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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    2010-021215-16
    Trial protocol
    CZ   FI   SK   HU  
    Global end of trial date
    13 Aug 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Mar 2018
    First version publication date
    06 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    H9P-MC-LNBQ
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01187407
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Eli Lilly and Company: 12182
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Centre, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877-CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 8772854559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess whether LY2216684 (12 mg to 18 mg flexible dose QD) is superior to placebo QD in the adjunctive treatment of patients with Major Depressive Disorder who were identified as partial responders to an adequate course of treatment with an SSRI during an 11-week, double-blind, acute adjunctive treatment period.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    Subjects are being treated with one of the following SSRIs that have been approved for MDD treatment within the participating country: escitalopram, citalopram, sertraline, fluoxetine, paroxetine, and fluvoxamine; and have been treated with their SSRI at least 6 weeks prior to Visit 2 with at least the last 4 consecutive weeks at a stable optimized dose prior to Visit 2. The SSRI should be prescribed, including dose, in a manner consistent with labeling guidelines within the participating country.
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 146
    Country: Number of subjects enrolled
    United States: 750
    Country: Number of subjects enrolled
    Croatia: 53
    Country: Number of subjects enrolled
    Czech Republic: 258
    Country: Number of subjects enrolled
    Finland: 116
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Japan: 117
    Country: Number of subjects enrolled
    Romania: 31
    Worldwide total number of subjects
    1480
    EEA total number of subjects
    613
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1390
    From 65 to 84 years
    90
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    First 3 weeks of study was double-blind Confirmation Phase during which participants (pts) continued to receive their SSRI with adjunctive placebo. If randomization criteria were met, pts were randomized to adjunctive LY2216684 or adjunctive placebo. If criteria were not met, pts continued on placebo and remained in the study to maintain the blind.

    Period 1
    Period 1 title
    Confirmation (CF) Phase, 3 Weeks
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Arm title
    Placebo + SSRI (Pre-randomized Participants)
    Arm description
    Placebo: administered orally, once daily (QD) for 3 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets are given orally to the participants.

    Number of subjects in period 1
    Placebo + SSRI (Pre-randomized Participants)
    Started
    1480
    Entered Discontinuation (DC) Phase
    25 [1]
    Completed
    1390
    Not completed
    90
         Protocol deviation
    13
         Physician decision
    2
         Lack of efficacy
    4
         Adverse event, non-fatal
    29
         Consent withdrawn by subject
    29
         Sponsor Decision
    4
         Lost to follow-up
    9
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who discontinued the CF Phase had the option to enter the DC phase. Participants who completed the CF Phase entered the AT Phase.
    Period 2
    Period 2 title
    Adjunctive Treatment (AT) Phase, 8 Weeks
    Is this the baseline period?
    Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    12 or 18 mg LY2216684 + SSRI (Randomized Participants)
    Arm description
    LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, QD for 8 weeks, adjunctive to an SSRI
    Arm type
    Experimental

    Investigational medicinal product name
    LY2216684
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally

    Arm title
    6 mg LY2216684 + SSRI (Randomized Participants)
    Arm description
    LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI
    Arm type
    Experimental

    Investigational medicinal product name
    LY2216684
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI.

    Arm title
    Placebo + SSRI (Randomized Participants)
    Arm description
    Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI

    Arm title
    Placebo + SSRI (Non-randomized Participants)
    Arm description
    Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is confirmatory phase, baseline characteristics & endpoints are reported for reporting groups in period 2."
    Number of subjects in period 2 [3]
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants) Placebo + SSRI (Non-randomized Participants)
    Started
    232
    226
    231
    701
    Entered Discontinuation (DC) Phase
    212
    215
    220
    660
    Completed
    196
    191
    202
    626
    Not completed
    36
    35
    29
    75
         Protocol deviation
    6
    5
    3
    10
         Physician decision
    -
    -
    1
    2
         Lack of efficacy
    3
    8
    5
    13
         Adverse event, non-fatal
    13
    6
    5
    12
         Consent withdrawn by subject
    9
    9
    11
    22
         Sponsor Decision
    2
    2
    2
    7
         Lost to follow-up
    3
    5
    2
    9
    Notes
    [3] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline period includes only the adjunctive treatment phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    12 or 18 mg LY2216684 + SSRI (Randomized Participants)
    Reporting group description
    LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, QD for 8 weeks, adjunctive to an SSRI

