Major Depressive DisorderPhase 3NCT01173601

A Fixed Dose Study of Adjunctive Treatment to Antidepressant Therapy for Adults With Major Depressive Disorder

A Phase 3 study testing LY2216684 and SSRI in people with Major Depressive Disorder, run by Eli Lilly and Company at 63 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 primary purpose of this study is to assess whether at least 1 dose of LY2216684 (12 milligrams [mg] or 18 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… Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Major Depressive Disorder
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: 1,416 participants
Where: 63 sitesin 7 countries
Study dates: Nov 2010to Oct 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)
Women of child-bearing potential may participate but must test negative for pregnancy at the time of study entry; both women/men agree to use a reliable method of birth control
Are taking a selective serotonin reuptake inhibitor (SSRI) approved for MDD treatment within the participant's country. 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 a DSM-IV-TR 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, 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, transcranial magnetic stimulation, or psychosurgery
Have received electroconvulsive therapy in the last year
Enrollment in a clinical study for an investigational drug
Serious or unstable medical condition
History of seizure disorders
Have initiated psychotherapy or other non-drug therapies (such as acupuncture or hypnosis) within 12 weeks prior to enrollment or any time during the study. Have no change in intensity of psychotherapy within the last 6 weeks prior to enrollment or at 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

63 sites in 7 countries.

Country

City, postcode or hospital

63 sites in 7 countries

United States22 sites

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Allentown, Pennsylvania, 18104
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Atlanta, Georgia, 30328
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Austin, Texas, 78731
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Baltimore, Maryland, 21208
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Berlin, New Jersey, 08009
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Dallas, Texas, 75230
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Dayton, Ohio, 45417
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Denver, Colorado, 80212
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Irvine, California, 92618
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Jacksonville, Florida, 32256
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Jamaica, New York, 11432
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La Habra, California, 90631
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Marietta, Georgia, 30060
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Memphis, Tennessee, 38119
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Middleburg Heights, Ohio, 44130
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Milwaukee, Wisconsin, 53227
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Murray, Utah, 84123
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New York, New York, 10023
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Redlands, California, 92374
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San Antonio, Texas, 78229
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St Louis, Missouri, 63109
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Sugar Land, Texas, 77478

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Ukraine11 sites

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Chernihiv District, 14000
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Dnipropetrovsk, 49005
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Donetsk, 83037
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Kherson, 73488
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Kyiv, 01030
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Luhansk, 91045
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Odesa, 65006
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Poltava, 36013
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Simferopol, 95006
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Uzhhorod, 88000
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Vinnytsia, 21005

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Poland10 sites

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?Uromin, 09-300
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Bialystok, 15-879
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Bydgoszcz, 85021
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Chełmno, 86-200
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Gdansk, 80-546
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Gorlice, 38/300
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Katowice, 40340
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Leszno, 64-100
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Lublin, 20-045
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Tuszyn, 95-080

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Japan7 sites

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Fukuoka, 810-0001
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Fukushima, 960-0102
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Hyōgo, 660-0882
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Kanagawa, 238-0042
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Nagano, 390-0303
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Saga, 843-0023
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Tokyo, 170-0002

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Latvia5 sites

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Daugavpils, LV-5417
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Jelgava, LV-3008
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Liepāja, LV-3400
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Sigulda, LV-2150
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Strenči, LV-4730

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South Africa5 sites

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Bellville, 7530
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Cape Town, 7530
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Centurion, 0157
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George, 6529
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West Cape, 7500

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Russia3 sites

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Moscow, 107076
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Rostov-on-Don, 344007
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Yekaterinburg, 620036

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About this study

Official title: A Randomized, Placebo-Controlled, Double-Blind Study of LY2216684 Fixed-Dose 12 Milligrams (mg) and 18 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 Phase, participants were randomized to adjunctive LY2216684 or adjunctive placebo if they met the following randomization criteria: 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
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 NCT01173601
Study group	Role	What they receive
12 milligrams (mg) LY2216684 + SSRI	Experimental	LY2216684: 12 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 (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the LY2216684 12-mg treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early entered a 2-week Discontinuation (DC) Phase. Participants were randomly assigned to either abrupt DC or tapered DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase. Receives: Drug: LY2216684; Drug: SSRI
18 milligrams (mg) LY2216684 + SSRI	Experimental	LY2216684: 12 milligrams (mg), administered orally, once daily (QD) for 1 week, followed by 18 mg, administered orally, once daily for 7 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 (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the LY2216684 18-mg treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early entered a 2-week Discontinuation (DC) Phase. Participants were randomly assigned to either abrupt DC or tapered DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase. Receives: Drug: LY2216684; Drug: SSRI
Placebo + SSRI	Placebo comparator	Placebo: Tablet equivalent to LY2216684, administered orally, once daily (QD) for 11 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 (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the placebo treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early had the option to enter the Discontinuation (DC) Phase. Participants who had received placebo were assigned to the abrupt DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase. 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. 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 (20)

Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Global Functional Impairment Scale
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 Function Impairment Score is the sum of the 3 items, and scores ranged from 0 to 30 with higher values indicating 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 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. 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 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. 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. 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 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 (0-3), 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 8-10 represent 'borderline' and 0-7 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. 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 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 (0-3), 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 8-10 represent 'borderline' and 0-7 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 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 Sheehan Disability Scale (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 that measures 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 the 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 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 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 at risk, 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 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]) to 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 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. 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
The Percentage of Participants Experiencing Treatment-Emergent Adverse Events as a Function of CYP2D6 Phenotype
Treatment-emergent adverse events (TEAEs) were events that first occurred or worsened during the treatment phase. CYP2D6 functional phenotype was classified as poor metabolizer (PM) or non-poor metabolizer (non-PM). The percentage of participants who reported the TEAE is presented for each phenotype classification. Only TEAEs for which there was a statistically significant treatment-by-SSRI therapy interaction were included: tinnitus and influenza. A summary of serious and other non-serious adverse events regardless of causality is located in the Report of Adverse Events module.
Measured: Through 8 weeks
Change From Randomization to Week 8 in Blood Pressure (BP)
Blood pressure (BP) measurements were collected when the participant was in a sitting position. Three measurements of sitting BP 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: 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.

Nov 2010Oct 2013

First posted2 Aug 2010 (estimated)
Study startNov 2010
Primary completionOct 2013
Study completionOct 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 DisorderStudies 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: 1,416 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01173601
Sponsor's protocol ID: 11316
Other IDs: H9P-MC-LNBM
Status last verified: Mar 2018
First submitted: 29 Jul 2010
Last updated: 17 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 trials

Study at a glance

From the registry record, last updated by the sponsor on 17 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 Fixed-Dose 12 Milligrams (mg) and 18 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: NCT01173601
Acronym / sponsor ID: 11316
Conditions: Major Depressive Disorder
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 1,416 participants (actual)
Lead sponsor: Eli Lilly and CompanyIndustry (pharma, biotech, devices)
Study start: Nov 2010
Primary completion: Oct 2013 (actual)
Study completion: Oct 2013 (actual)
First posted: 2 Aug 2010 (estimated)
Results: Posted 17 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 milligrams (mg) LY2216684 + SSRI	Experimental	Drug: LY2216684, Drug: SSRILY2216684: 12 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 (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the LY2216684 12-mg treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early entered a 2-week Discontinuation (DC) Phase. Participants were randomly assigned to either abrupt DC or tapered DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase.
18 milligrams (mg) LY2216684 + SSRI	Experimental	Drug: LY2216684, Drug: SSRILY2216684: 12 milligrams (mg), administered orally, once daily (QD) for 1 week, followed by 18 mg, administered orally, once daily for 7 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 (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the LY2216684 18-mg treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early entered a 2-week Discontinuation (DC) Phase. Participants were randomly assigned to either abrupt DC or tapered DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase.
Placebo + SSRI	Placebo comparator	Drug: Placebo, Drug: SSRIPlacebo: Tablet equivalent to LY2216684, administered orally, once daily (QD) for 11 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 (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the placebo treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early had the option to enter the Discontinuation (DC) Phase. Participants who had received placebo were assigned to the abrupt DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase.

