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Vortioxetine, 5, 10, and 20 mg, Relapse Prevention Study in Adults With Major Depressive Disorder (MDD)

Sponsor
Takeda (Industry)
Overall Status
Completed
CT.gov ID
NCT02371980
Collaborator
(none)
1,106
Enrollment
79
Locations
5
Arms
50.4
Actual Duration (Months)
14
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of vortioxetine (5, 10, and 20 mg) versus placebo during the first 28 weeks of the 32-week double-blind treatment period in the prevention of relapse in participants with MDD who responded to acute treatment with vortioxetine 10 mg.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

The drug being tested in this study is called vortioxetine. Vortioxetine is being tested for the prevention of relapse in adults with major depressive disorder (MDD) who respond to daily treatment with vortioxetine. This study will look at relapse rates of MDD in people who take vortioxetine.

The study will enroll approximately 1100 participants. All participants will receive vortioxetine 10 mg open-label for the first 16 weeks of the study. Participants who meet the appropriate MDD response criteria from the Week 8 Visit through Week 16 Visit will be eligible for randomization into the double-blind treatment period. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

  • Vortioxetine 5 mg

  • Vortioxetine 10 mg

  • Vortioxetine 20 mg

  • Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient

All participants will be asked to take one capsule at the same time each day throughout the study.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to 55 weeks. Participants will make 19 visits to the clinic, and will be contacted by telephone 4 weeks after last dose of study drug for a follow-up assessment.

Study Design

Study Type:
Interventional
Actual Enrollment :
1106 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blind, Placebo-Controlled, Phase 4, Relapse Prevention Study Evaluating the Efficacy and Safety of Vortioxetine (5, 10 and 20 mg) in Adults With Major Depressive Disorder
Actual Study Start Date :
Feb 10, 2015
Actual Primary Completion Date :
Mar 1, 2019
Actual Study Completion Date :
Apr 25, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Open-label: Vortioxetine 10 mg

Vortioxetine 10 mg, capsules, orally, once, daily (QD) up to 8 weeks. Participants who achieved response (defined as a ≥50% reduction in Montgomery Asberg Depression Rating Scale (MADRS) total score from Baseline) continued to receive vortioxetine 10 mg, capsules, orally, QD for up to Week 16 (stabilization period) in the Open-label Period.

Drug: Vortioxetine
Vortioxetine capsules
Other Names:
  • LuAA21004

    		•
    Placebo Comparator: Double-blind: Placebo

    Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine placebo-matching capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.

    Drug: Placebo
    Vortioxetine placebo-matching capsules
    Experimental: Double-blind: Vortioxetine 5 mg

    Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 5 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.

    Drug: Vortioxetine
    Vortioxetine capsules
    Other Names:
  • LuAA21004

    		•
    Experimental: Double-blind: Vortioxetine 10 mg

    Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 10 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.

    Drug: Vortioxetine
    Vortioxetine capsules
    Other Names:
  • LuAA21004

    		•
    Placebo Comparator: Double-blind: Vortioxetine 20 mg

    Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 20 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.

    Drug: Vortioxetine
    Vortioxetine capsules
    Other Names:
  • LuAA21004

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Time From Randomization to Relapse of Major Depressive Disorder During the First 28 Weeks of the 32-Week Double-Blind Treatment Period [From date of double-blind randomization (Week 16) up to relapse or first 28 weeks of Double-blind Period which occurs first (Up to Week 44)]

      Relapse was defined as either 1) MADRS Score ≥22, 2) lack of efficacy as determined by the investigator or 3) other unsatisfactory treatment response judged by the investigator. Time to relapse was defined as date of relapse - date of randomization + 1 (where date of relapse is the date of last dose, or date of last contact if date of last dose is missing, for participant with a relapse). Participants without relapse were censored at date of withdrawal or date of Week 28 visit, whichever was earliest. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (i.e., apparent sadness, reported sadness, inner tension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score ranges from 0 to 60. Higher scores indicate greater severity of symptoms. The inter-quartile range (IQR) was 25th percentile to 75th percentile.

    Secondary Outcome Measures

    1. Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score [Double-blind Baseline (BL) II and Double-blind Period: Weeks 2, 4, 8, 12, 16, 20, 24, 28, and 32]

      MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (i.e., apparent sadness, reported sadness, inner tension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60. Higher score indicates greater severity of symptoms. Baseline II is defined as the last non-missing observation prior to the first dose of double-blind study drug. Mixed model for repeated measures (MMRM) was used for analyses.

    2. Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) Score at Each Week Assessed [Double-blind Baseline (BL) II and Double-blind Period: Weeks 2, 4, 8, 12, 16, 20, 24, 28, and 32]

      The CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participant who have the same diagnosis. Considering total clinical experience, a participant was assessed on severity of mental illness on the following scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=extremely ill. Baseline II is defined as the last non-missing observation prior to the first dose of double-blind study drug. MMRM was used for analyses.

    3. Clinical Global Impression Scale-Global Improvement Scale (CGI-I) Score [Week 32]

      The CGI-I scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on a 7-point scale where 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.