    Reporting group title
    6 mg LY2216684 + SSRI (Randomized Participants)
    Reporting group description
    LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI

    Reporting group title
    Placebo + SSRI (Randomized Participants)
    Reporting group description
    Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI

    Reporting group title
    Placebo + SSRI (Non-randomized Participants)
    Reporting group description
    Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI

    Reporting group values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants) Placebo + SSRI (Non-randomized Participants) Total
    Number of subjects
    232 226 231 701 1390
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    46.63 ± 12 47.06 ± 12.76 47.3 ± 12.1 46.35 ± 12.42 -
    Gender, Male/Female
    Units: Subjects
        Male
    83 73 75 236 467
        Female
    149 153 156 465 923
    Region of Enrollment
    Units: Subjects
        United States
    103 98 104 377 682
        CzechRepublic
    44 44 46 119 253
        Slovakia
    33 35 34 39 141
        Finland
    18 12 17 61 108
        Croatia
    9 10 7 26 52
        Japan
    20 23 19 53 115
        Hungary
    2 2 1 3 8
        Romania
    3 2 3 23 31
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    11 9 14 49 83
        Not Hispanic or Latino
    183 181 178 562 1104
        Unknown or Not Reported
    38 36 39 90 203
    Race
    Units: Subjects
        American Indian or Alaska Native
    1 0 3 4 8
        Asian
    21 26 20 54 121
        Native Hawaiian or Pacific Islander
    0 0 0 0 0
        Black or African American
    16 25 18 63 122
        White
    192 173 186 572 1123
        More than one race
    2 2 3 8 15
        Unknown or Not Reported
    0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo + SSRI (Pre-randomized Participants)
    Reporting group description
    Placebo: administered orally, once daily (QD) for 3 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)
    Reporting group title
    12 or 18 mg LY2216684 + SSRI (Randomized Participants)
    Reporting group description
    LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, QD for 8 weeks, adjunctive to an SSRI

    Reporting group title
    6 mg LY2216684 + SSRI (Randomized Participants)
    Reporting group description
    LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI

    Reporting group title
    Placebo + SSRI (Randomized Participants)
    Reporting group description
    Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI

    Reporting group title
    Placebo + SSRI (Non-randomized Participants)
    Reporting group description
    Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI

    Subject analysis set title
    LY2216684
    Subject analysis set type
    Full analysis
    Subject analysis set description
    LY2216684: flexible dose of 12 or 18 milligrams (mg) or fixed dose of 6 mg, administered orally, once daily (QD)

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

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    End point title
    Change From Randomization to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score [1]
    End point description
    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. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Primary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    231
    221
    228
    Units: units on a scale
        least squares mean (standard error)
    -9.36 ± 0.55
    -9.59 ± 0.55
    -9.36 ± 0.54
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo + SSRI (Randomized Participants) v 12 or 18 mg LY2216684 + SSRI (Randomized Participants)
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.997 [2]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [2] - Primary comparison
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    6 mg LY2216684 + SSRI (Randomized Participants) v Placebo + SSRI (Randomized Participants)
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.769 [3]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [3] - Secondary comparison.

