A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder (ESCAPE-TRD)

A Randomized, Open-label, Rater-Blinded, Active-Controlled, International, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Flexibly Dosed Esketamine Nasal Spray Compared With Quetiapine Extended-Release in Adult and Elderly Participants With Treatment-Resistant Major Depressive Disorder Who Are Continuing a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor

The primary purpose of this study is to evaluate the efficacy of flexibly dosed esketamine nasal spray compared with quetiapine extended-release (XR), both in combination with a continuing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI), in achieving remission in participants who have treatment-resistant major depressive disorder (MDD) with a current moderate to severe depressive episode.

Study Overview

• Status: Completed
• Conditions: Depressive Disorder, Major
• Intervention / Treatment: Drug: Esketamine 28 mg; Drug: Esketamine 56 mg; Drug: Esketamine 84 mg; Drug: SSRI/SNRI; Drug: Quetiapine XR 50 mg; Drug: Quetiapine XR 100 mg; Drug: Quetiapine XR 150 mg

Detailed Description

A depressive state with classical symptoms such as low (depressive/sad) mood, markedly diminished interest in activities, significant weight loss/gain, insomnia or hypersomnia, psychomotor agitation/retardation, excessive fatigue, inappropriate guilt, diminished concentration, and recurrent thoughts of death, persisting for more than 2 weeks is classified as major depressive disorder (MDD). The mechanism of action of ketamine is distinct from conventional antidepressants (ADs), which target the monoamines (serotonin, norepinephrine, and/or dopamine). Esketamine, the S-enantiomer of ketamine, is approved and widely used for the induction and maintenance of anesthesia via intramuscular or intravenous (IV) administration. There is a significant unmet need to develop novel AD treatments based on the relevant psychophysiological pathways underlying MDD. The goal of any novel treatment would be the rapid and long-lasting relief of depressive symptoms, especially in participants with treatment-resistant depression (TRD), who lack a sufficient response to the currently available treatment strategies. The study consists of a Screening Phase (up to 14 days), an Acute Phase (8 Weeks), a Maintenance Phase (24 Weeks) and a Safety Follow-up Phase (2 Weeks). Safety assessment includes adverse event, serious adverse events, physical examination, vital signs, electrocardiogram, clinical safety laboratory assessments, suicidal risk monitoring. The total duration of the study is approximately 36 Weeks for all participants.