    4. Time From Randomization to Relapse of Major Depressive Disorder During the Entire 32-Week Double-Blind Treatment Period [From date of double-blind randomization (Week 16) up to relapse or 32 weeks of Double-blind Period which occurs first (Up to Week 44)]

      Relapse was defined as either 1) MADRS Score ≥22, 2) lack of efficacy as determined by the investigator or 3) other unsatisfactory treatment response judged by the investigator. Time to relapse was defined as date of relapse - date of randomization + 1 (where date of relapse is the date of last dose, or date of last contact if date of last dose is missing, for participant with a relapse). Participants without relapse were censored. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (i.e., apparent sadness, reported sadness, inner tension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score ranges from 0 to 60. Higher scores indicate greater severity of symptoms. The IQR was 25th percentile to 75th percentile.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

    2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

    3. Suffers from recurrent major depressive disorder (MDD) as the primary diagnosis according to Diagnostic & Statistical Manual of Mental Disorders, 4th Edition - Text Revision (DSM-IV-TR) criteria (classification code 296.3x), and the current episode is confirmed by the Mini International Neuropsychiatric Interview (MINI).

    4. Reported duration of the current episode is ≥8 weeks and ≤18months.

    5. Had at least 2 other major depressive episodes (MDEs) before the current episode.

    6. Has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26 at the Screening and Baseline I visits.

    7. Is a man or woman aged 18 to 75 years, inclusive.

    8. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of the informed consent throughout the duration of the study and for 30 days after the last dose.

    Exclusion Criteria:

    1. Has received any investigational compound within 30 days prior to screening or 5 half-lives prior to screening, whichever is longer.

    2. Has previously or is currently participating in this study.

    3. Has participated in 2 or more clinical studies in the year prior to screening, or has participated in a clinical trial for a psychiatric condition that is exclusionary per this protocol.

    4. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

    5. Has one or more of the following:

    6. Any current psychiatric disorder which is the primary focus of treatment other than MDD as defined in the DSM-IV-TR, and assessed by the MINI.

    7. Current or history of: manic or hypomanic episode, schizophrenia or any other psychotic disorder, including schizoaffective disorder, major depression with psychotic features, bipolar depression with psychotic features, obsessive compulsive disorder (OCD), mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR.

    8. Current diagnosis or history of alcohol or other substance abuse or dependence (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in full and sustained remission for at least 3 months from the day of screening (Participant must also have negative urine drug screen at Screening and Baseline I.)

    9. Presence or history of a clinically significant neurological disorder (including epilepsy) as determined by the investigator.

    10. Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, etc).

    11. Any Axis II disorder as defined by DSM-IV-TR that might compromise the study.

    12. The current depressive symptoms of the participant are considered by the investigator to have been resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each.

    13. Has a history of lack of response to previous adequate treatment with vortioxetine for any MDD episode with adequate treatment considered to be known dose of vortioxetine in the approved recommended dose range for at least 6 weeks duration.

    14. Has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to Screening.

    15. Has started receiving formal cognitive or behavioral therapy, systematic psychotherapy within 30 days from screening or plans to initiate such therapy during the study (supportive therapy, marital therapy and bereavement counseling are allowed).

    16. Has a significant risk of suicide according to the investigator's clinical judgment or has a score ≥5 on item 10 (suicidal thoughts) of the MADRS or has made a suicide attempt in the previous 6 months.

    17. Is required to take excluded medications or it is anticipated that the participant will require treatment with at least 1 of the disallowed concomitant medications during the study.

    18. Has a clinically significant unstable illness, for example hepatic impairment or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, hematological, infectious, dermatological disorder or metabolic disturbance.

    Note: For the purposes of this protocol fibromyalgia, obstructive sleep apnea, chronic pain diagnosis, and morbid obesity (BMI of > 40) are considered unstable due to the potential impact on assessment of the primary endpoint.

    1. Has a known history of or currently has increased intraocular pressure or is at risk of acute narrow-angle glaucoma.

    2. Has 1 or more laboratory value outside the normal range, based on the blood or urine samples taken at the Screening Visit, that are considered by the investigator to be clinically significant; or the participant has any of the following values at the

    Screening Visit:

    1. A serum creatinine value >1.5 times the upper limits of normal (ULN).

    2. A serum total bilirubin value >1.5 xULN.

    3. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value

    2 xULN.

    1. Has glycosylated hemoglobin (HbA1C) ≥7% at screening and no prior diagnosis of diabetes and/or treatment for diabetes. NOTE: Participants with known stable diabetes are not excluded.

    2. Has a thyroid stimulating hormone (TSH) value outside the normal range at the Screening Visit that is deemed clinically significant by the investigator. NOTE: Free T4 will be checked if TSH is out of range. If free T4 is abnormal the participant will be excluded.

    3. Has clinically significant abnormal vital signs as determined by the investigator.

    4. Has an abnormal electrocardiogram (ECG) as determined by the central reader and confirmed as clinically significant by the investigator.

    5. Is positive for Hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies, or has a history of human immunodeficiency virus (HIV) infection.

    6. Has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability or efficacy.

    7. The participant, in the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable for any reason.

    8. Has a history of hypersensitivity or allergies to vortioxetine.

    9. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.