    Secondary: Change From Randomization to Week 8 in the Sheehan Disability Scale (SDS) Global Functional Impairment Score

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    End point title
    Change From Randomization to Week 8 in the Sheehan Disability Scale (SDS) Global Functional Impairment Score [4]
    End point description
    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. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    225
    210
    221
    Units: units on a scale
        least squares mean (standard error)
    -5.43 ± 0.43
    -6.29 ± 0.44
    -4.3 ± 0.43
    No statistical analyses for this end point

    Secondary: Change From Randomization to Week 8 in the Fatigue Associated With Depression (FAsD) Impact Subscale Score

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    End point title
    Change From Randomization to Week 8 in the Fatigue Associated With Depression (FAsD) Impact Subscale Score [5]
    End point description
    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. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    225
    210
    221
    Units: units on a scale
        least squares mean (standard error)
    -0.71 ± 0.06
    -0.67 ± 0.06
    -0.56 ± 0.06
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving a Montgomery-Asberg Depression Rating Scale (MADRS) total score of less than or equal to 10 up to week 8

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    End point title
    Percentage of participants achieving a Montgomery-Asberg Depression Rating Scale (MADRS) total score of less than or equal to 10 up to week 8 [6]
    End point description
    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%. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value. Last observation carried forward (LOCF) methodology was used.
    End point type
    Secondary
    End point timeframe
    Randomization up to 8 weeks
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    231
    221
    228
    Units: percentage of participants
        number (not applicable)
    26.84
    29.41
    26.32
    No statistical analyses for this end point

    Secondary: 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

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    End point title
    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 [7]
    End point description
    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%. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value. All random
    End point type
    Secondary
    End point timeframe
    Randomization up to 8 weeks
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    231
    221
    228
    Units: percentage of participants
        number (not applicable)
    17.75
    19
    14.47
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in the Hospital and Anxiety and Depression Scale (HADS) anxiety subscale score

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    End point title
    Change from randomization to week 8 in the Hospital and Anxiety and Depression Scale (HADS) anxiety subscale score [8]
    End point description
    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. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    231
    220
    228
    Units: units on a scale
        least squares mean (standard error)
    -2.24 ± 0.24
    -2.64 ± 0.24
    -2.05 ± 0.24
    No statistical analyses for this end point

    Secondary: 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

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    End point title
    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 [9]
    End point description
    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%. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value. Last observation carried forward (LOCF) methodology was used.
    End point type
    Secondary
    End point timeframe
    Randomization up to 8 weeks
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    231
    221
    228
    Units: percentage of participants
        number (not applicable)
    30.74
    30.84
    32.46
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in the Hospital Anxiety and Depression Scale (HADS) depression subscale score

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    End point title
    Change from randomization to week 8 in the Hospital Anxiety and Depression Scale (HADS) depression subscale score [10]
    End point description
    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. Change from randomization to week 8 in the Hospital Anxiety and Depression Scale (HADS) depression subscale score
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    231
    220
    228
    Units: units on a scale
        least squares mean (standard error)
    -3.4 ± 0.26
    -3.62 ± 0.27
    -2.55 ± 0.26
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in Clinical Global Impressions of Severity (CGI-S)

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    End point title
    Change from randomization to week 8 in Clinical Global Impressions of Severity (CGI-S) [11]
    End point description
    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 All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    231
    220
    228
    Units: units on a scale
        least squares mean (standard error)
    -1.2 ± 0.08
    -1.2 ± 0.08
    -1.14 ± 0.07
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) individual items

