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

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ClinicalTrials.gov Identifier: NCT01173601
Recruitment Status : Completed
First Posted : August 2, 2010
Results First Posted : April 17, 2018
Last Update Posted : April 17, 2018
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

July 29, 2010
August 2, 2010
February 17, 2018
April 17, 2018
April 17, 2018
November 2010
October 2013   (Final data collection date for primary outcome measure)
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.
Change from baseline to week 11 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score [ Time Frame: Baseline, 11 weeks ]
Complete list of historical versions of study NCT01173601 on ClinicalTrials.gov Archive Site
  • Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Global Functional Impairment Scale [ Time Frame: Randomization, 8 weeks ]
    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.
  • Change From Randomization to Week 8 in Fatigue Associated With Depression (FAsD) Impact Subscale Score [ Time Frame: Randomization, 8 weeks ]
    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.
  • 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 ]
    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%.
  • 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 ]
    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%.
  • Change From Randomization to Week 8 in Hospital and Anxiety and Depression Scale (HADS) Anxiety Subscale Score [ Time Frame: Randomization, 8 weeks ]
    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.
  • 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 ]
    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%.
  • Change From Randomization to Week 8 in Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score [ Time Frame: Randomization, 8 weeks ]
    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.
  • Change From Randomization to Week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) Individual Items [ 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 item score, treatment-by-visit and baseline item score-by-visit.
  • Change From Randomization to Week 8 in Clinical Global Impressions of Severity (CGI-S) [ Time Frame: Randomization, 8 weeks ]
    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.
  • Change From Randomization to Week 8 in Fatigue Associated With Depression (FAsD) Average Score and Experience Subscale Score [ Time Frame: Randomization, 8 weeks ]
    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.
  • Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Items [ Time Frame: Randomization, 8 weeks ]
    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.
  • 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 ]
    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.
  • Change From Randomization to Week 8 in the EuroQol Questionnaire-5 Dimension (EQ-5D) [ Time Frame: Randomization, 8 weeks ]
    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.
  • Percentage of Treatment Emergent (TE) Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Randomization through 8 weeks ]
    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.
  • Change From Randomization to Week 8 in Arizona Sexual Experiences (ASEX) Scale [ Time Frame: Randomization, 8 weeks ]
    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.
  • Change From Randomization to Week 8 in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) [ Time Frame: Randomization, 8 weeks ]
    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.
  • The Percentage of Participants Experiencing Treatment-Emergent Adverse Events as a Function of CYP2D6 Phenotype [ Time Frame: Through 8 weeks ]
    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.
  • Change From Randomization to Week 8 in Blood Pressure (BP) [ Time Frame: Randomization, 8 weeks ]
    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.
  • Change From Randomization to Week 8 in Pulse Rate [ Time Frame: Randomization, 8 weeks ]
    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.
  • Pharmacokinetics: Plasma Concentrations of LY2216684 [ Time Frame: 1 week, 4 weeks, and 8 weeks ]
    A validated bioanalytical assay was used to determine plasma LY2216684 concentrations.
  • Change from baseline to week 11 in Sheehan Disability Scale (SDS) Global Functional Impairment scale [ Time Frame: Baseline, 11 weeks ]
  • Change from baseline to week 11 in Fatigue Associated with Depression (FAsD) impact subscale score [ Time Frame: Baseline, 11 weeks ]
  • Percentage of patients achieving a MADRS total score of less than or equal 10 at week 11 [ Time Frame: 11 weeks ]
  • Percentage of patients achieving a MADRS total score of less than or equal 10 at 2 consecutive measurements including the patient's last measurement [ Time Frame: Through 11 weeks ]
  • Change from baseline to week 11 in Hospital and Anxiety and Depression Scale (HADS) anxiety subscale score [ Time Frame: Baseline, 11 weeks ]
  • Percent of patients who have a greater than or equal to 50 percent improvement in the MADRS total score from baseline to week 11 [ Time Frame: Baseline, 11 weeks ]
  • Change from baseline to week 11 in HADS depression subscale score [ Time Frame: Baseline, 11 weeks ]
  • Change from baseline to week 11 in MADRS individual items [ Time Frame: Baseline, 11 weeks ]
  • Change from baseline to week 11 in Clinical Global Impressions of Severity (CGI-S) [ Time Frame: Baseline, 11 weeks ]
  • Change from baseline to week 11 in FAsD average score and experience subscale score [ Time Frame: Baseline, 11 weeks ]
  • Change from baseline to week 11 in Sheehan Disability Scale (SDS) items [ Time Frame: Baseline, 11 weeks ]
  • Change from baseline to week 11 in the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) [ Time Frame: Baseline, 11 weeks ]
  • Change from baseline to week 11 in the EuroQol Questionnaire-5 Dimension (EQ-5D) [ Time Frame: Baseline, 11 weeks ]
  • Percentage of treatment emergent suicidal ideation and behaviors assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Through 13 weeks ]
  • Change from baseline to week 11 in Arizona Sexual Experiences (ASEX) scale [ Time Frame: Baseline, 11 weeks ]
  • Change from baseline to week 11 in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) [ Time Frame: Baseline, 11 weeks ]
  • The number of patients experiencing treatment emergent adverse events as a function of CYP2D6 genotype [ Time Frame: Through 11 weeks ]
Not Provided
Not Provided
 
A Fixed Dose Study of Adjunctive Treatment to Antidepressant Therapy for Adults With Major Depressive Disorder
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
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 with a selective serotonin reuptake inhibitor (SSRI) during an 8-week, double-blind, acute adjunctive treatment phase.
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.
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Major Depressive Disorder
  • Drug: LY2216684
    Other Name: Edivoxetine
  • Drug: Placebo
  • Drug: SSRI
    Participants should have been on their SSRI for at least 6 weeks prior and were to continue on their stable dose throughout the study.
    Other Name: Selective Serotonin Reuptake Inhibitor
  • Experimental: 12 milligrams (mg) LY2216684 + SSRI

    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.

    Interventions:
    • Drug: LY2216684
    • Drug: SSRI
  • Experimental: 18 milligrams (mg) LY2216684 + SSRI

    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.

    Interventions:
    • Drug: LY2216684
    • Drug: SSRI
  • Placebo Comparator: Placebo + SSRI

    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.

    Interventions:
    • Drug: Placebo
    • Drug: SSRI

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
1416
1344
October 2013
October 2013   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • Presence of another primary psychiatric illness:

    • Have had or currently have any additional ongoing Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) Axis 1 condition other than major depression within 1 year of screening
    • Have had any anxiety disorder that was considered a primary diagnosis within the past year (including panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and social phobia, but excluding specific phobias)
    • Have a current or previous diagnosis of a bipolar disorder, schizophrenia, or other psychotic disorder
    • Have a history of substance abuse and/or dependence within the past 1 year (drug categories defined by DSM-IV-TR), not including caffeine and nicotine
    • Have a DSM-IV-TR Axis II disorder that, in the judgment of the investigator, would interfere with compliance with protocol
  • Have any diagnosed medical condition that could be exacerbated by noradrenergic agents including unstable hypertension, unstable heart disease, tachycardia, tachyarrhythmia, narrow-angle glaucoma, 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
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Japan,   Latvia,   Poland,   Russian Federation,   South Africa,   Ukraine,   United States
 
 
NCT01173601
11316
H9P-MC-LNBM ( Other Identifier: Eli Lilly and Company )
Yes
Not Provided
Not Provided
Eli Lilly and Company
Eli Lilly and Company
Not Provided
Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
Eli Lilly and Company
March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP