the start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). 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
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in The Fatigue Associated With Depression (FAsD) Average Score and Experience Subscale Score
The FAsD is a participant-rated scale with a total of 13 items. Six of the 13 items ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Seven of the 13 items ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The experience subscale score was derived by taking the mean of Items 1 through 6, and the average score was the mean of Items 1 through 13 (derived by taking the mean of all applicable items for each participant). Item 12 applied only to participants with a spouse or significant other and Item 13 applied to participants who had a job or who went to school. 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.
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Items
The SDS was completed by the participant and used to assess the effect of the participant's symptoms on their work (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline item score, treatment-by-visit, and baseline item score-by-visit.
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)
The Q-LES-Q-SF is a self-administered 16 item questionnaire measuring degree of enjoyment and satisfaction experienced in various areas of daily life during the past week on a 5-point Likert scale (1=very poor and 5=very good). The total raw score is the sum of Items 1 to 14 and ranges from 14 to 70. The raw scores are converted to and expressed as the percentage of the maximum possible score. Higher scores indicate higher levels of enjoyment/satisfaction. 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.
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in the EuroQol Questionnaire-5 Dimension (EQ-5D)
The EQ-5D Visual Analog Scale is a generic, multidimensional, health-related, quality-of-life instrument. Overall health state score is self-reported using a visual analogue scale, marked on a scale of 0 to 100 with 0 representing worst imaginable health state and 100 representing best imaginable health state. 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.
Measured: Randomization, 8 weeks
Percentage of Participants With Treatment-emergent (TE) Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation was defined as a "yes" answer to any 1 of 5 suicidal ideation questions, which included a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation and behavior are defined as treatment-emergent (TE) if not present at baseline. Percentage of participants was calculated by dividing the number of participants with suicide-related TE events by the total number of participants analyzed, multiplied by 100%. A summary of serious and other non-serious adverse events, regardless of causality, is located in the Reported Adverse Event module.
Measured: Randomization through 8 weeks
Change From Randomization to Week 8 in the Arizona Sexual Experiences (ASEX) Scale
The ASEX scale was used to assess sexual functioning in both males and females. The ASEX total score for the male and female version was calculated as the sum of the responses (rated from 1 [extremely] to 6 [no/never]) of the 5 items of the ASEX scale. Total scores ranged from 5 to 30, with higher scores indicating greater sexual dysfunction. 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.
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)
The CPFQ is a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item was scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total scores ranged from 7 to 42. Higher scores indicate greater disease severity. 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.
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in Blood Pressure
Blood pressure measurements were collected when the participant was in a sitting position. Three measurements of sitting blood pressure collected at approximately 1-minute intervals at every visit were averaged and used as the value for the visit. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline value, treatment-by-visit, and baseline value-by-visit.
Measured: Randomization, 8 weeks
Change From Randomization to Week 8 in Pulse Rate
Pulse measurements were collected when the participant was in a sitting position. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline value, treatment-by-visit, and baseline value-by-visit.
Measured: Randomization, 8 weeks
Pharmacokinetics: Plasma Concentrations of LY2216684
A validated bioanalytical assay was used to determine plasma LY2216684 concentrations.
Measured: Pre-randomization, 1 week, 4 weeks, and 8 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Mar 2011Aug 2013

First posted24 Aug 2010 (estimated)
Study startMar 2011
Primary completionAug 2013
Study completionAug 2013

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Major Depressive Disorder (MDD)Studies of the same condition, open and under way.
More trials run by Eli Lilly and CompanyThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 1,480 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01187407
Sponsor's protocol ID: 12182
Other IDs: H9P-MC-LNBQ
Status last verified: Mar 2018
First submitted: 20 Aug 2010
Last updated: 24 Apr 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Stauffer VL, Liu P, Goldberger C, Marangell LB, Nelson C, Gorwood P, Fava M. Is the Noradrenergic Symptom Cluster a Valid Construct in Adjunctive Treatment of Major Depressive Disorder? J Clin Psychiatry. 2017 Mar;78(3):317-323. doi: 10.4088/JCP.15m09972.
PubMed 27685842
Ball SG, Ferguson MB, Martinez JM, Pangallo BA, Nery ES, Dellva MA, Sparks J, Zhang Q, Liu P, Bangs M, Goldberger C. Efficacy outcomes from 3 clinical trials of edivoxetine as adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment. J Clin Psychiatry. 2016 May;77(5):635-42. doi: 10.4088/JCP.14m09619.
PubMed 27035159

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Major Depressive Disorder (MDD) trials

Study at a glance

From the registry record, last updated by the sponsor on 24 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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
ClinicalTrials.gov ID: NCT01187407
Acronym / sponsor ID: 12182
Conditions: Major Depressive Disorder (MDD)
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 1,480 participants (actual)
Lead sponsor: Eli Lilly and CompanyIndustry (pharma, biotech, devices)
Study start: Mar 2011
Primary completion: Aug 2013 (actual)
Study completion: Aug 2013 (actual)
First posted: 24 Aug 2010 (estimated)
Results: Posted 24 Apr 2018

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 3

Arm	Type	Receives
12 or 18 mg flexible dose LY2216684 + SSRI	Experimental	Drug: LY2216684, Drug: Placebo, Drug: SSRILY2216684: 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.
6 mg fixed dose LY2216684 + SSRI	Experimental	Drug: LY2216684, Drug: Placebo, Drug: SSRILY2216684: 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.
Placebo + SSRI	Placebo comparator	Drug: Placebo, Drug: SSRIPlacebo: 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

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

Key exclusion criteria (17 listed)

Presence of another primary psychiatric illness:
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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
LY2216684Also: Edivoxetine	Drug	12 or 18 mg flexible dose LY2216684 + SSRI, 6 mg fixed dose LY2216684 + SSRI
Placebo	Drug	12 or 18 mg flexible dose LY2216684 + SSRI, 6 mg fixed dose LY2216684 + SSRI, Placebo + SSRI
SSRIAlso: selective serotonin reuptake inhibitorParticipants should have been on their SSRI for at least 6 weeks prior and were to continue on their stable dose throughout the study	Drug	12 or 18 mg flexible dose LY2216684 + SSRI, 6 mg fixed dose LY2216684 + SSRI, Placebo + SSRI

Primary outcome

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.