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    End point title
    Change from randomization to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) individual items [12]
    End point description
    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. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    231
    220
    228
    Units: units on a scale
    least squares mean (standard error)
        Apparent sadness (n=231, 220, 228)
    -1.34 ± 0.08
    -1.25 ± 0.08
    -1.26 ± 0.08
        Reported sadness (n=231, 219, 228)
    -1.41 ± 0.09
    -1.31 ± 0.09
    -1.26 ± 0.09
        Inner tension (n=231, 220, 228)
    -0.96 ± 0.08
    -0.91 ± 0.08
    -0.07 ± 0.08
        Reduced sleep (n=231, 220, 228)
    -0.82 ± 0.09
    -0.96 ± 0.09
    -0.92 ± 0.09
        Reduced appetite (n=231, 220, 228)
    -0.57 ± 0.08
    -0.67 ± 0.08
    -0.71 ± 0.08
        Concentration difficulties (n=231, 220, 228)
    -1.13 ± 0.08
    -1.14 ± 0.08
    -0.98 ± 0.08
        Lassitude (n=231, 220, 228)
    -1.15 ± 0.09
    -1.07 ± 0.09
    -1.16 ± 0.09
        Inability to feel (n=231, 220, 228)
    -1.11 ± 0.09
    -1.3 ± 0.09
    -1.14 ± 0.09
        Pessimistic thoughts (n=231, 220, 228)
    -0.84 ± 0.07
    -0.82 ± 0.07
    -0.91 ± 0.07
        Suicidal thoughts (n=231, 220, 228)
    -0.17 ± 0.03
    -0.19 ± 0.03
    -0.17 ± 0.03
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in Sheehan Disability Scale (SDS) items

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    End point title
    Change from randomization to week 8 in Sheehan Disability Scale (SDS) items [13]
    End point description
    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. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    225
    210
    221
    Units: units on a scale
    least squares mean (standard error)
        Work impairment score (n=151, 138, 145)
    -1.81 ± 0.19
    -1.93 ± 0.2
    -1.32 ± 0.19
        Social life impairment score (n= 225, 210, 221)
    -1.79 ± 0.16
    -2.11 ± 0.16
    -1.52 ± 0.16
        Family life impairment score (n=225, 210, 221)
    -1.75 ± 0.15
    -2.16 ± 0.15
    -1.47 ± 0.15
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in The Fatigue Associated with Depression (FAsD) average score and experience subscale score

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    End point title
    Change from randomization to week 8 in The Fatigue Associated with Depression (FAsD) average score and experience subscale score [14]
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    225
    210
    221
    Units: units on a scale
    least squares mean (standard error)
        FAsD average score
    -0.67 ± 0.05
    -0.68 ± 0.06
    -0.53 ± 0.05
        FAsD experience score
    -0.63 ± 0.06
    -0.67 ± 0.06
    -0.5 ± 0.06
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)

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    End point title
    Change from randomization to week 8 in the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) [15]
    End point description
    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. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    224
    210
    221
    Units: percentage of maximum possible score
        least squares mean (standard error)
    10.54 ± 1
    10.5 ± 1.02
    8.74 ± 0.99
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in the EuroQol Questionnaire-5 Dimension (EQ-5D)

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    End point title
    Change from randomization to week 8 in the EuroQol Questionnaire-5 Dimension (EQ-5D) [16]
    End point description
    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. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    225
    210
    229
    Units: units on a scale
        least squares mean (standard error)
    11.457 ± 1.218
    11.895 ± 1.239
    9.53 ± 1.207
    No statistical analyses for this end point

    Secondary: Percentage of participants with treatment-emergent (TE) suicidal ideation and behaviors assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    Percentage of participants with treatment-emergent (TE) suicidal ideation and behaviors assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) [17]
    End point description
    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-SAE, regardless of causality, is located in the Reported Adverse Event module. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Secondary
    End point timeframe
    Randomization through 8 weeks
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    232
    221
    228
    Units: percentage of participants
    number (not applicable)
        TE suicidal ideation (n=232, 221, 228)
    5.17
    3.62
    4.39
        TE suicidal behavior (n=203, 198, 202)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in the Arizona Sexual Experiences (ASEX) scale

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    End point title
    Change from randomization to week 8 in the Arizona Sexual Experiences (ASEX) scale [18]
    End point description
    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. Change from randomization to week 8 in the Arizona Sexual Experiences (ASEX) scale
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    224
    209
    220
    Units: units on a scale
        least squares mean (standard error)
    -1.62 ± 0.29
    -1.29 ± 0.29
    -0.97 ± 0.29
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)