    10. The participant is considered to be treatment resistant, eg, the participant has not responded to adequate monotherapy treatments of at least 6 weeks' duration, or has only responded to combination or augmentation therapy.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 NoesisPharma Phoenix Arizona United States 85032
    2 SW Biomedical Research, LLC Tucson Arizona United States 85712
    3 CNS Research Science, Inc. Cerritos California United States 90703
    4 Collaborative Neuroscience Network, LLC Garden Grove California United States 92845
    5 Irvine Center for Clinical Research, Inc. Irvine California United States 92614
    6 Synergy Clinical Research of Escondido Lemon Grove California United States 91945
    7 Pharmacology Research Institute Los Alamitos California United States 90720
    8 Pacific Institute of Medical Research Los Angeles California United States 90024
    9 CNRI - Los Angeles, LLC Pico Rivera California United States 90660
    10 CNRI - San Diego, LLC San Diego California United States 92102
    11 Artemis Institute for Clinical Research, LLC San Diego California United States 92103
    12 University of California San Diego Medical Center San Diego California United States 92103
    13 Pasadena Research Institute San Gabriel California United States 91776
    14 Collaborative Neuroscience Network, LLC Torrance California United States 90502
    15 Research Center for Clinical Studies, Inc. Norwalk Connecticut United States 06851
    16 CNS Clinical Research Group Coral Springs Florida United States 33067
    17 Gulfcoast Medical Research Center, LLC Fort Myers Florida United States 33912
    18 MD Clinical Hallandale Beach Florida United States 33009
    19 Indago Research & Health Center, Inc. Hialeah Florida United States 33012
    20 Clinical Neuroscience Solutions, Inc. Jacksonville Florida United States 32256
    21 Meridien Research Maitland Florida United States 32751
    22 Sarkis Clinical Trials - Parent Ocala Florida United States 34474
    23 Clinical Neuroscience Solutions, Inc. Orlando Florida United States 32801
    24 Stedman Clinical Trials, LLC Tampa Florida United States 33613
    25 Janice L. Miller, M.D., PA d/b/a Janus Center for Psychiatric Reseach West Palm Beach Florida United States 33407
    26 Radiant Research, Inc. Atlanta Georgia United States 30328
    27 Atlanta Center for Medical Research Atlanta Georgia United States 30331
    28 iResearch Atlanta, LLC Decatur Georgia United States 30030
    29 Alexian Brothers Center for Psychiatric Research Arlington Heights Illinois United States 60005
    30 Rush St Lukes Presbyterian Medical Center Chicago Illinois United States 60612
    31 Capstone Clinical Research, Inc. Libertyville Illinois United States 60048
    32 Goldpoint Clinical Research, LLC Indianapolis Indiana United States 46260
    33 Buynak Clinical Research Valparaiso Indiana United States 46383
    34 Phoenix Medical Research, Inc. Prairie Village Kansas United States 66208
    35 Heartland Research Associates, LLC Wichita Kansas United States 67207
    36 Lake Charles Clinical Trials, LLC Lake Charles Louisiana United States 70629
    37 Pharmasite Research, Inc. Baltimore Maryland United States 21208
    38 Potomac Grove Clinical Research Center Gaithersburg Maryland United States 20877
    39 Boston Clinical Trials & Medical Research Boston Massachusetts United States 02131
    40 Univ. of Massachussetts Memorial Health Care Systems Worcester Massachusetts United States 01605-2610
    41 Altea Research Institute Las Vegas Nevada United States 89102
    42 Hassman Research Institute Berlin New Jersey United States 08009
    43 Montefiore Medical Center PRIME Bronx New York United States 10467
    44 Erie County Medical Center Corporation Buffalo New York United States 14215
    45 Neurobehavioral Research, Inc. Cedarhurst New York United States 11516
    46 CNS Research Science, Inc. Jamaica New York United States 11432
    47 Village Clinical Research, Inc. New York New York United States 10003
    48 Manhattan Behavioral Medicine, PLLC New York New York United States 10022
    49 Finger Lakes Clinical Research Rochester New York United States 14618
    50 Duke University Medical Center Durham North Carolina United States 27710
    51 Clinical Trials of America, Inc Hickory North Carolina United States 28601
    52 NorthCoast Clinical Trials, Inc. Beachwood Ohio United States 44122
    53 Patient Priority Clinical Sites, LLC Cincinnati Ohio United States 45215
    54 IPS Research Company Oklahoma City Oklahoma United States 73103
    55 Cutting Edge Research Group, Inc. Oklahoma City Oklahoma United States 73116
    56 Summit Research Network (Oregon) Inc. Portland Oregon United States 97210
    57 Oregon Center for Clinical Investigations, Inc. Portland Oregon United States 97214
    58 Suburban Research Associates Media Pennsylvania United States 19063
    59 Keystone Clinical Studies, LLC Norristown Pennsylvania United States 19403
    60 University of Pennsylvania School of Medicine Philadelphia Pennsylvania United States 19104
    61 Lincoln Research Lincoln Rhode Island United States 02865
    62 Medical University of South Carolina (MUSC) Charleston South Carolina United States 29401
    63 Coastal Carolina Research Center, Inc Mount Pleasant South Carolina United States 29464
    64 Clinical Neuroscience Solutions, Inc. Memphis Tennessee United States 38119
    65 FutureSearch Clinical Trials, L.P. Austin Texas United States 78731
    66 BioBehavioral Research of Austin Austin Texas United States 78759
    67 FutureSearch Trials of Dallas, LP Dallas Texas United States 75231
    68 Bayou City Research, Ltd. Houston Texas United States 77007
    69 Houston Clinical Trials, LLC Houston Texas United States 77098
    70 Pillar Clinical Research, LLC Richardson Texas United States 75080
    71 Clinical Trials of Texas, Inc. San Antonio Texas United States 78229
    72 Radiant Research, Inc. Murray Utah United States 84123
    73 Neuropsychiatric Associates Woodstock Vermont United States 05091
    74 University of Virginia Health System Charlottesville Virginia United States 22903
    75 Virginia Commonwealth University Medical Center Richmond Virginia United States 23298-5054
    76 Eastside Therapeutic Resource Everett Washington United States 98201
    77 Summit Research Network (Seattle), LLC Seattle Washington United States 98104
    78 Frontier Institute Spokane Washington United States 99204
    79 Northbrooke Research Center Brown Deer Wisconsin United States 53223

    Sponsors and Collaborators

    • Takeda

    Investigators

    • Study Director: Medical Director Clinical Science, Takeda

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Takeda
    ClinicalTrials.gov Identifier:
    NCT02371980
    Other Study ID Numbers:
    • LuAA21004_402
    • U1111-1161-4956
    First Posted:
    Feb 26, 2015
    Last Update Posted:
    Jan 6, 2021
    Last Verified:
    Dec 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Takeda
    Drug therapy
    Additional relevant MeSH terms:
    Depressive Disorder
    Depression
    Depressive Disorder, Major
    Vortioxetine

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 74 investigative sites in the United States from 10 February 2015 to 25 April 2019.
    Pre-assignment Detail Participants with diagnosis of major depressive disorder (MDD) were enrolled to receive vortioxetine 10 mg in the Open-label Period for up to 16 weeks. Responders (defined below) were randomized in 1:1:1:1 ratio to receive vortioxetine 5 mg, 10 mg or 20 mg or placebo for up to 32 weeks in the Double-blind Period.
    Arm/Group Title Open-label: Vortioxetine 10 mg Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Arm/Group Description Vortioxetine 10 mg, capsules, orally, once, daily (QD) up to 8 weeks. Participants who achieved response (defined as a ≥50% reduction in Montgomery Asberg Depression Rating Scale (MADRS) total score from Baseline) continued to receive vortioxetine 10 mg, capsules, orally, QD for up to Week 16 (stabilization period) in the Open-label Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine placebo-matching capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 5 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 10 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 20 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.
    Period Title: Open-label Period
    STARTED 1106 0 0 0 0
    COMPLETED 580 0 0 0 0
    NOT COMPLETED 526 0 0 0 0
    Period Title: Open-label Period
    STARTED 0 151 140 145 144
    COMPLETED 0 70 84 96 86
    NOT COMPLETED 0 81 56 49 58

    Baseline Characteristics

    Arm/Group Title Open-label: Vortioxetine 10 mg
    Arm/Group Description Vortioxetine 10 mg, capsules, orally, once, daily (QD) up to 8 weeks. Participants who achieved response (defined as a ≥50% reduction in Montgomery Asberg Depression Rating Scale (MADRS) total score from Baseline) continued to receive vortioxetine 10 mg, capsules, orally, QD for up to Week 16 (stabilization period) in the Open-label Period.
    Overall Participants 1106
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    44.3
    (13.69)
    Sex: Female, Male (Count of Participants)
    Female
    807
    73%
    Male
    299
    27%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    145
    13.1%
    Not Hispanic or Latino
    961
    86.9%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    7
    0.6%
    Asian
    19
    1.7%
    Native Hawaiian or Other Pacific Islander
    10
    0.9%
    Black or African American
    258
    23.3%
    White
    790
    71.4%
    More than one race
    19
    1.7%
    Unknown or Not Reported
    3
    0.3%
    Region of Enrollment (Count of Participants)
    United States
    1106
    100%
    Height (cm) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cm]
    167.7
    (9.38)
    Weight (kg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg]
    82.92
    (18.695)
    Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    29.39
    (5.731)
    Smoking Classification (Count of Participants)
    Participant has Never Smoked
    705
    63.7%
    Participant is a Current Smoker
    215
    19.4%
    Participant is an Ex-smoker
    186
    16.8%
    Alcohol Consumption (Count of Participants)
    Participant has Never Consumed
    332
    30%
    Consumes Once Monthly or Less Consumes Often
    286
    25.9%
    Consumes Once a Week
    167
    15.1%
    Consumes 2 to 6 Times per Week
    159
    14.4%
    Consumes Daily
    11
    1%
    Participant was an Ex-Drinker
    151
    13.7%

