A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression

NCT ID: NCT02493868

Last Updated: 2025-04-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 719 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-01
• Study Completion Date: 2018-02-16

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.

Conditions

Depressive Disorder, Treatment-Resistant

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Intranasal Esketamine plus oral antidepressant

Open-Label Induction Phase: Direct-entry participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen in the Open-label Induction Phase. Participants will initiate a new oral antidepressant on Day 1 of this phase. Optimization Phase: Direct-entry and transferred-entry participants will self-administer intranasal esketamine (same dose) at weekly treatment sessions for the first 4 weeks of this phase, then individualized to either once weekly or once every other week based on depressive symptoms. Participants continue same oral antidepressant treatment from induction phase. Maintenance Phase: Direct-entry and transferred-entry participants assigned to esketamine will self-administer intranasal esketamine (same dose) once weekly or once every other week based on depressive symptoms. Participants continue same oral antidepressant treatment from induction phase.

Group Type: EXPERIMENTAL

Esketamine

Intervention Type: DRUG

Open-label induction phase: Direct entry participants start at a dose of 56 mg on Day 1. On Day 4, the dose may be increased to 84 mg or remain at 56 mg. From Day 8 to 22, dose may be increased to 84 mg, remain the same or be reduced to 56 mg from 84 mg per protocol, at investigator's discretion based on efficacy and/or tolerability. On Day 25, a dose reduction from 84 mg to 56 mg is permitted but no dose increase is permitted. Optimization Phase: Direct-entry and transferred-entry participants will self-administer intranasal esketamine (same dose) for first 4 weeks, then individualized to either once weekly or once every other week based on depressive symptoms. Maintenance Phase: All participants assigned to esketamine will self-administer intranasal esketamine once weekly or once every other week based on depressive symptoms.

Duloxetine (Oral Antidepressant)

Intervention Type: DRUG

Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).

Escitalopram (Oral antidepressant)

Intervention Type: DRUG

Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be titrated upto a maximum dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.

Sertraline (Oral Antidepressant)

Intervention Type: DRUG

Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline will be titrated upto a maximum dose of 200 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.

Venlafaxine Extended Release (XR) (Oral Antidepressant)

Intervention Type: DRUG

Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release will be titrated upto a maximum dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day.

Placebo Plus Oral Antidepressant

Optimization Phase: Transferred-entry participants will self-administer intranasal placebo at weekly treatment sessions for the first 4 weeks of this phase, then individualized to either once weekly or once every other week based on depressive symptoms. Participants continue same oral antidepressant treatment from induction phase. Maintenance Phase: Direct-entry and transferred-entry participants assigned to intranasal placebo will self-administer intranasal placebo once weekly or once every other week based on depressive symptoms. Participants continue same oral antidepressant treatment from induction phase.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Optimization Phase: Transferred-entry participant will self-administer intranasal placebo at weekly treatment sessions for the first 4 weeks of this phase, then individualized to either once weekly or once every other week based on depressive symptoms. Maintenance Phase: Direct-entry and transferred-entry participants assigned to placebo will self-administer matching intranasal placebo once weekly or once based on depressive symptoms.

Duloxetine (Oral Antidepressant)

Intervention Type: DRUG

Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).

Escitalopram (Oral antidepressant)

Intervention Type: DRUG

Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be titrated upto a maximum dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.

Sertraline (Oral Antidepressant)

Intervention Type: DRUG

Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline will be titrated upto a maximum dose of 200 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.

Venlafaxine Extended Release (XR) (Oral Antidepressant)

Intervention Type: DRUG

Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release will be titrated upto a maximum dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day.

Interventions

Esketamine

Open-label induction phase: Direct entry participants start at a dose of 56 mg on Day 1. On Day 4, the dose may be increased to 84 mg or remain at 56 mg. From Day 8 to 22, dose may be increased to 84 mg, remain the same or be reduced to 56 mg from 84 mg per protocol, at investigator's discretion based on efficacy and/or tolerability. On Day 25, a dose reduction from 84 mg to 56 mg is permitted but no dose increase is permitted. Optimization Phase: Direct-entry and transferred-entry participants will self-administer intranasal esketamine (same dose) for first 4 weeks, then individualized to either once weekly or once every other week based on depressive symptoms. Maintenance Phase: All participants assigned to esketamine will self-administer intranasal esketamine once weekly or once every other week based on depressive symptoms.

Intervention Type: DRUG

Placebo

Optimization Phase: Transferred-entry participant will self-administer intranasal placebo at weekly treatment sessions for the first 4 weeks of this phase, then individualized to either once weekly or once every other week based on depressive symptoms. Maintenance Phase: Direct-entry and transferred-entry participants assigned to placebo will self-administer matching intranasal placebo once weekly or once based on depressive symptoms.

Intervention Type: DRUG

Duloxetine (Oral Antidepressant)

Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).

Intervention Type: DRUG

Escitalopram (Oral antidepressant)

Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be titrated upto a maximum dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.

Intervention Type: DRUG

Sertraline (Oral Antidepressant)

Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline will be titrated upto a maximum dose of 200 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.

Intervention Type: DRUG

Venlafaxine Extended Release (XR) (Oral Antidepressant)

Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release will be titrated upto a maximum dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Research & Development, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Janssen Research & Development, LLC Clinical Trial

Role: STUDY_DIRECTOR

Janssen Research & Development, LLC

Locations

Birmingham, Alabama, United States

Little Rock, Arkansas, United States

Anaheim, California, United States

Garden Grove, California, United States

Glendale, California, United States

Oakland, California, United States

Orange, California, United States

San Diego, California, United States

San Marcos, California, United States

San Rafael, California, United States

Hartford, Connecticut, United States

Bradenton, Florida, United States

Gainesville, Florida, United States

Miami, Florida, United States

Orlando, Florida, United States

Tampa, Florida, United States

Atlanta, Georgia, United States

Chicago, Illinois, United States

Hoffman Estates, Illinois, United States

Joliet, Illinois, United States

Maywood, Illinois, United States

Schaumburg, Illinois, United States

Skokie, Illinois, United States

Prairie Village, Kansas, United States

Wichita, Kansas, United States

Lake Charles, Louisiana, United States

Baltimore, Maryland, United States

Gaithersburg, Maryland, United States

Boston, Massachusetts, United States

New Bedford, Massachusetts, United States

Quincy, Massachusetts, United States

Watertown, Massachusetts, United States

Worcester, Massachusetts, United States

Rochester Hills, Michigan, United States

Minneapolis, Minnesota, United States

O'Fallon, Missouri, United States

Saint Charles, Missouri, United States

Omaha, Nebraska, United States

New York, New York, United States

Durham, North Carolina, United States

Hickory, North Carolina, United States

Oklahoma City, Oklahoma, United States

Media, Pennsylvania, United States

Philadelphia, Pennsylvania, United States

Scranton, Pennsylvania, United States

Lincoln, Rhode Island, United States

Providence, Rhode Island, United States

Arlington, Texas, United States

Austin, Texas, United States

Dallas, Texas, United States

Houston, Texas, United States

Charlottesville, Virginia, United States

Waukesha, Wisconsin, United States

Aalst, , Belgium

Bruges, , Belgium

Brussels, , Belgium

Heusden-Zolder, , Belgium

Liège, , Belgium

Yvoir, , Belgium

Belo Horizonte, , Brazil

Curitiba, , Brazil

Fortaleza, , Brazil

Goiânia, , Brazil

Itapira, , Brazil

Passo Fundo, , Brazil

Porto Alegre, , Brazil

Rio de Janeiro, , Brazil

Santo André, , Brazil

São José do Rio Preto, , Brazil

São Paulo, , Brazil

Calgary, Alberta, Canada

Vancouver, British Columbia, Canada

Kingston, Ontario, Canada

Ottawa, Ontario, Canada

Toronto, Ontario, Canada

Montreal, Quebec, Canada

Brno, , Czechia

Hostivice, , Czechia

Klecany, , Czechia

Kutná Hora, , Czechia

Litoměřice, , Czechia

Pilsen, , Czechia

Prague, , Czechia

Strakonice, , Czechia

Pärnu, , Estonia

Tallinn, , Estonia

Tartu, , Estonia

Clermont-Ferrand, , France

Douai, , France

Nantes, , France

Nîmes, , France

Paris, , France

Poitiers, , France

Toulon, , France

Berlin, , Germany

Cham, , Germany

Gelsenkirchen, , Germany

Halle, , Germany

Mainz, , Germany

Mittweida, , Germany

Pfaffenhofen, , Germany

Prien am Chiemsee, , Germany

Balassagyarmat, , Hungary

Budapest, , Hungary

Debrecen, , Hungary

Győr, , Hungary

Pécs, , Hungary

Sopron, , Hungary

Szeged, , Hungary

Szekszárd, , Hungary

Vác, , Hungary

Guadalajara, , Mexico

León, , Mexico

Mexico City, , Mexico

Monterrey, , Mexico

San Luis Potosí City, , Mexico

Bełchatów, , Poland

Bialystok, , Poland

Bydgoszcz, , Poland

Gdansk, , Poland

Leszno, , Poland

Lodz, , Poland

Lublin, , Poland

Pruszków, , Poland

Torun, , Poland

Tuszyn, , Poland

Warsaw, , Poland

Bratislava, , Slovakia

Liptovský Mikuláš, , Slovakia

Rimavská Sobota, , Slovakia

Rožňava, , Slovakia

Svidník, , Slovakia

Alcorcón, , Spain

Barcelona, , Spain

Palma, , Spain

Pamplona, , Spain

Ponferrada, , Spain

Sabadell, , Spain

Salamanca, , Spain

Vitoria-Gasteiz, , Spain

Lund, , Sweden

Skövde, , Sweden

Solna, , Sweden

Stockholm, , Sweden

Adana, , Turkey (Türkiye)

Ankara, , Turkey (Türkiye)

Bursa, , Turkey (Türkiye)

Denizli, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Izmir, , Turkey (Türkiye)

Kucukcekmece/Istanbul, , Turkey (Türkiye)

Manisa, , Turkey (Türkiye)

Oanakkale, , Turkey (Türkiye)

Sakarya, , Turkey (Türkiye)

Samsun, , Turkey (Türkiye)

Countries

United States; Belgium; Brazil; Canada; Czechia; Estonia; France; Germany; Hungary; Mexico; Poland; Slovakia; Spain; Sweden; Turkey (Türkiye)

References

Kern Sliwa J, Naranjo RR Jr, Turkoz I, Petrillo MP, Cabrera P, Trivedi M. Effects of esketamine nasal spray on depressive symptom severity in adults with treatment-resistant depression and associations between the Montgomery-Asberg Depression Rating Scale and the 9-item Patient Health Questionnaire. CNS Spectr. 2024 Jun;29(3):176-186. doi: 10.1017/S1092852924000105. Epub 2024 Apr 1.

Reference Type: DERIVED

PMID: 38557430 (View on PubMed)

Castro M, Wilkinson ST, Al Jurdi RK, Petrillo MP, Zaki N, Borentain S, Fu DJ, Turkoz I, Sun L, Brown B, Cabrera P. Efficacy and Safety of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression Who Completed a Second Induction Period: Analysis of the Ongoing SUSTAIN-3 Study. CNS Drugs. 2023 Aug;37(8):715-723. doi: 10.1007/s40263-023-01026-3. Epub 2023 Aug 9.

Reference Type: DERIVED

PMID: 37558912 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36149841 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35022754 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34235612 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32860422 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31166571 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217051&amp;parentIdentifier=CR107128&amp;attachmentIdentifier=d913e5fa-3636-4665-a11c-7b69d8a8df62&amp;fileName=ESKETINTRD3003_(CR107128)_Additional_results_data_CH.pdf&amp;versionIdentifier=

A Randomized, Double-blind, Multicenter, Active-controlled Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Treatment-resistant Depression

Other Identifiers

ESKETINTRD3003

Identifier Type: OTHER

Identifier Source: secondary_id

2014-004586-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CR107128

Identifier Type: -

Identifier Source: org_study_id