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    End point title
    Change from randomization to week 8 in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) [19]
    End point description
    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. All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    225
    210
    221
    Units: units on a scale
        least squares mean (standard error)
    -4.74 ± 0.38
    -4.67 ± 0.39
    -3.64 ± 0.38
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in blood pressure

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    End point title
    Change from randomization to week 8 in blood pressure [20]
    End point description
    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. Change from randomization to week 8 in blood pressure.
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    232
    220
    228
    Units: millimeters of mercury (mmHg)
    least squares mean (standard error)
        Systolic blood pressure
    1.64 ± 0.62
    2.93 ± 0.63
    0.78 ± 0.62
        Diastolic blood pressure
    3.46 ± 0.49
    4.47 ± 0.5
    1.01 ± 0.49
    No statistical analyses for this end point

    Secondary: Change from randomization to week 8 in pulse rate

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    End point title
    Change from randomization to week 8 in pulse rate [21]
    End point description
    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. Change from randomization to week 8 in pulse rate
    End point type
    Secondary
    End point timeframe
    Randomization, 8 weeks
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for all randomized participants per the protocol or Statistical Analysis Plan.
    End point values
    12 or 18 mg LY2216684 + SSRI (Randomized Participants) 6 mg LY2216684 + SSRI (Randomized Participants) Placebo + SSRI (Randomized Participants)
    Number of subjects analysed
    232
    220
    228
    Units: beats per minute (bpm)
        least squares mean (standard error)
    9.26 ± 0.65
    7.32 ± 0.66
    -1.03 ± 0.65
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Plasma concentrations of LY2216684

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    End point title
    Pharmacokinetics: Plasma concentrations of LY2216684
    End point description
    A validated bioanalytical assay was used to determine plasma LY2216684 concentrations. Participants exposed to LY2216684 with evaluable plasma concentration values. Samples with concentrations below the lower quantification limit (BQL) of the assay were treated as missing values for the analysis and samples with incomplete dosing information were not included in the pharmacokinetic assessment.
    End point type
    Secondary
    End point timeframe
    Pre-randomization, 1 week, 4 weeks, and 8 weeks
    End point values
    LY2216684
    Number of subjects analysed
    400
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        6-mg dose (n=197)
    17 ± 10.2
        12-mg dose (n=197)
    32.2 ± 21.1
        18-mg dose (n=136)
    52.4 ± 34.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo + SSRI (Pre-randomized) - CF Phase
    Reporting group description
    Placebo: administered orally, once daily for 3 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Includes all enrolled who did not discontinue for the reason 'Lost to Follow-up' at the first post-baseline visit during the Confirmation (CF) Phase.

    Reporting group title
    6 mg LY2216684 + SSRI (Randomized) - AT Phase
    Reporting group description
    LY2216684: fixed dose of 6 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Includes randomized participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-randomization visit during the Adjunctive Treatment (AT) Phase.

    Reporting group title
    12 or 18 mg LY2216684 + SSRI (Randomized) - AT Phase
    Reporting group description
    LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Includes randomized participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-randomization visit during the Adjunctive Treatment (AT) Phase.

    Reporting group title
    Placebo + SSRI (Randomized) - AT Phase
    Reporting group description
    Placebo: administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Includes randomized participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-randomization visit during the Adjunctive Treatment (AT) Phase.

    Reporting group title
    Placebo + SSRI (Non-randomized) - AT Phase
    Reporting group description
    Placebo: administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Includes all non-randomized participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-randomization visit during the Adjunctive Treatment (AT) Phase.

    Reporting group title
    Placebo + SSRI (Pre-randomized) - DC Phase
    Reporting group description
    No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all enrolled participants who abruptly discontinued placebo after early withdrawal during the Confirmation (CF) Phase and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.

    Reporting group title
    6 mg LY2216684 + SSRI (Randomized) - DC Phase
    Reporting group description
    No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all randomized participants who abruptly discontinued LY2216684 either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.

    Reporting group title
    12 or 18 mg Flex-dose LY2216684 - DC Phase
    Reporting group description
    No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all randomized participants who abruptly discontinued LY2216684 either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.

    Reporting group title
    Placebo + SSRI (Randomized) - DC Phase
    Reporting group description
    No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all randomized participants who abruptly discontinued placebo either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.

    Reporting group title
    Placebo + SSRI (Non-randomized) - DC Phase
    Reporting group description
    No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all non-randomized participants who abruptly discontinued placebo either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.

    Serious adverse events
    Placebo + SSRI (Pre-randomized) - CF Phase 6 mg LY2216684 + SSRI (Randomized) - AT Phase 12 or 18 mg LY2216684 + SSRI (Randomized) - AT Phase Placebo + SSRI (Randomized) - AT Phase Placebo + SSRI (Non-randomized) - AT Phase Placebo + SSRI (Pre-randomized) - DC Phase 6 mg LY2216684 + SSRI (Randomized) - DC Phase 12 or 18 mg Flex-dose LY2216684 - DC Phase Placebo + SSRI (Randomized) - DC Phase Placebo + SSRI (Non-randomized) - DC Phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 1476 (0.47%)
    1 / 223 (0.45%)
    2 / 232 (0.86%)
    2 / 231 (0.87%)
    5 / 699 (0.72%)
    3 / 25 (12.00%)
    2 / 213 (0.94%)
    0 / 212 (0.00%)
    1 / 220 (0.45%)
    2 / 659 (0.30%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    accidental overdose
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    1 / 699 (0.14%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    atrial fibrillation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 1476 (0.14%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    0 / 699 (0.00%)
    1 / 25 (4.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory failure
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    1 / 699 (0.14%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    syncope
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    0 / 699 (0.00%)
    0 / 25 (0.00%)
    1 / 213 (0.47%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    inflammation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    1 / 232 (0.43%)
    0 / 231 (0.00%)
    0 / 699 (0.00%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    mania
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 1476 (0.07%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    0 / 699 (0.00%)
    1 / 25 (4.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    suicidal ideation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 1476 (0.14%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    0 / 699 (0.00%)
    1 / 25 (4.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    suicide attempt
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    1 / 699 (0.14%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    cervical dysplasia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed [1]
    1 / 979 (0.10%)
    1 / 152 (0.66%)
    0 / 149 (0.00%)
    0 / 156 (0.00%)
    0 / 464 (0.00%)
    0 / 16 (0.00%)
    1 / 148 (0.68%)
    0 / 133 (0.00%)
    0 / 145 (0.00%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    fibrocystic breast disease
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    1 / 699 (0.14%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    metrorrhagia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed [2]
    0 / 979 (0.00%)
    0 / 152 (0.00%)
    0 / 149 (0.00%)
    1 / 156 (0.64%)
    0 / 464 (0.00%)
    0 / 16 (0.00%)
    0 / 148 (0.00%)
    0 / 133 (0.00%)
    0 / 145 (0.00%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    osteoarthritis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 1476 (0.07%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    1 / 231 (0.43%)
    0 / 699 (0.00%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    1 / 220 (0.45%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    appendicitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    1 / 232 (0.43%)
    0 / 231 (0.00%)
    0 / 699 (0.00%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    diverticulitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    1 / 699 (0.14%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    mastitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    1 / 699 (0.14%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 1476 (0.00%)
    0 / 223 (0.00%)
    0 / 232 (0.00%)
    0 / 231 (0.00%)
    1 / 699 (0.14%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: this is gender specific AE, number reported includes only the female subjects.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: this is gender specific AE, number reported includes only the female subjects.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + SSRI (Pre-randomized) - CF Phase 6 mg LY2216684 + SSRI (Randomized) - AT Phase 12 or 18 mg LY2216684 + SSRI (Randomized) - AT Phase Placebo + SSRI (Randomized) - AT Phase Placebo + SSRI (Non-randomized) - AT Phase Placebo + SSRI (Pre-randomized) - DC Phase 6 mg LY2216684 + SSRI (Randomized) - DC Phase 12 or 18 mg Flex-dose LY2216684 - DC Phase Placebo + SSRI (Randomized) - DC Phase Placebo + SSRI (Non-randomized) - DC Phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    231 / 1476 (15.65%)
    39 / 223 (17.49%)
    57 / 232 (24.57%)
    38 / 231 (16.45%)
    115 / 699 (16.45%)
    0 / 25 (0.00%)
    22 / 213 (10.33%)
    18 / 212 (8.49%)
    17 / 220 (7.73%)
    64 / 659 (9.71%)
    Cardiac disorders
    tachycardia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    6 / 1476 (0.41%)
    5 / 223 (2.24%)
    12 / 232 (5.17%)
    0 / 231 (0.00%)
    2 / 699 (0.29%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    0 / 212 (0.00%)
    0 / 220 (0.00%)
    0 / 659 (0.00%)
         occurrences all number
    6
    5
    12
    0
    2
    0
    0
    0
    0
    0
    Nervous system disorders
    headache
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    112 / 1476 (7.59%)
    15 / 223 (6.73%)
    14 / 232 (6.03%)
    22 / 231 (9.52%)
    61 / 699 (8.73%)
    0 / 25 (0.00%)
    19 / 213 (8.92%)
    13 / 212 (6.13%)
    14 / 220 (6.36%)
    47 / 659 (7.13%)
         occurrences all number
    127
    18
    15
    33
    81
    0
    19
    14
    14
    54
    Gastrointestinal disorders
    nausea
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    77 / 1476 (5.22%)
    12 / 223 (5.38%)
    12 / 232 (5.17%)
    9 / 231 (3.90%)
    25 / 699 (3.58%)
    0 / 25 (0.00%)
    4 / 213 (1.88%)
    2 / 212 (0.94%)
    2 / 220 (0.91%)
    13 / 659 (1.97%)
         occurrences all number
    80
    13
    17
    10
    41
    0
    4
    2
    2
    13
    Skin and subcutaneous tissue disorders
    hyperhidrosis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    34 / 1476 (2.30%)
    7 / 223 (3.14%)
    18 / 232 (7.76%)
    4 / 231 (1.73%)
    11 / 699 (1.57%)
    0 / 25 (0.00%)
    0 / 213 (0.00%)
    4 / 212 (1.89%)
    0 / 220 (0.00%)
    7 / 659 (1.06%)
         occurrences all number
    35
    8
    19
    4
    11
    0
    0
    4
    0
    7
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    35 / 1476 (2.37%)
    7 / 223 (3.14%)
    12 / 232 (5.17%)
    7 / 231 (3.03%)
    27 / 699 (3.86%)
    0 / 25 (0.00%)
    1 / 213 (0.47%)
    1 / 212 (0.47%)
    2 / 220 (0.91%)
    5 / 659 (0.76%)
         occurrences all number
    35
    7
    12
    7
    27
    0
    1
    1
    2
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jul 2011
    1.Clarification that the GRID-HAMD17, SAFER criteria, and evaluation of assessed by central rater at Visit 1. 2.Clarification added to exclusion criterion. 3.Added allowance of episodic use of specified benzodiazepines; 4.Added clarifying language regarding timing and assessment of vitals and body weight, PCS criteria for blood pressure, and C-SSRS assessment.
    01 May 2012
    1.Updated planned LPV. 2.Moved FAsD subscale from secondary gatekeeper objective to additional secondary objective. 3.Updated statistical methodology section. 4.Updated details of how the sample size and power calculations are provided to ERBs
    02 Aug 2012
    1.Added language for "re-screening"; 2.Made modifications to interim analysis based on regulatory input and updated statistical methods.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27035159
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