• Study Type: Interventional
• Enrollment (Actual): 676
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma de Buenos Aires, Argentina, C1405BOA
    • FunDaMos
  • Ciudad Autónoma De Buenos Aires, Argentina, C1133AAH
    • Fundacion para el Estudio y Tratamiento de las Enfermedades Mentales
  • Cordoba, Argentina, 5000
    • Fundacion Lennox
  • Cordoba, Argentina, X5003DCE
    • Instituto Médico DAMIC
  • Cordoba, Argentina, 5000FJF
    • CEN Consultorios Especializados en Neurociencias
  • Cordoba, Argentina, X5009BIN
    • Sanatorio Prof Leon S Morra S A
  • La Plata, Argentina, 1900
    • Instituto de Neurociencias San Agustín
  • Rosario, Argentina, 2000
    • C I A P Centro de investigacion y Asistencia en Psiquiatria
• Austria
  • Graz, Austria, 8036
    • Medical University Graz
  • Vienna, Austria, 1010
    • Schmitz and Schmitz
  • Vienna, Austria, 1090
    • Medical University Vienna MUV
• Belgium
  • Alken, Belgium, 3570
    • Anima
  • Duffel, Belgium, 2570
    • Pz Duffel
  • Henri Chapelle, Belgium, 4841
    • Clinique Psychiatrique des Frères Alexiens
  • Heusden-Zolder, Belgium, 3550
    • Sint-Franciskusziekenhuis
  • Lede, Belgium, 9340
    • ARIADNE
  • Liege, Belgium, 4000
    • CHU de Liège
• Brazil
  • Belo Horizonte, Brazil, 30150-270
    • CPN - Centro de Pesquisa em Neurociências Ltda
  • Curitiba, Brazil, 80240-280
    • Trial Tech Tecnologia em Pesquisas com Medicamentos
  • Rio de Janeiro, Brazil, 22270 060
    • Ruschel Medicina e Pesquisa Clínica Ltda
  • Sao Paulo, Brazil, 05003-090
    • BR Trials
  • Sao Paulo, Brazil, 04020-060
    • C J S Carvalho & Carvalho LTDA (Viver - Centro De Desospitalizacao Humana)
• Bulgaria
  • Kardzhali, Bulgaria, 6600
    • State Psychiatric Hospital Kardzhali
  • Pleven, Bulgaria, 5800
    • UMHAT 'Dr. Georgi Stranski', EAD
  • Plovdiv, Bulgaria, 4002
    • Mental Health Center - Plovdiv
  • Rousse, Bulgaria, 7003
    • Mental Health Center - Rousse
  • Sofia, Bulgaria, 1113
    • Multiprofile Hospital for Active Treatment in Neurology and Psychiatry Sveti Naum
  • Sofia, Bulgaria, 1377
    • Centre for Mental Health Prof.N.Shipkovenski EOOD
  • Sofia, Bulgaria, 1202
    • MHC - Sofia, EOOD
  • Sofia, Bulgaria, 1431
    • University Multiprofile Hospital for Active Treatment - UMHAT Alexandrovska EAD
• Czechia
  • Brno, Czechia, 60200
    • Psychiatricka ambulance Saint Anne s.r.o.
  • Brno, Czechia, 61500
    • Psychiatricka ambulance, MUDr. Marta Holanova
  • Hradec Kralove-Vekose, Czechia, 50341
    • NeuropsychiatrieHK, s.r.o.
  • Plzen, Czechia, 31200
    • A Shine S R O
  • Prague, Czechia, 18600
    • Institut neuropsychiatricke pece
  • Praha 10, Czechia, 109 00
    • Ad71 S.R.O.
  • Praha 10, Czechia, 10000
    • Clintrial s r o
  • Praha 6, Czechia, 16000
    • Medical Services Prague S R O
• Denmark
  • Aalborg, Denmark, 9000
    • Aalborg University Hospital
  • Esbjerg N, Denmark, 6715
    • Psykiatrien i Region Syddanmark
• Finland
  • Helsinki, Finland, 00270
    • Mederon LTD at ARTES
  • Helsinki, Finland, 120
    • Psykiatrinen Palvelukeskus Solvum Oy
  • Kuopio, Finland, 70110
    • Savon Psykiatripalvelu
• Germany
  • Aachen, Germany, 52074
    • Universitaetsklinikum der RWTH Aachen
  • Alzey, Germany, 55232
    • Rheinhessen Fachklinik Alzey
  • Berlin, Germany, 12203
    • Charite Campus Benjamin Franklin
  • Berlin, Germany, 10629
    • emovis GmbH
  • Berlin, Germany, 12209
    • Medizinisches Versorgungszentrum LiO GmbH
  • Berlin, Germany, 13187
    • Praxis Dr. med. Kirsten Hahn
  • Berlin, Germany, 13585
    • Vivantes Klinikum Spandau
  • Berlin, Germany, 13156
    • Alexander Schulze - Germany
  • Bonn, Germany, 53105
    • Universitätsklinikum Bonn
  • Chemnitz, Germany, 09131
    • Klinikum Chemnitz gGmbH
  • Cottbus, Germany, 3048
    • Carl-Thiem-Klinikum Cottbus gGmbH
  • Dortmund, Germany, 44287
    • Klinikum Dortmund gGmbH
  • Dresden, Germany, 01307
    • Universitatsklinikum Carl Gustav Carcus Dresden
  • Frankfurt Am Main, Germany, 60528
    • Universitätsklinikum Frankfurt
  • Freiburg, Germany, 79104
    • Universitätsklinikum Freiburg - Abteilung für Psychiatrie u. Psychotherapie mit Poliklinik
  • Gera, Germany, 7548
    • SRH Waldklinikum Gera GmbH
  • Gottingen, Germany, 37075
    • Georg August Universitat Universitatsmedizin Gottingen
  • Greifswald, Germany, 17489
    • Evangelisches Krankenhaus Bethanien gGmbH
  • Hamburg, Germany, 20253
    • Klinische Forschung Hamburg
  • Hamburg, Germany, 20251
    • Universitaetsklinik Hamburg-Eppendorf
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Hannover, Germany, 30159
    • Klinische Forschung Hannover-Mitte GmbH
  • Heidelberg, Germany, 69115
    • Universitat Heidelberg
  • Hennigsdorf, Germany, 16761
    • Oberhavel Kliniken GmbH
  • Homburg, Germany, 66421
    • Universitätsklinikum des Saarlandes
  • Jena, Germany, 7743
    • Universitätsklinikum Jena
  • Leipzig, Germany, 04275
    • Panakeia - Arzneimittelforschung GmbH
  • Magdeburg, Germany, 39120
    • Universitaetsklinikum Magdeburg A.oe.R
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg Universität Mainz
  • Mittweida, Germany, 09648
    • Pharmakologisches Studienzentrum Chemnitz GmbH
  • Munster, Germany, 48147
    • Universitatsklinikum Munster
  • Neuruppin, Germany, 16816
    • Ruppiner Kliniken
  • Nurnberg, Germany, 90402
    • Praxis Prof. Steinwachs
  • Oberhausen, Germany, 46145
    • Johanniter Krankenhaus Oberhausen
  • Pfaffenhofen, Germany, 85276
    • Danuvius Klinik Pfaffenhofen Fachklinik für Psychiatrie, Psychotherapie und Psychosomatik
  • Schwerin, Germany, 19055
    • Klinische forschung Schwerin GmbH
  • Schwerin, Germany, 19053
    • Somni Bene GmbH
  • Stralsund, Germany, 18437
    • Klinikum der Hansestadt Stralsund GmbH-Ambulanz-Klinik für Psychiatrie und Psychotherapie - Germany
• Greece
  • Athens, Greece, 11528
    • Aiginition Hospital of Athens
  • Athens, Greece, 124 62
    • 'Dafni' Psychiatric Hospital of Attica
  • Crete, Greece, 71409
    • Venizeleio General Hospital
  • Heraklion, Greece, 71305
    • Psychiatric Clinic 'Agios Charalampos'
  • Ioannina, Greece, 45110
    • University General Hospital of Ioannina
  • Patras, Greece, 26504
    • University General Hospital of Rio Patras
  • Thessaloniki, Greece, 54636
    • 424 Military Hospital of Thessaloniki
  • Thessaloniki, Greece, 56430
    • Psychiatric Hospital of Thessaloniki
  • Thessaloniki, Greece, 57010
    • G Papanikolaou Hospital of Thessaloniki
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem
  • Budapest, Hungary, 1125
    • Eszak Kozep budai Centrum Uj Szent Janos Korhaz es Szakrendelo Budai Csaladkozpontu
  • Budapest, Hungary, 1137
    • Processus Kft
  • Debrecen, Hungary, 4031
    • Debreceni Egyetem, Kenézy Gyula Egyetemi Oktatókórház
  • Gyongyos, Hungary, 3200
    • Bugat Pal Korhaz
  • Gyor, Hungary, H-9024
    • Petz Aladar Megyei Oktato Korhaz
  • Kalocsa, Hungary, 6300
    • Bács-Kiskun Megyei Kórház a Szegedi Tudományegyetem Általános Orvostudományi Kar Oktató Kórháza
  • Nyiregyhaza, Hungary, 4400
    • Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház
  • Pecs, Hungary, 7623
    • Pecsi Tudomanyegyetem Klinikai Kozpont
• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center
  • Hod Hasharon, Israel, 45100
    • Shalvata Mental Health Center
  • Lod, Israel, 7129434
    • Beer Yaakov Mental Health Center
  • Petach Tikva, Israel, 4910002
    • Geha Mental Health Center
  • Ramat Gan, Israel, 52621
    • Sheba Medical Center
  • Telaviv, Israel, 6423914
    • Tel Aviv Sourasky Medical Center
• Kazakhstan
  • Almaty, Kazakhstan, 50012
    • Republican Scientific and Practical Center of Mental Health
  • Nur-Sultan, Kazakhstan
    • Medical Center for Psychological Healt SME
  • Ust'-Kamenogorsk, Kazakhstan, 70016
    • East-Kazakhstan Regional Centre of Mental Health
• Korea, Republic of
  • Gwangju, Korea, Republic of, 61469
    • Chonnam National University Hospital
  • Iksan, Korea, Republic of, 570 711
    • Wonkwang University Hospital
  • Seoul, Korea, Republic of, 02841
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital Yonsei University Health System
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 02447
    • KyungHee University Hospital
• Malaysia
  • Ipoh, Malaysia, 30990
    • Hospital Raja Permaisuri Bainun
  • Kuala Lumpur, Malaysia, 50586
    • Hospital Kuala Lumpur
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
  • Serdang, Malaysia, 43400
    • Hospital Pengajar Universiti Putra Malaysia
  • Seremban, Malaysia, 70300
    • Hospital Tuanku Jaafar
• Netherlands
  • Amsterdam, Netherlands, 1081 GN
    • Brain Research Center
  • Amsterdam, Netherlands, 1105 AZ
    • AMC
  • Leiden, Netherlands, 2300 RC
    • LUMC
• Norway
  • Hordaland, Norway, 5021
    • Haukeland University Hospital
  • Moss, Norway, 1535
    • Sykehuset Ostfold
  • Trondheim, Norway, 7000
    • St Olav University Hospital
• Poland
  • Bialystok, Poland, 15-404
    • Mlynowamed Specjalistyczny Psychiatryczny Gabinet Lekarski Joanna Lazarczyk
  • Bydgoszcz, Poland, 85 794
    • Osrodek Badan Klinicznych CLINSANTE S C
  • Gdansk, Poland, 80 546
    • Centrum Badan Klinicznych PI House sp z o o
  • Gdansk, Poland, 80 214
    • Uniwersyteckie Centrum Kliniczne
  • Katowice, Poland, 40-568
    • Centrum Medyczne Care Clinic Katowice
  • Leszno, Poland, 64-100
    • Niepubliczny Zaklad Opieki Psychiatrycznej MENTIS
  • Lodz, Poland, 91-229
    • Specjalistyczny Psychiatryczny Zespol Opieki Zdrowotnej w Lodzi Szpital im. J. Babinskiego
  • Lodz, Poland, 92-216
    • SPZOZ CSK UM w Lodzi Klinika Zaburzen Afektywnych i Psychotycznych
  • Lublin, Poland, 20 109
    • Centrum Medyczne Luxmed Sp z o o
  • Torun, Poland, 87 100
    • Osrodek Badan Klinicznych CLINSANTE S C
• Portugal
  • Braga, Portugal, 4710-243
    • Hospital de Braga
  • Guilhufe - Penafiel, Portugal, 4564-007
    • Centro Hospitalar do Tâmega e Sousa, EPE - Hospital Padre Americo, Vale do Sousa
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar de Lisboa Norte Hospital Santa Maria
  • Lisboa, Portugal, 1400 038
    • Fund. Champalimaud
  • Lisbon, Portugal, 1350-352
    • Hosp. Cuf Tejo
  • Loures, Portugal, 2674-514
    • Uls Loures Odivelas - Hosp. Loures
• South Africa
  • Cape Town, South Africa, 7530
    • Cape Town Clinical Research Centre
  • Cape Town, South Africa, 7550
    • Flexivest 14 Research
  • Garsfontein, South Africa, 00 45
    • Gert Bosch Pretoria South Africa
• Sweden
  • Goteborg, Sweden, 41717
    • Psykiatriska Kliniken
  • Halmstad, Sweden, SE-30248
    • Affecta Pskyiatrimottagning
  • Lulea, Sweden, 97180
    • Psykiatriska Kliniken
  • Lund, Sweden, 22222
    • ProbarE i Lund AB
  • Skovde, Sweden, SE-54150
    • ONE LIFETIME Lakarmottagning
  • Stockholm, Sweden, 113 29