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)
Women of child-bearing potential may participate but must test negative for pregnancy at the time of study entry; both women/men agree to use a reliable method of birth control
Are taking a selective serotonin reuptake inhibitor (SSRI) approved for MDD treatment within the participant's country. 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, 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 milligrams (mg) LY2216684 + SSRI, 18 milligrams (mg) LY2216684 + SSRI
Placebo	Drug	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 milligrams (mg) LY2216684 + SSRI, 18 milligrams (mg) 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. 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.

20 secondary outcomes

Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Global Functional Impairment Scale
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in 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 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 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 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 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 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 Arizona Sexual Experiences (ASEX) Scale
Time frame: Randomization, 8 weeks
Change From Randomization to Week 8 in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)
Time frame: Randomization, 8 weeks
The Percentage of Participants Experiencing Treatment-Emergent Adverse Events as a Function of CYP2D6 Phenotype
Time frame: Through 8 weeks
Change From Randomization to Week 8 in Blood Pressure (BP)
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: 1 week, 4 weeks, and 8 weeks

Results and safety

Results posted to the registry on 17 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)	1,416	1,328
12 mg LY2216684 + SSRI (Randomized Participants)	0	0
18 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 mg LY2216684 + SSRI n = 230	18 mg LY2216684 + SSRI n = 230	Placebo + SSRI n = 240
Value	-8.47 (0.52)	-8.70 (0.53)	-7.77 (0.51)

12 mg LY2216684 + SSRI vs Placebo + SSRI: p = 0.338, Mixed Models Analysis
18 mg LY2216684 + SSRI vs Placebo + SSRI: p = 0.201, 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.

20 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse event data was collected over the 3-week double blind adjunctive placebo lead-in confirmation phase, the 8 week double-blind placebo-controlled adjunctive active treatment phase, and the 2-week discontinuation (DC) phase.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Placebo + SSRI (Pre-randomized) CF Phase	2 of 1,413 (0.1%)	240 of 1,413 (17%)	Not reported
12 mg LY2216684 + SSRI (Randomized) AT Phase	3 of 231 (1.3%)	71 of 231 (30.7%)	Not reported
18 mg LY2216684 + SSRI (Randomized) AT Phase	2 of 230 (0.9%)	73 of 230 (31.7%)	Not reported
Placebo + SSRI (Randomized) AT Phase	1 of 240 (0.4%)	36 of 240 (15%)	Not reported
Placebo + SSRI (Non-randomized) AT Phase	5 of 627 (0.8%)	100 of 627 (15.9%)	Not reported
Placebo + SSRI (Pre-randomized) Discontinuation Phase	1 of 20 (5%)	3 of 20 (15%)	Not reported
12 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)	1 of 108 (0.9%)	17 of 108 (15.7%)	Not reported
12 mg LY2216684 + SSRI (Taper Discontinuation Phase)	1 of 100 (1%)	15 of 100 (15%)	Not reported
18 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)	0 of 108 (0%)	18 of 108 (16.7%)	Not reported
18 mg LY2216684 + SSRI (Taper Discontinuation Phase)	1 of 107 (0.9%)	19 of 107 (17.8%)	Not reported
Placebo + SSRI (Randomized) Discontinuation Phase	0 of 221 (0%)	39 of 221 (17.6%)	Not reported
Placebo + SSRI (Non-randomized) Discontinuation Phase	1 of 585 (0.2%)	106 of 585 (18.1%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 17 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

63 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, run by Eli Lilly and Company at 63 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 17 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 63 sites in United States, Ukraine, Poland, Japan, Latvia 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 17 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 NCT01173601, 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 17 Apr 2018; AzTrials last refreshed its copy on 6 Nov 2026.