Clinical TrialTreatment-Resistant Depression (TRD)EsketaminePlaceboCompleted
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)
This Phase III interventional trial (n=676) evaluated flexibly dosed esketamine nasal spray versus quetiapine XR, both with a continuing SSRI/SNRI, in participants with treatment-resistant major depressive disorder.
Target Enrollment
676 participants
Study Type
Phase III interventional
Design
Randomized
Registry
Detailed Description
Randomized, parallel-group Phase III trial comparing flexibly dosed esketamine nasal spray (28/56/84 mg) plus continuing SSRI/SNRI against quetiapine XR augmentation of SSRI/SNRI in adults with treatment-resistant major depressive disorder.
Treatment included an 8-week acute phase (induction: twice-weekly dosing initially) followed by a 24-week maintenance phase with once-weekly or once-every-2-weeks dosing; safety assessments included AEs/SAEs, vitals, ECG, labs and C-SSRS monitoring.
Primary objective was efficacy for remission in participants with TRD; background SSRI/SNRI was continued and could be optimised per SmPC throughout the study.
Study Arms & Interventions
Esketamine
experimentalFlexibly dosed esketamine nasal spray plus continuing SSRI/SNRI; induction then maintenance schedule.
Interventions
- Esketamine56 - 84 mgvia Other• twice-weekly (Day1–Week4), then weekly (Week5–8), then weekly or every 2 weeks (Week9–32)
Nasal spray; doses 28, 56, or 84 mg; 28 mg initial option for elderly/Japanese ancestry; flexible uptitration per protocol.
- Compoundvia Other• daily
Continuing SSRI/SNRI (background treatment; dose optimised per SmPC).
Quetiapine XR
active comparatorQuetiapine XR augmentation of continuing SSRI/SNRI per SmPC versus esketamine arm.
Interventions
- Placebovia Other• daily
Quetiapine XR 50→150 mg (adults) with possible increase to 300 mg/day per investigator; elderly schedule differs; encoded as active comparator (name/doses in notes).
- Compoundvia Other• daily
Continuing SSRI/SNRI (background treatment; dose optimised per SmPC).
Participants
Ages
18 – 74
Sexes
Male & Female
BMI
-
Psychosis History
-
Inclusion Criteria
- At screening, participant must meet DSM-5 criteria for single-episode MDD or recurrent MDD without psychotic features confirmed by MINI.
- IDS-C30 total score >=34 at screening and baseline.
- On current SSRI/SNRI at screening with documented nonresponse (<25% improvement) after adequate dose/duration (>=6 weeks) and showing minimal clinical improvement at screening.
- Current antidepressant treatment preceded by nonresponse to 1–5 different consecutive adequate AD treatments within current episode.
- Treated with at least 2 different antidepressant substance classes at adequate dose/duration resulting in nonresponse in current episode.
- Must be on a single oral SSRI/SNRI on Day 1 prior to randomization.
Exclusion Criteria
- Received esketamine or ketamine in current episode.
- Received quetiapine extended- or immediate-release >50 mg/day in current episode.
- Depressive symptoms in current episode previously nonresponsive to adequate ECT course (>=7 unilateral/bilateral ECT treatments).
- No signs of clinical improvement on current SSRI/SNRI as determined at screening.
- Received vagal nerve stimulation or deep brain stimulation in current episode.
- Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders, current OCD, intellectual disability, autism spectrum disorder, borderline personality disorder, antisocial/histrionic/narcissistic personality disorder.
- Age at onset of first MDD episode >=55 years.
- Homicidal ideation or intent per investigator; suicidal ideation with some intent within 1 month prior to screening or C-SSRS Item 4 or 5 positive, or suicidal behaviour within past year.
Primary Results(4 publications)
Participants
N = 676H. et al. 2024 →
Response Rates
MADRS ≤10 (remission)
no relapse through Week 32 after remission at Week 8 (MADRS ≤10)
MADRS ≤12 (remission)
remaining relapse-free through Week 32 after remission at Week 8 (MADRS ≤12)
≥50% improvement in MADRS score from baseline
Adverse Events (from all publications)
| Arm / Group | n | Any TEAE | Severe | Serious | Discont. |
|---|---|---|---|---|---|
| Esketamineexperimental | 336 | — | — | — | — |
| Quetiapine XRactive_comparator | 340 | — | — | — | — |
| Esketamineexperimental | 314 | 289(92.0%) | — | 19(6.1%) | 14(4.5%) |
| Quetiapine XRactive_comparator | 316 | 248(78.5%) | — | 15(4.7%) | 32(10.1%) |
| Esketamineexperimental | 165 | — | — | — | — |
| Quetiapine XRactive_comparator | 156 | — | — | — | — |
* Safety summary counts (TEAEs) not explicitly provided in the text/tables of this sensitivity analysis paper; paper focuses on efficacy endpoints.
* Safety analysis set n=314. TEAEs include dizziness, headache, somnolence, nausea, dissociation, and vertigo. Discontinuation due to TEAEs (n=14) was lower than quetiapine arm.
* Safety analysis set n=316. Discontinuation due to TEAEs (n=32) was higher than ESK arm. Most common TEAEs leading to discontinuation were sedation, weight increase, dizziness, and fatigue.
* The paper is a post hoc analysis of work productivity loss (WPL) and costs; it does not provide summary counts for TEAEs, although it mentions that both treatments are associated with adverse events like sedation, dizziness, and nausea.
Study Details
- StatusCompleted
- PhasePhase III
- Typeinterventional
- DesignRandomized
- Target Enrollment676 participants
- TimelineStart: 2020-08-21End: 2022-07-15
- Compounds
- Topic
Study Team
Sponsors & Collaborators
- Janssen Research & DevelopmentPrimary Sponsor
Locations
Fundacion para el Estudio y Tratamiento de las Enfermedades Mentales — Buenos Aires, Argentina
FunDaMos — Buenos Aires, Argentina
CEN Consultorios Especializados en Neurociencias — Córdoba, Argentina
Fundacion Lennox — Córdoba, Argentina
Instituto Medico DAMIC — Córdoba, Argentina
Sanatorio Prof Leon S Morra S A — Córdoba, Argentina
Instituto de Neurociencias San Agustin — La Plata, Argentina
C I A P Centro de investigacion y Asistencia en Psiquiatria — Rosario, Argentina
Medical University Graz — Graz, Austria
Schmitz and Schmitz — Vienna, Austria
Medical University Vienna MUV — Vienna, Austria
Anima — Alken, Belgium
Pz Duffel — Duffel, Belgium
Clinique Psychiatrique des Frères Alexiens — Henri-Chapelle, Belgium
Sint-Franciskusziekenhuis — Heusden-Zolder, Belgium
ARIADNE — Lede, Belgium
CHU de Liege — Liège, Belgium
CPN - Centro de Pesquisa em Neurociências Ltda — Belo Horizonte, Brazil
Trial Tech Tecnologia em Pesquisas com Medicamentos — Curitiba, Brazil
Ruschel Medicina e Pesquisa Clínica Ltda — Rio de Janeiro, Brazil
C J S Carvalho & Carvalho LTDA (Viver - Centro De Desospitalizacao Humana) — São Paulo, Brazil
BR Trials — São Paulo, Brazil
State Psychiatric Hospital Kardzhali — Kardzhali, Bulgaria
UMHAT 'Dr. Georgi Stranski', EAD — Pleven, Bulgaria
Mental Health Center - Plovdiv — Plovdiv, Bulgaria
Mental Health Center - Rousse — Rousse, Bulgaria
Multiprofile Hospital for Active Treatment in Neurology and Psychiatry Sveti Naum — Sofia, Bulgaria
MHC - Sofia, EOOD — Sofia, Bulgaria
Centre for Mental Health Prof.N.Shipkovenski EOOD — Sofia, Bulgaria
University Multiprofile Hospital for Active Treatment - UMHAT Alexandrovska EAD — Sofia, Bulgaria
Psychiatricka ambulance Saint Anne s.r.o. — Brno, Czechia
Psychiatricka ambulance, MUDr. Marta Holanova — Brno, Czechia
NeuropsychiatrieHK, s.r.o. — Hradec Kralove-Vekose, Czechia
A Shine S R O — Pilsen, Czechia
Clintrial s r o — Prague, Czechia
AD71 s.r.o. — Prague, Czechia
Medical Services Prague S R O — Prague, Czechia
Institut Neuropsychiatricke pece — Prague, Czechia
Aalborg University Hospital — Aalborg, Denmark
Psykiatrien i Region Syddanmark — Esbjerg N, Denmark
Mederon LTD at ARTES — Helsinki, Finland
Psykiatrinen Palvelukeskus Solvum Oy — Helsinki, Finland
Savon Psykiatripalvelu — Kuopio, Finland
Universitaetsklinikum der RWTH Aachen — Aachen, Germany
Rheinhessen Fachklinik Alzey — Alzey, Germany
Emovis GmbH — Berlin, Germany
Charite Campus Benjamin Franklin — Berlin, Germany
Medizinisches Versorgungszentrum LiO GmbH — Berlin, Germany
Alexander Schulze - Germany — Berlin, Germany
Praxis Dr. med. Kirsten Hahn — Berlin, Germany
Vivantes Klinikum Spandau — Berlin, Germany
Universitatsklinikum Bonn — Bonn, Germany
Klinikum Chemnitz gGmbH — Chemnitz, Germany
Carl-Thiem-Klinikum Cottbus gGmbH — Cottbus, Germany
Klinikum Dortmund gGmbH — Dortmund, Germany
Universitatsklinikum Carl Gustav Carcus Dresden — Dresden, Germany
Universitatsklinikum Frankfurt — Frankfurt am Main, Germany
Universitätsklinikum Freiburg - Abteilung für Psychiatrie u. Psychotherapie mit Poliklinik — Freiburg im Breisgau, Germany
SRH Waldklinikum Gera GmbH — Gera, Germany
Georg August Universitat Universitatsmedizin Gottingen — Göttingen, Germany
Evangelisches Krankenhaus Bethanien gGmbH — Greifswald, Germany
Universitaetsklinik Hamburg-Eppendorf — Hamburg, Germany
Klinische Forschung Hamburg — Hamburg, Germany
Klinische Forschung Hannover-Mitte GmbH — Hanover, Germany
Medizinische Hochschule Hannover — Hanover, Germany
Universität Heidelberg — Heidelberg, Germany
Oberhavel Kliniken GmbH — Hennigsdorf, Germany
Universitätsklinikum des Saarlandes — Homburg, Germany
Universitatsklinikum Jena — Jena, Germany
Panakeia - Arzneimittelforschung GmbH — Leipzig, Germany
Universitaetsklinikum Magdeburg A.oe.R — Magdeburg, Germany
Universitatsmedizin der Johannes Gutenberg Universitat Mainz — Mainz, Germany
Pharmakologisches Studienzentrum Chemnitz GmbH — Mittweida, Germany
Universitatsklinikum Munster — Münster, Germany
Ruppiner Kliniken — Neuruppin, Germany
Praxis Prof. Steinwachs — Nuremberg, Germany
Johanniter Krankenhaus Oberhausen — Oberhausen, Germany
Danuvius Klinik Pfaffenhofen Fachklinik für Psychiatrie, Psychotherapie und Psychosomatik — Pfaffenhofen, Germany
Somni Bene GmbH — Schwerin, Germany
Klinische Forschung Schwerin GmbH — Schwerin, Germany
Klinikum der Hansestadt Stralsund GmbH-Ambulanz-Klinik für Psychiatrie und Psychotherapie - Germany — Stralsund, Germany
Aiginition Hospital of Athens — Athens, Greece
'Dafni' Psychiatric Hospital of Attica — Athens, Greece
Venizeleio General Hospital — Crete, Greece
Psychiatric Clinic 'Agios Charalampos' — Heraklion, Greece
University General Hospital of Ioannina — Ioannina, Greece
University General Hospital of Rio Patras — Pátrai, Greece
424 Military Hospital of Thessaloniki — Thessaloniki, Greece
Psychiatric Hospital of Thessaloniki — Thessaloniki, Greece
G Papanikolaou Hospital of Thessaloniki — Thessaloniki, Greece
Semmelweis Egyetem — Budapest, Hungary
Eszak Kozep budai Centrum Uj Szent Janos Korhaz es Szakrendelo Budai Csaladkozpontu — Budapest, Hungary
Processus Kft — Budapest, Hungary
Debreceni Egyetem, Kenézy Gyula Egyetemi Oktatókórház — Debrecen, Hungary
Bugat Pal Korhaz — Gyöngyös, Hungary
Petz Aladar Megyei Oktato Korhaz — Győr, Hungary
Bács-Kiskun Megyei Kórház a Szegedi Tudományegyetem Általános Orvostudományi Kar Oktató Kórháza — Kalocsa, Hungary
Szabolcs-Szatmar-Bereg Megyei Korhazak es Egyetemi Oktatokorhaz — Nyíregyháza, Hungary
Pecsi Tudomanyegyetem Klinikai Kozpont — Pécs, Hungary
Rambam Medical Center — Haifa, Israel
Shalvata Mental Health Center — Hod HaSharon, Israel
Beer Yaakov Mental Health Center — Lod, Israel
Geha Mental Health Center — Petah Tikva, Israel
Sheba Medical Center — Ramat Gan, Israel
Tel Aviv Sourasky Medical Center — Telaviv, Israel
Republican Scientific and Practical Center of Mental Health — Almaty, Kazakhstan
Medical Center for Psychological Healt SME — Nur-Sultan, Kazakhstan
East-Kazakhstan Regional Centre of Mental Health — Ust-Kamenogorsk, Kazakhstan
Hospital Raja Permaisuri Bainun — Ipoh, Malaysia
Hospital Kuala Lumpur — Kuala Lumpur, Malaysia
University Malaya Medical Centre — Kuala Lumpur, Malaysia
Hospital Pengajar Universiti Putra Malaysia — Serdang, Malaysia
Hospital Tuanku Jaafar — Seremban, Malaysia
Brain Research Center — Amsterdam, Netherlands
AMC — Amsterdam, Netherlands
LUMC — Leiden, Netherlands
Haukeland University Hospital — Hordaland, Norway
Sykehuset Ostfold — Moss, Norway
St Olav University Hospital — Trondheim, Norway
Mlynowamed Specjalistyczny Psychiatryczny Gabinet Lekarski Joanna Lazarczyk — Bialystok, Poland
Osrodek Badan Klinicznych CLINSANTE S C — Bydgoszcz, Poland
Uniwersyteckie Centrum Kliniczne — Gdansk, Poland
Centrum Badan Klinicznych PI House sp z o o — Gdansk, Poland
Centrum Medyczne Care Clinic Katowice — Katowice, Poland
Niepubliczny Zaklad Opieki Psychiatrycznej MENTIS — Leszno, Poland
Specjalistyczny Psychiatryczny Zespol Opieki Zdrowotnej w Lodzi Szpital im. J. Babinskiego — Lodz, Poland
SPZOZ CSK UM w Lodzi Klinika Zaburzen Afektywnych i Psychotycznych — Lodz, Poland
Centrum Medyczne Luxmed Sp z o o — Lublin, Poland
Osrodek Badan Klinicznych CLINSANTE S C — Torun, Poland
Hospital de Braga — Braga, Portugal
Centro Hospitalar do Tâmega e Sousa, EPE - Hospital Padre Americo, Vale do Sousa — Guilhufe - Penafiel, Portugal
Hosp. Cuf Tejo — Lisbon, Portugal
Fund. Champalimaud — Lisbon, Portugal
Centro Hospitalar de Lisboa Norte Hospital Santa Maria — Lisbon, Portugal
Uls Loures Odivelas - Hosp. Loures — Loures, Portugal
Cape Town Clinical Research Centre — Cape Town, South Africa
Flexivest 14 Research — Cape Town, South Africa
Gert Bosch Pretoria South Africa — Garsfontein, South Africa
Chonnam National University Hospital — Gwangju, South Korea
Wonkwang University Hospital — Iksan, South Korea
KyungHee University Hospital — Seoul, South Korea
Korea University Anam Hospital — Seoul, South Korea
Severance Hospital Yonsei University Health System — Seoul, South Korea
Samsung Medical Center — Seoul, South Korea
Psykiatriska kliniken — Gothenburg, Sweden
Affecta Pskyiatrimottagning — Halmstad, Sweden
Psykiatriska kliniken — Luleå, Sweden
ProbarE i Lund AB — Lund, Sweden
ONE LIFETIME Lakarmottagning — Skövde, Sweden
ProbarE i Stockholm AB — Stockholm, Sweden
Changhua Christian Hospital — Changhua, Taiwan
Hualien Tzu Chi Hospital — Hualien City, Taiwan
Kai-Syuan Psychiatric Hospital — Kaohsiung City, Taiwan
Chang Gung Memorial Hospital — Kaohsiung City, Taiwan
National Cheng Kung University Hospital — Tainan, Taiwan
National Taiwan University Hospital — Taipei, Taiwan
Mackay Memorial Hospital — Taipei, Taiwan
Taipei Medical University — Taipei, Taiwan
Taipei Veterans General Hospital — Taipei, Taiwan
Chang Gung Memorial Hospital — Taoyuan District, Taiwan
Hacettepe University Medical Faculty — Ankara, Turkey (Türkiye)
Bursa Yuksek Ihtisas Training and Research Hospital — Bursa, Turkey (Türkiye)
Uludag University Medical Faculty — Bursa, Turkey (Türkiye)
Bakirkoy Mental Health Training and Research Hospital — Istanbul, Turkey (Türkiye)
Erenkoy Mental Health Hospital — Istanbul, Turkey (Türkiye)
Uskudar University Neuropsychiatry Hospital — Istanbul, Turkey (Türkiye)
Ege Universitesi Tip Fakultesi — Izmir, Turkey (Türkiye)
Selcuk University Medical Faculty — Konya, Turkey (Türkiye)
Liv Hospital — Samsun, Turkey (Türkiye)
Namik Kemal University — Tekirdağ, Turkey (Türkiye)
American Center for Psychiatry and Neurology — Abu Dhabi, United Arab Emirates