    • ProbarE i Stockholm AB
• Taiwan
  • ChangHua, Taiwan, 500
    • Changhua Christian Hospital
  • Hualien, Taiwan, 970
    • Hualien Tzu Chi Hospital
  • Kaohsiung, Taiwan, 80276
    • Kai-Syuan Psychiatric Hospital
  • Kaohsiung, Taiwan, 83342
    • Chang Gung Memorial Hospital
  • Tainan, Taiwan, 70403
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Taipei, Taiwan, 10449
    • Mackay Memorial Hospital
  • Taipei City, Taiwan, 110
    • Taipei Medical University
  • Taoyuan, Taiwan, 333
    • Chang Gung Memorial Hospital
• Turkey
  • Ankara, Turkey, 6100
    • Hacettepe University Medical Faculty
  • Bursa, Turkey, 16285
    • Bursa Yuksek Ihtisas Training and Research Hospital
  • Bursa, Turkey, 16285
    • Uludag University Medical Faculty
  • Istanbul, Turkey, 34736
    • Erenkoy Mental Health Hospital
  • Istanbul, Turkey, 34147
    • Bakirkoy Mental Health Training and Research Hospital
  • Istanbul, Turkey, 34768
    • Uskudar University Neuropsychiatry Hospital
  • Izmir, Turkey, 34371
    • Ege Universitesi Tip Fakultesi
  • Konya, Turkey, 42130
    • Selcuk University Medical Faculty
  • Samsun, Turkey, 55020
    • Liv Hospital
  • Tekirdag, Turkey, 59030
    • Namik Kemal University
• United Arab Emirates
  • Abu Dhabi, United Arab Emirates, 51133
    • American Center for Psychiatry and Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• At screening, each participant must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) or recurrent MDD, without psychotic features, based on clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI)
• At screening and baseline, each participant must have an Inventory of Depressive Symptomatology - Clinician-rated, 30 item (IDS-C30) total score of greater than or equal to (>=) 34
• Must be on a current antidepressive treatment that includes an selective serotonin reuptake inhibitor (SSRI)/ serotonin-norepinephrine reuptake inhibitor (SNRI) at screening that resulted in nonresponse (less than 25% improvement of symptoms) after having been given at an adequate dosage (based on antidepressive dosages from SmPC [or local equivalent, if applicable]) for an adequate duration of at least 6 weeks and having been uptitrated to the maximum tolerated dose; however, at screening the participant must show signs of minimal clinical improvement to be eligible for the study. Clinical improvement of a participant on their current AD treatment will be retrospectively evaluated in a qualified psychiatric interview performed by an experienced clinician. At baseline (Day 1) prior to randomization, the investigator will evaluate any changes in the participant's signs/symptoms of depression since the screening assessment and confirm that the inclusion criteria for the current AD treatment are still met (that is nonresponse and minimal clinical improvement)
• The current antidepressive treatment, was immediately preceded by nonresponse to at least 1 but not more than 5 different, consecutive treatments (all within the current moderate to severe antidepressive episode) with anti-depressants (ADs) taken at an adequate dosage for an adequate duration of at least 6 weeks and must be documented
• Must have been treated with at least 2 different antidepressive substance classes among the treatments taken at an adequate dosage for an adequate duration of at least 6 weeks resulting in nonresponse in the current moderate to severe depressive episode (including the current treatment with an selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor [SSRI/SNRI])
• Must be on a single oral SSRI/SNRI on Day 1 prior to randomization