    Outcome Measures

    1. Primary Outcome
    Title Time From Randomization to Relapse of Major Depressive Disorder During the First 28 Weeks of the 32-Week Double-Blind Treatment Period
    Description Relapse was defined as either 1) MADRS Score ≥22, 2) lack of efficacy as determined by the investigator or 3) other unsatisfactory treatment response judged by the investigator. Time to relapse was defined as date of relapse - date of randomization + 1 (where date of relapse is the date of last dose, or date of last contact if date of last dose is missing, for participant with a relapse). Participants without relapse were censored at date of withdrawal or date of Week 28 visit, whichever was earliest. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (i.e., apparent sadness, reported sadness, inner tension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score ranges from 0 to 60. Higher scores indicate greater severity of symptoms. The inter-quartile range (IQR) was 25th percentile to 75th percentile.
    Time Frame From date of double-blind randomization (Week 16) up to relapse or first 28 weeks of Double-blind Period which occurs first (Up to Week 44)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) included all participants who were randomized in the double-blind period and received at least 1 dose of double-blind study drug.
    Arm/Group Title Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Arm/Group Description Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine placebo-matching capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 5 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 10 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 20 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.
    Measure Participants 151 140 145 144
    Median (Inter-Quartile Range) [weeks]
    NA
    NA
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-blind: Vortioxetine 5 mg
    Comments Double-blind Vortioxetine 5mg Vs Double-blind Placebo
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.006
    Comments Gate-keeping fixed-sequence testing procedure was used for multiple comparisons.
    Method Cox Proportional Hazards Model
    Comments Cox proportional hazards model with a factor for treatment and baseline II MADRS total score as a covariate, using the exact method to handle ties.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.517
    Confidence Interval (2-Sided) 95%
    0.323 to 0.828
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-blind: Vortioxetine 10 mg
    Comments Double-blind Vortioxetine 10 mg Vs Double-blind Placebo
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments Gate-keeping fixed-sequence testing procedure was used for multiple comparisons.
    Method Cox Proportional Hazards Model
    Comments Cox proportional hazards model with a factor for treatment and baseline II MADRS total score as a covariate, using the exact method to handle ties.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.476
    Confidence Interval (2-Sided) 95%
    0.296 to 0.767
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-blind: Vortioxetine 20 mg
    Comments Double-blind Vortioxetine 20 mg Vs Double-blind Placebo
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.003
    Comments Gate-keeping fixed-sequence testing procedure was used for multiple comparisons.
    Method Cox Proportional Hazards Model
    Comments Cox proportional hazards model with a factor for treatment and baseline II MADRS total score as a covariate, using the exact method to handle ties.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.483
    Confidence Interval (2-Sided) 95%
    0.298 to 0.782
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score
    Description MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (i.e., apparent sadness, reported sadness, inner tension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60. Higher score indicates greater severity of symptoms. Baseline II is defined as the last non-missing observation prior to the first dose of double-blind study drug. Mixed model for repeated measures (MMRM) was used for analyses.
    Time Frame Double-blind Baseline (BL) II and Double-blind Period: Weeks 2, 4, 8, 12, 16, 20, 24, 28, and 32

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were randomized in the double-blind period and received at least 1 dose of double-blind study drug. Number analyzed is the number of participants with data available for analysis at the given time-point.
    Arm/Group Title Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Arm/Group Description Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine placebo-matching capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 5 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 10 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 20 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.
    Measure Participants 151 140 145 144
    Change From BL II at Week 2
    2.70
    (0.461)
    2.23
    (0.490)
    1.47
    (0.471)
    2.29
    (0.481)
    Change From BL II at Week 4
    4.99
    (0.576)
    2.56
    (0.599)
    1.98
    (0.581)
    2.48
    (0.602)
    Change From BL II at Week 8
    5.98
    (0.688)
    3.03
    (0.698)
    2.14
    (0.679)
    2.97
    (0.708)
    Change From BL II at Week 12
    6.43
    (0.704)
    3.51
    (0.701)
    1.92
    (0.684)
    2.79
    (0.707)
    Change From BL II at Week 16
    5.77
    (0.724)
    3.73
    (0.707)
    2.08
    (0.688)
    3.14
    (0.712)
    Change From BL II at Week 20
    5.95
    (0.699)
    3.34
    (0.673)
    1.86
    (0.653)
    3.18
    (0.675)
    Change From BL II at Week 24
    5.69
    (0.765)
    3.78
    (0.733)
    2.19
    (0.707)
    3.16
    (0.730)
    Change From BL II at Week 28
    5.07
    (0.774)
    3.18
    (0.730)
    2.72
    (0.699)
    3.20
    (0.726)
    Change From BL II at Week 32
    6.55
    (0.858)
    3.46
    (0.815)
    2.58
    (0.784)
    2.97
    (0.815)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.421
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean (LSM) Difference
    Estimated Value -0.48
    Confidence Interval (2-Sided) 95%
    -1.63 to 0.68
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.590
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.037
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.23
    Confidence Interval (2-Sided) 95%
    -2.39 to -0.08
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.589
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.488
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.41
    Confidence Interval (2-Sided) 95%
    -1.57 to 0.75
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.592
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.43
    Confidence Interval (2-Sided) 95%
    -3.93 to -0.93
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.765
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -3.00
    Confidence Interval (2-Sided) 95%
    -4.49 to -1.51
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.761
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.50
    Confidence Interval (2-Sided) 95%
    -4.02 to -0.98
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.775
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.95
    Confidence Interval (2-Sided) 95%
    -4.76 to -1.13
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.924
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -3.84
    Confidence Interval (2-Sided) 95%
    -5.64 to -2.03
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.919
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -3.00
    Confidence Interval (2-Sided) 95%
    -4.84 to -1.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.939
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.92
    Confidence Interval (2-Sided) 95%
    -4.76 to -1.08
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.938
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -4.51
    Confidence Interval (2-Sided) 95%
    -6.34 to -2.68
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.934
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -3.64
    Confidence Interval (2-Sided) 95%
    -5.50 to -1.78
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.949
    Estimation Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.033
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.04
    Confidence Interval (2-Sided) 95%
    -3.92 to -0.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.957
    Estimation Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -3.69
    Confidence Interval (2-Sided) 95%
    -5.55 to -1.82
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.952
    Estimation Comments
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.007
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.63
    Confidence Interval (2-Sided) 95%
    -4.52 to -0.73
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.967
    Estimation Comments
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 20
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.004
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.61
    Confidence Interval (2-Sided) 95%
    -4.40 to -0.82
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.912
    Estimation Comments
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 20
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -4.09
    Confidence Interval (2-Sided) 95%
    -5.86 to -2.31
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.906
    Estimation Comments
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 20
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.003
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.76
    Confidence Interval (2-Sided) 95%
    -4.57 to -0.96
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.921
    Estimation Comments
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.057
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.92
    Confidence Interval (2-Sided) 95%
    -3.89 to 0.06
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.008
    Estimation Comments
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -3.50
    Confidence Interval (2-Sided) 95%
    -5.46 to -1.55
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.997
    Estimation Comments
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.012
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.53
    Confidence Interval (2-Sided) 95%
    -4.51 to -0.55
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.011
    Estimation Comments
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 28
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.061
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.90
    Confidence Interval (2-Sided) 95%
    -3.88 to 0.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.012
    Estimation Comments
    Statistical Analysis 23
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 28
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.018
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.36
    Confidence Interval (2-Sided) 95%
    -4.31 to -0.40
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.997
    Estimation Comments
    Statistical Analysis 24
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 28
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.065
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.88
    Confidence Interval (2-Sided) 95%
    -3.87 to 0.12
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.015
    Estimation Comments
    Statistical Analysis 25
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 32
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.007
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter MMRM Model
    Estimated Value -3.09
    Confidence Interval (2-Sided) 95%
    -5.31 to -0.86
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.136
    Estimation Comments
    Statistical Analysis 26
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 32
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -3.97
    Confidence Interval (2-Sided) 95%
    -6.16 to -1.77
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.122
    Estimation Comments
    Statistical Analysis 27
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 32
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -3.58
    Confidence Interval (2-Sided) 95%
    -5.82 to -1.34
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.143
    Estimation Comments
    3. Secondary Outcome
    Title Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) Score at Each Week Assessed
    Description The CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participant who have the same diagnosis. Considering total clinical experience, a participant was assessed on severity of mental illness on the following scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=extremely ill. Baseline II is defined as the last non-missing observation prior to the first dose of double-blind study drug. MMRM was used for analyses.
    Time Frame Double-blind Baseline (BL) II and Double-blind Period: Weeks 2, 4, 8, 12, 16, 20, 24, 28, and 32

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were randomized in the double-blind period and received at least 1 dose of double-blind study drug. Number analyzed is the number of participants with data available for analysis at the given time-point.
    Arm/Group Title Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Arm/Group Description Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine placebo-matching capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 5 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 10 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 20 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.
    Measure Participants 151 140 145 144
    Change From BL II at Week 2
    0.35
    (0.065)
    0.32
    (0.069)
    0.26
    (0.067)
    0.27
    (0.068)
    Change From BL II at Week 4
    0.61
    (0.075)
    0.32
    (0.078)
    0.30
    (0.076)
    0.25
    (0.078)
    Change From BL II at Week 8
    0.68
    (0.091)
    0.38
    (0.092)
    0.29
    (0.089)
    0.30
    (0.093)
    Change From BL II at Week 12
    0.74
    (0.092)
    0.46
    (0.091)
    0.24
    (0.089)
    0.35
    (0.092)
    Change From BL II at Week 16
    0.62
    (0.094)
    0.50
    (0.091)
    0.25
    (0.088)
    0.34
    (0.091)
    Change From BL II at Week 20
    0.61
    (0.094)
    0.40
    (0.089)
    0.17
    (0.086)
    0.28
    (0.089)
    Change From BL II at Week 24
    0.60
    (0.103)
    0.45
    (0.098)
    0.24
    (0.094)
    0.37
    (0.097)
    Change From BL II at Week 28
    0.45
    (0.101)
    0.33
    (0.094)
    0.30
    (0.090)
    0.34
    (0.093)
    Change From BL II at Week 32
    0.59
    (0.108)
    0.41
    (0.101)
    0.26
    (0.097)
    0.22
    (0.100)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.732
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.03
    Confidence Interval (2-Sided) 95%
    -0.20 to 0.14
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.085
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.273
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.09
    Confidence Interval (2-Sided) 95%
    -0.26 to 0.07
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.085
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.361
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.08
    Confidence Interval (2-Sided) 95%
    -0.24 to 0.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.085
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.004
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.28
    Confidence Interval (2-Sided) 95%
    -0.48 to -0.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.099
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method Least Squares Mean Difference
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.31
    Confidence Interval (2-Sided) 95%
    -0.50 to -0.12
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.099
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.36
    Confidence Interval (2-Sided) 95%
    -0.55 to -0.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.100
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.014
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.30
    Confidence Interval (2-Sided) 95%
    -0.54 to -0.06
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.121
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.39
    Confidence Interval (2-Sided) 95%
    -0.63 to -0.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.121
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.38
    Confidence Interval (2-Sided) 95%
    -0.62 to -0.14
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.123
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.025
    Comments
    Method Least Squares Mean Difference
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.27
    Confidence Interval (2-Sided) 95%
    -0.51 to -0.03
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.122
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.50
    Confidence Interval (2-Sided) 95%
    -0.74 to -0.26
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.122
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.39
    Confidence Interval (2-Sided) 95%
    -0.63 to -0.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.124
    Estimation Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.333
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.12
    Confidence Interval (2-Sided) 95%
    -0.36 to 0.12
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.123
    Estimation Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.37
    Confidence Interval (2-Sided) 95%
    -0.61 to -0.13
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.122
    Estimation Comments
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.023
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.28
    Confidence Interval (2-Sided) 95%
    -0.53 to -0.04
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.124
    Estimation Comments
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 20
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.092
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.20
    Confidence Interval (2-Sided) 95%
    -0.44 to 0.03
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.121
    Estimation Comments
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 20
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.44
    Confidence Interval (2-Sided) 95%
    -0.67 to -0.20
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.121
    Estimation Comments
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 20
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.008
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.33
    Confidence Interval (2-Sided) 95%
    -0.57 to -0.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.122
    Estimation Comments
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.248
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.16
    Confidence Interval (2-Sided) 95%
    -0.42 to 0.11
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.135
    Estimation Comments
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.006
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.37
    Confidence Interval (2-Sided) 95%
    -0.63 to -0.10
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.133
    Estimation Comments
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.087
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.23
    Confidence Interval (2-Sided) 95%
    -0.50 to 0.03
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.135
    Estimation Comments
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 28
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.362
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.12
    Confidence Interval (2-Sided) 95%
    -0.38 to 0.14
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.131
    Estimation Comments
    Statistical Analysis 23
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 28
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.251
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.15
    Confidence Interval (2-Sided) 95%
    -0.40 to 0.10
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.129
    Estimation Comments
    Statistical Analysis 24
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 28
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.391
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.11
    Confidence Interval (2-Sided) 95%
    -0.37 to 0.14
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.131
    Estimation Comments
    Statistical Analysis 25
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Change From Baseline II at Week 32
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.209
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.18
    Confidence Interval (2-Sided) 95%
    -0.45 to 0.10
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.141
    Estimation Comments
    Statistical Analysis 26
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Change From Baseline II at Week 32
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.018
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.33
    Confidence Interval (2-Sided) 95%
    -0.60 to -0.06
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.139
    Estimation Comments
    Statistical Analysis 27
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Change From Baseline II at Week 32
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.009
    Comments
    Method MMRM
    Comments MMRM with treatment, visit, BL II score, treatment by visit interaction as fixed factors, center as random effect, and unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.37
    Confidence Interval (2-Sided) 95%
    -0.65 to -0.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.141
    Estimation Comments
    4. Secondary Outcome
    Title Clinical Global Impression Scale-Global Improvement Scale (CGI-I) Score
    Description The CGI-I scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on a 7-point scale where 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.
    Time Frame Week 32

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were randomized in the double-blind period and received at least 1 dose of double-blind study drug. Overall number of participants analyzed is the number of participants with data available for analyses.
    Arm/Group Title Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Arm/Group Description Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine placebo-matching capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 5 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 10 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 20 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.
    Measure Participants 119 120 126 144
    Mean (Standard Deviation) [scores on scale]
    4.4
    (1.47)
    3.9
    (1.51)
    3.5
    (1.72)
    3.7
    (1.56)
    5. Secondary Outcome
    Title Time From Randomization to Relapse of Major Depressive Disorder During the Entire 32-Week Double-Blind Treatment Period
    Description Relapse was defined as either 1) MADRS Score ≥22, 2) lack of efficacy as determined by the investigator or 3) other unsatisfactory treatment response judged by the investigator. Time to relapse was defined as date of relapse - date of randomization + 1 (where date of relapse is the date of last dose, or date of last contact if date of last dose is missing, for participant with a relapse). Participants without relapse were censored. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (i.e., apparent sadness, reported sadness, inner tension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score ranges from 0 to 60. Higher scores indicate greater severity of symptoms. The IQR was 25th percentile to 75th percentile.
    Time Frame From date of double-blind randomization (Week 16) up to relapse or 32 weeks of Double-blind Period which occurs first (Up to Week 44)

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were randomized in the double-blind period and received at least 1 dose of double-blind study drug.
    Arm/Group Title Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Arm/Group Description Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine placebo-matching capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 5 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 10 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 20 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.
    Measure Participants 151 140 145 144
    Median (Inter-Quartile Range) [weeks]
    NA
    NA
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 5 mg
    Comments Double-blind Vortioxetine 5mg Vs Double-blind Placebo
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments Gate-keeping fixed-sequence testing procedure was used for multiple comparisons.
    Method Cox Proportional Hazards Model
    Comments Cox proportional hazards model with a factor for treatment and baseline II MADRS total score as a covariate, using the exact method to handle ties.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.481
    Confidence Interval (2-Sided) 95%
    0.302 to 0.766
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 10 mg
    Comments Double-blind Vortioxetine 10 mg Vs Double-blind Placebo
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments Gate-keeping fixed-sequence testing procedure was used for multiple comparisons.
    Method Cox Proportional Hazards Model
    Comments Cox proportional hazards model with a factor for treatment and baseline II MADRS total score as a covariate, using the exact method to handle ties.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.455
    Confidence Interval (2-Sided) 95%
    0.286 to 0.725
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-blind: Placebo, Double-blind: Vortioxetine 20 mg
    Comments Double-blind Vortioxetine 20 mg Vs Double-blind Placebo
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments Gate-keeping fixed-sequence testing procedure was used for multiple comparisons.
    Method Cox Proportional Hazards Model
    Comments Cox proportional hazards model with a factor for treatment and baseline II MADRS total score as a covariate, using the exact method to handle ties.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.484
    Confidence Interval (2-Sided) 95%
    0.304 to 0.771
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame From first dose of study drug and up to 30 days after the last dose (Up to 48 weeks)
    Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Arm/Group Title Open-label: Vortioxetine 10 mg Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Arm/Group Description Vortioxetine 10 mg, capsules, orally, once, daily (QD) up to 8 weeks. Participants who achieved response (defined as a ≥50% reduction in Montgomery Asberg Depression Rating Scale (MADRS) total score from Baseline) continued to receive vortioxetine 10 mg, capsules, orally, QD for up to Week 16 (stabilization period) in the Open-label Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine placebo-matching capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 5 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 10 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 20 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.
    All Cause Mortality
    Open-label: Vortioxetine 10 mg Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/1106 (0%) 0/151 (0%) 0/140 (0%) 1/145 (0.7%) 0/144 (0%)
    Serious Adverse Events
    Open-label: Vortioxetine 10 mg Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/1106 (0.8%) 1/151 (0.7%) 3/140 (2.1%) 4/145 (2.8%) 0/144 (0%)
    Cardiac disorders
    Cardiac failure 0/1106 (0%) 1/151 (0.7%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Ear and labyrinth disorders
    Vertigo 0/1106 (0%) 0/151 (0%) 1/140 (0.7%) 0/145 (0%) 0/144 (0%)
    Gastrointestinal disorders
    Abdominal pain upper 1/1106 (0.1%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Hepatobiliary disorders
    Cholecystitis acute 1/1106 (0.1%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Infections and infestations
    Post procedural cellulitis 0/1106 (0%) 0/151 (0%) 0/140 (0%) 1/145 (0.7%) 0/144 (0%)
    Pyelonephritis 0/1106 (0%) 0/151 (0%) 0/140 (0%) 1/145 (0.7%) 0/144 (0%)
    Appendicitis 1/1106 (0.1%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Injury, poisoning and procedural complications
    Ankle fracture 0/1106 (0%) 0/151 (0%) 1/140 (0.7%) 0/145 (0%) 0/144 (0%)
    Hand fracture 1/1106 (0.1%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus 1/1106 (0.1%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intraductal proliferative breast lesion 0/1106 (0%) 0/151 (0%) 1/140 (0.7%) 0/145 (0%) 0/144 (0%)
    Pregnancy, puerperium and perinatal conditions
    Abortion missed 1/1106 (0.1%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Psychiatric disorders
    Completed suicide 0/1106 (0%) 0/151 (0%) 0/140 (0%) 1/145 (0.7%) 0/144 (0%)
    Suicidal ideation 2/1106 (0.2%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Panic attack 1/1106 (0.1%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Renal and urinary disorders
    Nephrolithiasis 0/1106 (0%) 0/151 (0%) 0/140 (0%) 1/145 (0.7%) 0/144 (0%)
    Other (Not Including Serious) Adverse Events
    Open-label: Vortioxetine 10 mg Double-blind: Placebo Double-blind: Vortioxetine 5 mg Double-blind: Vortioxetine 10 mg Double-blind: Vortioxetine 20 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 417/1106 (37.7%) 16/151 (10.6%) 30/140 (21.4%) 27/145 (18.6%) 32/144 (22.2%)
    Gastrointestinal disorders
    Nausea 292/1106 (26.4%) 2/151 (1.3%) 4/140 (2.9%) 5/145 (3.4%) 13/144 (9%)
    Dry mouth 58/1106 (5.2%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)
    Infections and infestations
    Upper respiratory tract infection 0/1106 (0%) 6/151 (4%) 9/140 (6.4%) 9/145 (6.2%) 9/144 (6.3%)
    Nasopharyngitis 56/1106 (5.1%) 4/151 (2.6%) 7/140 (5%) 7/145 (4.8%) 8/144 (5.6%)
    Investigations
    Weight increased 0/1106 (0%) 3/151 (2%) 5/140 (3.6%) 7/145 (4.8%) 8/144 (5.6%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/1106 (0%) 2/151 (1.3%) 8/140 (5.7%) 0/145 (0%) 2/144 (1.4%)
    Nervous system disorders
    Headache 91/1106 (8.2%) 0/151 (0%) 0/140 (0%) 0/145 (0%) 0/144 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.

    Results Point of Contact

    Name/Title Medical Director
    Organization Takeda
    Phone +1-877-825-3327
    Email trialdisclosures@takeda.com
    Responsible Party:
    Takeda
    ClinicalTrials.gov Identifier:
    NCT02371980
    Other Study ID Numbers:
    • LuAA21004_402
    • U1111-1161-4956
    First Posted:
    Feb 26, 2015
    Last Update Posted:
    Jan 6, 2021
    Last Verified:
    Dec 1, 2020