Clinical trial NCT02493868: A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression
Official title: A Randomized, Double-blind, Multicenter, Active-Controlled Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Treatment-resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Depressive Disorder, Treatment-Resistant
Keywords: Treatment-resistant Depression
Esketamine
Placebo
Oral Antidepressant
Relapse prevention
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-07-10
Enrollment: 719
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the efficacy of intranasal esketamine plus an oral antidepressant compared with an oral antidepressant (active comparator) plus intranasal placebo in delaying relapse of depressive symptoms in participants with treatment-resistant depression (TRD) who are in stable remission after an induction and optimization course of intranasal esketamine plus an oral antidepressant.

Detailed description: This is a randomized, double-blind (neither the researchers nor the participant know what treatment the participants is receiving), active-controlled, multicenter (more than 1 study site) study in participants with TRD to assess the efficacy of intranasal esketamine plus an oral antidepressant compared with an oral antidepressant (active comparator) plus intranasal placebo in delaying relapse of depressive symptoms. The study will consist of 5 phases: Screening/Prospective Observational Phase (4-7weeks) for direct-entry participants only, Open-label Induction Phase (4-weeks) for direct-entry participants only, Optimization Phase (12-weeks; open-label for direct-entry participants and double-blind for transferred-entry participants), Maintenance Phase (variable duration; double-blind for all participants) and Follow-up Phase (2-weeks). Participants' safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

For Direct-Entry Participants

* At the time of signing the informed consent form (ICF), participant must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than \[\>\]18) to 64 years of age, inclusive - At the start of the screening/prospective observational phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single-episode MDD, the duration must be greater than or equal to \[\>=\] 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (MINI)
* At the start of the screening/prospective observational phase, participant must have an Inventory of Depressive Symptomatology-Clinician rated ( IDS-C30) total score of greater than or equal to (\>=) 34
* At the start of the screening/prospective observational phase, participants must have had nonresponse (less than or equal to 25 percent \[%\] improvement) to greater than or equal to (\>=1) but less than or equal to (\<=) 5 oral antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using the Massachusetts General Hospital (MGH-ATRQ )
* MGH-ATRQ and documented by medical history and pharmacy/prescription records, for the current episode of depression. In addition, the participant is taking different ongoing oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimal therapeutic dose
* The participant's current major depressive episode, depression symptom severity (Week 1 MADRS total score \>=28 required), and treatment response to antidepressant treatments used in the current depressive episode (retrospectively assessed) must be deemed valid for participation in a clinical study based on a Site-Independent Qualification Assessment For Transferred-Entry Participants
* The participant must have completed the double-blind induction phase in ESKETINTRD3001 or ESKETINTRD3002 and must have demonstrated response at the end of that phase (\>=50% reduction in the MADRS total score from baseline \[Day 1 pre-randomization\] at the end of the 4-week double-blind induction phase)

Exclusion Criteria:

* Participants who have previously demonstrated nonresponse of depressive symptoms to esketamine or ketamine in the current major depressive episode, to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (ie, duloxetine, escitalopram, sertraline, and venlafaxine extended release \[XR\]) in the current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT
* Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression
* Participant 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), 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, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
* Participant has homicidal ideation/intent, per the investigator's clinical judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of the screening/prospective observational phase, per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS)
* Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria

Primary outcomes:
measure: Time to Relapse in Participants With Stable Remission (Maintenance Phase)
timeFrame: Time from randomization to the first relapse during the maintenance phase (up to 92 Weeks)
Secondary outcomes:
measure: Time to Relapse in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
timeFrame: Time from randomization to the first relapse during the maintenance phase (up to 92 Weeks)
measure: Change From Baseline in MADRS Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in MADRS Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in PHQ-9 Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in Clinical Global Impression-Severity Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in Generalized Anxiety Disorder-7 Items (GAD-7) Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in Generalized Anxiety Disorder-7 Items Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Sum Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in EQ Visual Analogue Scale Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in EQ-5D-5L Health Status Index at Endpoint in Participants With Stable Remission (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in EuroQol-5 Dimension-5 Level Sum Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in EQ-5D-5L EQ Visual Analogue Scale Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in EQ-5D-5L Health Status Index at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
measure: Change From Baseline in Sheehan Disability Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
timeFrame: Baseline and Endpoint (Up to 92 Weeks)
Other outcomes:
Locations:
city: Birmingham
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state: Arkansas
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state: California
city: Garden Grove
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state: California
city: Oakland
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city: Orange
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city: Wichita
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city: Lake Charles
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state: Louisiana
city: Baltimore
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state: Maryland
city: Gaithersburg
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state: Maryland
city: Boston
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state: Massachusetts
city: New Bedford
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state: Massachusetts
city: Quincy
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state: Massachusetts
city: Watertown
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city: Worcester
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state: Massachusetts
city: Rochester Hills
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state: Michigan
city: Minneapolis
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state: Minnesota
city: O'Fallon
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state: Missouri
city: Saint Charles
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state: Missouri
city: Omaha
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state: Nebraska
city: New York
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state: New York
city: Durham
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state: North Carolina
city: Hickory
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state: North Carolina
city: Oklahoma City
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state: Oklahoma
city: Media
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state: Pennsylvania
city: Philadelphia
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city: Scranton
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state: Pennsylvania
city: Lincoln
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state: Rhode Island
city: Providence
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state: Rhode Island
city: Arlington
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state: Texas
city: Austin
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state: Texas
city: Dallas
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state: Texas
city: Houston
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state: Texas
city: Charlottesville
country: United States
state: Virginia
city: Waukesha
country: United States
state: Wisconsin
city: Aalst
country: Belgium
city: Brugge
country: Belgium
city: Brussel
country: Belgium
city: Heusden-Zolder
country: Belgium
city: Liège
country: Belgium
city: Yvoir
country: Belgium
city: Belo Horizonte
country: Brazil
city: Curitiba
country: Brazil
city: Fortaleza
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city: Goiania
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city: Itapira
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city: Passo Fundo
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city: Rio de Janeiro
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city: Sao Jose do Rio Preto
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city: São Paulo
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city: Calgary
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state: Alberta
city: Vancouver
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state: British Columbia
city: Kingston
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state: Ontario
city: Ottawa
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state: Ontario
city: Toronto
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state: Ontario
city: Montreal
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state: Quebec
city: Brno
country: Czechia
city: Hostivice
country: Czechia
city: Klecany
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city: Kutna Hora
country: Czechia
city: Litomerice
country: Czechia
city: Plzen
country: Czechia
city: Prague
country: Czechia
city: Praha 10
country: Czechia
city: Praha 1
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city: Praha 2
country: Czechia
city: Praha 6
country: Czechia
city: Strakonice 1
country: Czechia
city: Parnu
country: Estonia
city: Tallinn
country: Estonia
city: Tartu
country: Estonia
city: Clermont Ferrand
country: France
city: Douai
country: France
city: Nantes
country: France
city: Nimes Cedex 9
country: France
city: Paris
country: France
city: Poitiers
country: France
city: Toulon
country: France
city: Berlin
country: Germany
city: Cham
country: Germany
city: Gelsenkirchen
country: Germany
city: Halle (Saale)
country: Germany
city: Mainz
country: Germany
city: Mittweida
country: Germany
city: Pfaffenhofen
country: Germany
city: Prien
country: Germany
city: Balassagyarmat
country: Hungary
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Gyor
country: Hungary
city: Pecs
country: Hungary
city: Sopron
country: Hungary
city: Szeged
country: Hungary
city: Szekszárd
country: Hungary
city: Vác
country: Hungary
city: Guadalajara
country: Mexico
city: Leon
country: Mexico
city: Mexico City
country: Mexico
city: Monterrey
country: Mexico
city: San Luis Potosi
country: Mexico
city: San Luis Potosí
country: Mexico
city: Belchatow
country: Poland
city: Bialystok
country: Poland
city: Bydgoszcz
country: Poland
city: Gdansk
country: Poland
city: Leszno
country: Poland
city: Lodz
country: Poland
city: Lublin
country: Poland
city: Pruszkow
country: Poland
city: Torun
country: Poland
city: Tuszyn
country: Poland
city: Warszawa
country: Poland
city: Bratislava
country: Slovakia
city: Liptovsky Mikulas
country: Slovakia
city: Rimavska Sobota
country: Slovakia
city: Roznava
country: Slovakia
city: Svidnik
country: Slovakia
city: Alcorcón
country: Spain
city: Barcelona
country: Spain
city: Palma
country: Spain
city: Pamplona
country: Spain
city: Ponferrada
country: Spain
city: Sabadell
country: Spain
city: Salamanca
country: Spain
city: Vitoria Gasteiz
country: Spain
city: Lund
country: Sweden
city: Skovde
country: Sweden
city: Solna
country: Sweden
city: Stockholm
country: Sweden
city: Adana
country: Turkey
city: Ankara
country: Turkey
city: Bursa
country: Turkey
city: Denizli
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: Kucukcekmece/Istanbul
country: Turkey
city: Manisa
country: Turkey
city: Oanakkale
country: Turkey
city: Sakarya
country: Turkey
city: Samsun
country: Turkey
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Williamson DJ, Gogate JP, Kern Sliwa JK, Manera LS, Preskorn SH, Winokur A, Starr HL, Daly EJ. Longitudinal Course of Adverse Events With Esketamine Nasal Spray: A Post Hoc Analysis of Pooled Data From Phase 3 Trials in Patients With Treatment-Resistant Depression. J Clin Psychiatry. 2022 Sep 19;83(6):21m14318. doi: 10.4088/JCP.21m14318.
citation: Chen G, Chen L, Zhang Y, Li X, Lane R, Lim P, Daly EJ, Furey ML, Fedgchin M, Popova V, Singh JB, Drevets WC. Relationship Between Dissociation and Antidepressant Effects of Esketamine Nasal Spray in Patients With Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2022 Apr 19;25(4):269-279. doi: 10.1093/ijnp/pyab084.
citation: Doty RL, Popova V, Wylie C, Fedgchin M, Daly E, Janik A, Ochs-Ross R, Lane R, Lim P, Cooper K, Melkote R, Jamieson C, Singh J, Drevets WC. Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies. CNS Drugs. 2021 Jul;35(7):781-794. doi: 10.1007/s40263-021-00826-9. Epub 2021 Jul 7.
citation: Katz EG, Hough D, Doherty T, Lane R, Singh J, Levitan B. Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression. Clin Pharmacol Ther. 2021 Feb;109(2):536-546. doi: 10.1002/cpt.2024. Epub 2020 Oct 13.
citation: Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, Lane R, Lim P, Duca AR, Hough D, Thase ME, Zajecka J, Winokur A, Divacka I, Fagiolini A, Cubala WJ, Bitter I, Blier P, Shelton RC, Molero P, Manji H, Drevets WC, Singh JB. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019 Sep 1;76(9):893-903. doi: 10.1001/jamapsychiatry.2019.1189.