Exclusion Criteria:

• Received treatment with esketamine or ketamine in the current moderate to severe depressive episode
• Received treatment with quetiapine extended- or immediate-release in the current moderate to severe depressive episode of a dose higher than 50 milligram per day (mg/day)
• Had depressive symptoms in the current moderate to severe depressive episode that previously did not respond to an adequate course of treatment with electroconvulsive therapy (ECT), defined as at least 7 treatments with unilateral/bilateral ECT
• Has no signs of clinical improvement at all or with a significant improvement on their current AD treatment that includes an SSRI/SNRI as determined at screening by an experienced clinician during the qualified psychiatric interview
• Received vagal nerve stimulation or has received deep brain stimulation in the current episode of depression
• has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by the Mini International Neuropsychiatric Interview [MINI]), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality disorder, or antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
• age at onset of first episode of MDD was more than or equal to (>=) 55 years
• has homicidal ideation or intent, per the investigator's clinical judgment; or has suicidal ideation with some intent to act within 1 month prior to screening, per the investigator's clinical judgment; or based on the Columbia-Suicide Severity Rating Scale (C-SSRS), corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation, or a history of suicidal behavior within the past year prior to screening. Participants reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the acute phase should also be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Esketamine Arm; Participants will receive treatment with esketamine nasal spray (28 milligram [mg] [initial dose for elderly participants 65 to 74 years of age and adults of Japanese ancestry; may be used throughout the study in these populations; may be uptitrated in 28 mg increments], 56 mg [initial dose for adult participants aged 18 to 64 years and may be used for all age groups throughout the study], or 84 mg [maximum dose esketamine nasal spray may be uptitrated to]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Drug: Esketamine 28 mg; Esketamine will be self-administered at a dose of 28 mg as nasal spray.; Drug: Esketamine 56 mg; Esketamine will be self-administered at a dose of 56 mg as nasal spray.; Drug: Esketamine 84 mg; Esketamine will be self-administered at a dose of 84 mg (maximum uptitrated dose) as nasal spray.; Drug: SSRI/SNRI; Participants will continue to take SSRI/SNRI that is approved for use in depression in their country of participation; off-label use of any SSRI/SNRI is not permitted. The continuing SSRI/SNRI dosage may be optimized throughout the study, at the investigator's discretion and based on the SmPC (or local equivalent, if applicable).
Active Comparator: Comparator Arm; Participants will continue to take their current SSRI/SNRI augmented with quetiapine extended release (XR) as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable). In adult participants aged 18 to 64 years, the initial dose is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 [lowest effective dose]; a further dose increase to 300 mg/day on Day 5 and onward will be based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose is 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day will be based on individual participant evaluation no earlier than Day 22.	Drug: SSRI/SNRI; Participants will continue to take SSRI/SNRI that is approved for use in depression in their country of participation; off-label use of any SSRI/SNRI is not permitted. The continuing SSRI/SNRI dosage may be optimized throughout the study, at the investigator's discretion and based on the SmPC (or local equivalent, if applicable).; Drug: Quetiapine XR 50 mg; Quetiapine XR will be administered at an initial dose of 50 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.; Drug: Quetiapine XR 100 mg; Quetiapine XR will be administered at a dose of 100 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.; Drug: Quetiapine XR 150 mg; Quetiapine XR will be administered at a dose of 150 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) Score at Week 8	Percentage of participants with remission as assessed by the MADRS at Week 8 was reported. The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. A participant was defined as being in remission if the MADRS total score was less than or equal to (<=)10 and no treatment or study discontinuation before Week 8.	Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Both Remission at Week 8 and Relapse-free Until Week 32	Percentage of participants with both remission at Week 8 and relapse-free until Week 32 were reported. A participant was defined as being in remission if the MADRS total score was <= 10 and no treatment or study discontinuation before Week 8. A relapse was defined by any of following: a) Worsening of depressive symptoms as indicated by MADRS total score greater than or equal to (>=) 22 confirmed by 1 additional assessment of MADRS total score >= 22 within the next 5 to 15 days. The date of the second MADRS assessment was used for the date of relapse; b) Any psychiatric hospitalization for: worsening of depression, suicide prevention or suicide attempt, the start date of hospitalization was the date of relapse; c) Suicide attempt, completed suicide, or any other clinically relevant event determined by investigator's judgment to be indicative of a relapse of depressive illness, but without hospitalized. The onset of the event was used for the date of relapse.	Week 32
Change From Baseline in Clinician-rated Overall MADRS Score	Change from baseline in clinician-rated overall MADRS score was reported. The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed up for a total possible score range of 0 to 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts.	Baseline, Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF)	Change from baseline in clinician-rated overall MADRS score at LOCF was reported. The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed up for a total possible score range of 0 to 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score	Change from baseline in clinician-rated overall severity of depressive illness as assessed by CGI-S scale score was reported. The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 1 = normal (not at all ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. Negative change in score indicates improvement.	Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF	Change from Baseline in clinician-rated overall severity of depressive illness as assessed by CGI-S scale score at LOCF was reported. The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. A participant is assessed on severity of mental illness at the time of rating according to: 1 = normal (not at all ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 32