19 secondary outcomes

Change From Randomization to Week 8 in the Sheehan Disability Scale (SDS) Global Functional Impairment Score
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in the Fatigue Associated With Depression (FAsD) Impact Subscale Score
Time frame: Randomization, 8 weeks
Percentage of Participants Achieving a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of Less Than or Equal to 10 up to Week 8
Time frame: 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
Time frame: Randomization up to 8 weeks
Change From Randomization to Week 8 in the Hospital and Anxiety and Depression Scale (HADS) Anxiety Subscale Score
Time frame: 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
Time frame: Randomization up to 8 weeks
Change From Randomization to Week 8 in the Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) Individual Items
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in Clinical Global Impressions of Severity (CGI-S)
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in The Fatigue Associated With Depression (FAsD) Average Score and Experience Subscale Score
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Items
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in the EuroQol Questionnaire-5 Dimension (EQ-5D)
Time frame: Randomization, 8 weeks
Percentage of Participants With Treatment-emergent (TE) Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
Time frame: Randomization through 8 weeks
Change From Randomization to Week 8 in the Arizona Sexual Experiences (ASEX) Scale
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in Blood Pressure
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in Pulse Rate
Time frame: Randomization, 8 weeks
Pharmacokinetics: Plasma Concentrations of LY2216684
Time frame: Pre-randomization, 1 week, 4 weeks, and 8 weeks

Results and safety

Results posted to the registry on 24 Apr 2018, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Placebo + SSRI (Pre-randomized Participants)	1,480	1,390
12 or 18 mg LY2216684 + SSRI (Randomized Participants)	0	0
6 mg LY2216684 + SSRI (Randomized Participants)	0	0
Placebo + SSRI (Randomized Participants)	0	0
Placebo + SSRI (Non-randomized Participants)	0	0

Primary outcome: Change From Randomization to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score

Time frame: Randomization, 8 weeks. Least squares mean (Standard Error). Unit: units on a scale

Measure	12 or 18 mg Flexible Dose LY2216684 + SSRI n = 231	6 mg Fixed Dose LY2216684 + SSRI n = 220	Placebo + SSRI n = 228
Value	-9.36 (0.55)	-9.59 (0.55)	-9.36 (0.54)

12 or 18 mg Flexible Dose LY2216684 + SSRI vs Placebo + SSRI: p = 0.997, Mixed Models Analysis
6 mg Fixed Dose LY2216684 + SSRI vs Placebo + SSRI: p = 0.769, Mixed Models Analysis

Population analysed: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

19 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Placebo + SSRI (Pre-randomized) - CF Phase	7 of 1,476 (0.5%)	231 of 1,476 (15.7%)	Not reported
12 or 18 mg LY2216684 + SSRI (Randomized) - AT Phase	2 of 232 (0.9%)	57 of 232 (24.6%)	Not reported
6 mg LY2216684 + SSRI (Randomized) - AT Phase	1 of 223 (0.4%)	39 of 223 (17.5%)	Not reported
Placebo + SSRI (Randomized) - AT Phase	2 of 231 (0.9%)	38 of 231 (16.5%)	Not reported
Placebo + SSRI (Non-randomized) - AT Phase	5 of 699 (0.7%)	115 of 699 (16.5%)	Not reported
Placebo + SSRI (Pre-randomized) - DC Phase	3 of 25 (12%)	0 of 25 (0%)	Not reported
12 or 18 mg LY2216684 + SSRI (Randomized) - DC Phase	0 of 212 (0%)	18 of 212 (8.5%)	Not reported
6 mg LY2216684 + SSRI (Randomized) - DC Phase	2 of 213 (0.9%)	22 of 213 (10.3%)	Not reported
Placebo + SSRI (Randomized) - DC Phase	1 of 220 (0.5%)	17 of 220 (7.7%)	Not reported
Placebo + SSRI (Non-randomized) - DC Phase	2 of 659 (0.3%)	64 of 659 (9.7%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 24 Apr 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 27685842Stauffer VL, Liu P, Goldberger C, Marangell LB, Nelson C, Gorwood P, Fava M. Is the Noradrenergic Symptom Cluster a Valid Construct in Adjunctive Treatment of Major Depressive Disorder? J Clin Psychiatry. 2017 Mar;78(3):317-323. doi: 10.4088/JCP.15m09972.
Derived from this study: PubMed 27035159Ball SG, Ferguson MB, Martinez JM, Pangallo BA, Nery ES, Dellva MA, Sparks J, Zhang Q, Liu P, Bangs M, Goldberger C. Efficacy outcomes from 3 clinical trials of edivoxetine as adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment. J Clin Psychiatry. 2016 May;77(5):635-42. doi: 10.4088/JCP.14m09619.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

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) study director

Eli Lilly and Company

54 sites in 7 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing LY2216684 and SSRI in people with Major Depressive Disorder (MDD), run by Eli Lilly and Company at 54 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 54 sites in United States, Czechia, Japan, Finland, Slovakia and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Apr 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Randomization to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (time frame: Randomization, 8 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01187407, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Apr 2018.