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score	Clinician-rated overall severity of depressive illness as assessed by CGI-C scale score was reported. The CGI-C evaluates the total improvement whether or not entirely due to drug treatment on a scale of 1 to 7. Compared to the condition at baseline, a participant is assessed on how much he/she has changed, according to: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. Higher scores indicate more severity.	Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF	Number of participants with clinician-rated overall severity of depressive illness as assessed by CGI-C scale score at LOCF was reported. The CGI-C evaluates the total improvement whether or not entirely due to drug treatment on a scale of 1 to 7. Compared to the condition at baseline, a participant is assessed on how much he/she has changed, according to: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. Higher scores indicate more severity. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score	Change from baseline in participant-reported depressive symptoms as assessed by PHQ 9-item total score was reported. The PHQ-9 is a validated 9-item, patient-reported outcome (PRO) measure to assess depressive symptoms. Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19) and Severe (20-27).	Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF	Change from baseline in participant-reported depressive symptoms as assessed by PHQ 9-item total score at LOCF was reported. The PHQ-9 is a validated 9-item, PRO measure to assess depressive symptoms. Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19) and Severe (20-27). LOCF is defined as participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score	Change from baseline in participant-reported functional impairment and associated disability as assessed by SDS total score was reported. The SDS is a validated PRO measure consisting of a 5-item questionnaire that has been widely used and accepted for assessment of functional impairment and associated disability. The first 3 items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a rating scale from 0 to 10. It also has 1 item assessing days lost from school or work and 1 item assessing days of underproductivity. The scores for the first 3 items are summed to create a total score of 0 to 30, where higher score indicates greater impairment. Scores <=2 for each item and <= 6 for the total score are considered functional remission.	Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF	Change from baseline in participant-reported functional impairment and associated disability as assessed by SDS total score at LOCF was reported. The SDS is a validated PRO measure consisting of a 5-item questionnaire for assessment of functional impairment and associated disability. The first 3 items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a rating scale from 0 to 10. It also has 1 item assessing days lost from school or work and 1 item assessing days of underproductivity. The scores for the first 3 items are summed to create a total score of 0 to 30, where higher score indicates greater impairment. Scores <=2 for each item and <= 6 for the total score are considered functional remission. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score	Change from baseline in participant-reported HRQoL and health status as assessed by SF-36 scale score was reported. The SF-36 consists of 8 subscales (physical function, role limitations due to physical problems, pain, general health perception, vitality, social function, role limitations due to emotional problems, and mental health). Participants self-report on items in a subscale that have between 2-6 choices per item using likert-type responses (for example: none of the time, some of the time, etc.). Summations of item scores of the same subscale give the subscale scores, which are transformed into a range from 0 to 100; 0= worst HRQoL, 100=best HRQoL. Higher scores indicate better health status.	Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF	Change from baseline in participant-reported HRQoL and health status as assessed by SF-36 domain scores at LOCF was reported. The SF-36 consists of 8 subscales (physical function, role limitations due to physical problems, pain, general health perception, vitality, social function, role limitations due to emotional problems, and mental health). Participants self-report on items in a subscale that have between 2-6 choices per item using likert-type responses (for example: none of the time, some of the time, etc.). Summations of item scores of the same subscale give the subscale scores, which are transformed into a range from 0 to 100; 0= worst HRQoL, 100=best HRQoL. Higher scores indicate better health status. LOCF is defined as participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score	Change from baseline in participant-reported quality of life as assessed by QLDS total score was reported. The QLDS is a disease-specific validated PRO measure which assesses the impact that depression has on a participant's quality of life. It is a 34-item self-rated questionnaire which consists of dichotomous response questions, with the response being either True/Not True. Each statement on the QLDS is given a score of "1" or "0". A score of "1" is indicative of adverse quality of life. All item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition.	Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF	Change from baseline in participant-reported quality of life as assessed by QLDS total score at LOCF was reported. The QLDS is a disease-specific validated PRO measure which assesses the impact that depression has on a participant's quality of life. It is a 34-item self-rated questionnaire which consists of dichotomous response questions, with the response being either True/Not True. Each statement on the QLDS is given a score of "1" or "0". A score of "1" is indicative of adverse quality of life. All item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index	Change from baseline in participant-reported health-related quality of Life as assessed by EQ-5D-5L score: health status index was reported. The EQ-5D-5L is a standardized 2-part instrument used to measure health outcomes, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ Visual Analogue Scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (level 1 = no problem, level 2 = slight problems, level 3 = moderate problems, level 4 = severe problems, level 5 = extreme problems). The participant selects an answer for each of the 5 dimensions considering the response that best matches his or her health "today." Responses were used to generate health status index which ranges from 0 (dead) and 1 (full health), a lower score indicates worse health.	Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF	Change from baseline in participant-reported health-related quality of Life as assessed by EQ-5D-5L score: health status index at LOCF was reported. The EQ-5D-5L is a standardized 2-part instrument used to measure health outcomes, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (level 1 = no problem, level 2 = slight problems, level 3 = moderate problems, level 4 = severe problems, level 5 = extreme problems). The participant selects an answer for each of the 5 dimensions considering the response that best matches his or her health "today." LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS	Change from baseline in participant-reported health status as assessed by EQ-5D-5L Score: VAS was reported. The EQ-5D-5L is a standardized 2-part instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L descriptive system and the EQ-VAS. EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Positive change in score indicates improvement.	Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF	Change from baseline in participant-reported health status as assessed by EQ-5D-5L score: VAS at LOCF was reported. The EQ-5D-5L is a standardized 2-part instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L descriptive system and the EQ-VAS. EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Positive change in score indicates improvement. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire	Change from baseline in participant-reported work productivity as assessed by WPAI: depression questionnaire was reported. The WPAI-D questionnaire is a validated short instrument that assesses impairment in work and other regular activities over the past 7 days. The WPAI yields four types of scores: (a) Absenteeism (work time missed); (b) Presenteeism (impairment at work / reduced on-the-job effectiveness); (c) Work productivity loss (overall work impairment / absenteeism plus presenteeism); (d) Activity Impairment. The first three scores were derived only for respondents who were working (should be missing for non-working), but the last score was applicable for all respondents. Each score ranges from 0 to 100 with higher scores indicating greater impairment and less productivity.	Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF	Change from baseline in participant-reported work productivity as assessed by WPAI: depression questionnaire at LOCF was reported. The WPAI-D questionnaire is a validated short instrument that assesses impairment in work and other regular activities over the past 7 days. The WPAI yields four types of scores: (a) Absenteeism (work time missed); (b) Presenteeism (impairment at work / reduced on-the-job effectiveness); (c) Work productivity loss (overall work impairment / absenteeism plus presenteeism); (d) Activity Impairment. The first three scores were derived only for respondents who were working (should be missing for non-working), but the last score was applicable for all respondents. Each score ranges from 0 to 100 with higher scores indicating greater impairment and less productivity. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.	Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. TEAEs were those events if they started after administration of the first dose until 14 days after the last dose of study medication for other TEAEs except serious; and first dose until 30 days after the last dose of study medication for serious TEAEs.	Up to Week 35
Number of Participants With TEAEs of Special Interest	Number of participants with TEAEs of special interest were reported. It included significant TEAEs that were judged to be of special interest because of clinical importance, known or suspected class effects, or based on nonclinical signals. Events such as sedation, depersonalization/derealization disorder, depression suicidal, aggression, allergic cystitis, cholestasis and jaundice of hepatic origin, and many more were considered as TEAEs of special interest.	Up to Week 35
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score	Number of participants with suicidal ideation or behavior as assessed by C-SSRS score was reported. The C-SSRS is an assessment tool that evaluates suicidal ideation and behavior. Suicidal ideation consists of 5 items: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intention to act, active suicidal ideation with some intent to act without specific plan, and active suicidal ideation with specific plan and intent. Suicidal behavior consists of 5 items: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt (non-fatal), and completed suicide. The maximum score (from the 10 categories) assigned for each participant was summarized into one of three broad categories: No suicidal ideation or behavior (0), Suicidal ideation (1 - 5), Suicidal behavior (6 - 10). Total score ranges from 1 to 10. Higher scores indicate more severe suicidal ideation and behavior.	Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32

Collaborators and Investigators

• Sponsor: Janssen-Cilag International NV
• Investigators: Study Director: Janssen-Cilag International NV Clinical Trials, Janssen-Cilag International NV

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2020
• Primary Completion (Actual): January 20, 2022
• Study Completion (Actual): July 15, 2022

Study Registration Dates

• First Submitted: April 6, 2020
• First Submitted That Met QC Criteria: April 6, 2020
• First Posted (Actual): April 8, 2020

Study Record Updates

• Last Update Posted (Actual): April 29, 2025
• Last Update Submitted That Met QC Criteria: April 25, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Antipsychotic Agents; Quetiapine Fumarate; Esketamine
• Other Study ID Numbers: CR108787; 2019-002992-33 (EudraCT Number); 54135419TRD3013 (Other Identifier: Janssen-Cilag International NV)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Data Access (YODA) Project site at yoda.yale.edu

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes