A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression (SUSTAIN-1)

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

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.

Study Overview

• Status: Completed
• Conditions: Depressive Disorder, Treatment-Resistant
• Intervention / Treatment: Drug: Duloxetine (Oral Antidepressant); Drug: Esketamine; Drug: Escitalopram (Oral antidepressant); Drug: Sertraline (Oral Antidepressant); Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant); Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 719
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium
  • Brugge, Belgium
  • Brussel, Belgium
  • Heusden-Zolder, Belgium
  • Liège, Belgium
  • Yvoir, Belgium
• Brazil
  • Belo Horizonte, Brazil
  • Curitiba, Brazil
  • Fortaleza, Brazil
  • Goiania, Brazil
  • Itapira, Brazil
  • Passo Fundo, Brazil
  • Porto Alegre, Brazil
  • Rio de Janeiro, Brazil
  • Santo André, Brazil
  • Sao Jose do Rio Preto, Brazil
  • São Paulo, Brazil
• Canada
  • Alberta
    • Calgary, Alberta, Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
  • Ontario
    • Kingston, Ontario, Canada
    • Ottawa, Ontario, Canada
    • Toronto, Ontario, Canada
  • Quebec
    • Montreal, Quebec, Canada
• Czechia
  • Brno, Czechia
  • Hostivice, Czechia
  • Klecany, Czechia
  • Kutna Hora, Czechia
  • Litomerice, Czechia
  • Plzen, Czechia
  • Prague, Czechia
  • Praha 1, Czechia
  • Praha 10, Czechia
  • Praha 2, Czechia
  • Praha 6, Czechia
  • Strakonice 1, Czechia
• Estonia
  • Parnu, Estonia
  • Tallinn, Estonia
  • Tartu, Estonia
• France
  • Clermont Ferrand, France
  • Douai, France
  • Nantes, France
  • Nimes Cedex 9, France
  • Paris, France
  • Poitiers, France
  • Toulon, France
• Germany
  • Berlin, Germany
  • Cham, Germany
  • Gelsenkirchen, Germany
  • Halle (Saale), Germany
  • Mainz, Germany
  • Mittweida, Germany
  • Pfaffenhofen, Germany
  • Prien, Germany
• Hungary
  • Balassagyarmat, Hungary
  • Budapest, Hungary
  • Debrecen, Hungary
  • Gyor, Hungary
  • Pecs, Hungary
  • Sopron, Hungary
  • Szeged, Hungary
  • Szekszárd, Hungary
  • Vác, Hungary
• Mexico
  • Guadalajara, Mexico
  • Leon, Mexico
  • Mexico City, Mexico
  • Monterrey, Mexico
  • San Luis Potosi, Mexico
  • San Luis Potosí, Mexico
• Poland
  • Belchatow, Poland
  • Bialystok, Poland
  • Bydgoszcz, Poland
  • Gdansk, Poland
  • Leszno, Poland
  • Lodz, Poland
  • Lublin, Poland
  • Pruszkow, Poland
  • Torun, Poland
  • Tuszyn, Poland
  • Warszawa, Poland
• Slovakia
  • Bratislava, Slovakia
  • Liptovsky Mikulas, Slovakia
  • Rimavska Sobota, Slovakia
  • Roznava, Slovakia
  • Svidnik, Slovakia
• Spain
  • Alcorcón, Spain
  • Barcelona, Spain
  • Palma, Spain
  • Pamplona, Spain
  • Ponferrada, Spain
  • Sabadell, Spain
  • Salamanca, Spain
  • Vitoria Gasteiz, Spain
• Sweden
  • Lund, Sweden
  • Skovde, Sweden
  • Solna, Sweden
  • Stockholm, Sweden
• Turkey
  • Adana, Turkey
  • Ankara, Turkey
  • Bursa, Turkey
  • Denizli, Turkey
  • Istanbul, Turkey
  • Izmir, Turkey
  • Kucukcekmece/Istanbul, Turkey
  • Manisa, Turkey
  • Oanakkale, Turkey
  • Sakarya, Turkey
  • Samsun, Turkey
• United States
  • Alabama
    • Birmingham, Alabama, United States
  • Arkansas
    • Little Rock, Arkansas, United States
  • California
    • 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
  • Connecticut
    • Hartford, Connecticut, United States
  • Florida
    • Bradenton, Florida, United States
    • Gainesville, Florida, United States
    • Miami, Florida, United States
    • Orlando, Florida, United States
    • Tampa, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
  • Illinois
    • 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
  • Kansas
    • Prairie Village, Kansas, United States
    • Wichita, Kansas, United States
  • Louisiana
    • Lake Charles, Louisiana, United States
  • Maryland
    • Baltimore, Maryland, United States
    • Gaithersburg, Maryland, United States
  • Massachusetts
    • Boston, Massachusetts, United States
    • New Bedford, Massachusetts, United States
    • Quincy, Massachusetts, United States
    • Watertown, Massachusetts, United States
    • Worcester, Massachusetts, United States
  • Michigan
    • Rochester Hills, Michigan, United States
  • Minnesota
    • Minneapolis, Minnesota, United States
  • Missouri
    • O'Fallon, Missouri, United States
    • Saint Charles, Missouri, United States
  • Nebraska
    • Omaha, Nebraska, United States
  • New York
    • New York, New York, United States
  • North Carolina
    • Durham, North Carolina, United States
    • Hickory, North Carolina, United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
  • Pennsylvania
    • Media, Pennsylvania, United States
    • Philadelphia, Pennsylvania, United States
    • Scranton, Pennsylvania, United States
  • Rhode Island
    • Lincoln, Rhode Island, United States
    • Providence, Rhode Island, United States
  • Texas
    • Arlington, Texas, United States
    • Austin, Texas, United States
    • Dallas, Texas, United States
    • Houston, Texas, United States
  • Virginia
    • Charlottesville, Virginia, United States
  • Wisconsin
    • Waukesha, Wisconsin, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	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).; Drug: 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.; 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.; 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.; 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.
Experimental: 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.	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).; 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.; 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.; 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.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Relapse in Participants With Stable Remission (Maintenance Phase)	Relapse is defined as any of following: Montgomery-asberg depression rating scale (MADRS) total score greater than or equal to (>=) 22 for 2 consecutive assessments separated by 5-15 days and/or hospitalization for worsening depression or any other clinically relevant event to be suggestive of a relapse of depressive illness such as suicide attempt/completed suicide/hospitalization for suicide prevention; If hospitalized, start date of hospitalization will be date of relapse, if not hospitalized date of event will be used. MADRS: clinician-rated scale to measure depression severity and to detect changes due to antidepressant treatment. It has 10 items, scored from 0-6 (not present/normal-severe/continuous symptoms), with total score of 60. Higher scores mean more severe condition. Stable remission: MADRS total score less than or equal to (<=) 12 for at least 3 of last 4 weeks of OP phase, with 1 excursion total score greater than (>) 12 or one missing assessment at OP week 13 or 14.	Time from randomization to the first relapse during the maintenance phase (up to 92 Weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Relapse in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)	Relapse is defined as any of following: MADRS total score >= 22 for 2 consecutive assessments separated by 5-15 days and/or hospitalization for worsening depression or any other clinically relevant event to be suggestive of a relapse of depressive illness such as suicide attempt/completed suicide/hospitalization for suicide prevention; If hospitalized, start date of hospitalization will be date of relapse, if not hospitalized date of event will be used. MADRS: clinician-rated scale to measure depression severity and to detect changes due to antidepressant treatment. It has 10 items, scored from 0-6 (not present/normal-severe/continuous symptoms), with total score of 60. Higher scores mean more severe condition. Stable response is defined as >= 50 percent (%) reduction in MADRS total score from baseline (Day 1 of induction phase, prior to first intranasal dose) in each of the last 2 weeks of the OP phase, but without meeting criteria for stable remission.	Time from randomization to the first relapse during the maintenance phase (up to 92 Weeks)
Change From Baseline in MADRS Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)	MADRS: clinician-rated scale to measure depression severity and to detect changes due to antidepressant treatment. It has 10 items, scored from 0-6 (not present/normal - severe/continuous symptoms), with total score of 60. Higher scores mean more severe condition. The change from baseline in MADRS total score (last observation carried forward [LOCF] data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in MADRS Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)	MADRS: clinician-rated scale to measure depression severity and to detect changes due to antidepressant treatment. It has 10 items, scored from 0-6 (not present/normal - severe/continuous symptoms), with total score of 60. Higher scores mean more severe condition. The change from baseline in MADRS total score (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)	PHQ-9 is a 9-item, self-report scale assessing 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). The change from baseline in PHQ-9 total score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in PHQ-9 Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)	PHQ-9 is a 9-item, self-report scale assessing 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). The change from baseline in PHQ-9 total score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint in Participants With Stable Remission (Maintenance Phase)	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 0 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 0=not assessed; 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 patients. The change from baseline in CGI-S score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in Clinical Global Impression-Severity Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)	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 0 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 0=not assessed; 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 patients. The change from baseline in CGI-S score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in Generalized Anxiety Disorder-7 Items (GAD-7) Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)	GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21). Item responses are summed to yield a total score (range of 0 to 21), with higher scores indicating more anxiety. The change from baseline in GAD-7 total score, (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)
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)	GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21). Item responses are summed to yield a total score (range of 0 to 21), with higher scores indicating more anxiety. The change from baseline in GAD-7 total score, (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Sum Score at Endpoint in Participants With Stable Remission (Maintenance Phase)	EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a Health Status Index (HSI). HSI ranges from 0 (dead) to 1.00 (full health). 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). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) *5. Higher score indicates worst health state.	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in EQ Visual Analogue Scale Score at Endpoint in Participants With Stable Remission (Maintenance Phase)	EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine).	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in EQ-5D-5L Health Status Index at Endpoint in Participants With Stable Remission (Maintenance Phase)	EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a HSI. HSI ranges from 0 (dead) to 1.00 (full health).	Baseline and Endpoint (Up to 92 Weeks)
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)	EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a HSI. HSI ranges from 0 (dead) to 1.00 (full health). 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). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) *5. Higher score indicates worst health state.	Baseline and Endpoint (Up to 92 Weeks)
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)	EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine).	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in EQ-5D-5L Health Status Index at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)	EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a HSI. HSI ranges from 0 (dead) to 1.00 (full health).	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)	The SDS is a participant-reported outcome measure and is a 5-item questionnaire used and accepted for assessment of functional impairment and associated disability. The first 3 items assess disruption of 1: work/school 2: social life 3: family life/home responsibilities using a 0-10 rating scale. It also has one item on days lost from school or work and one item on days when underproductive. The score for the first 3 items are summed to create a total score of 0-30 where a higher score indicates greater impairment. The recall period is 7 days. Scores <= 4 for each item and <= 12 for the total score are considered response. Scores <= 2 for each item and <= 6 for the total score are considered remission. The change from baseline in SDS total Score, (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)
Change From Baseline in Sheehan Disability Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)	The SDS is a participant-reported outcome measure and is a 5-item questionnaire used and accepted for assessment of functional impairment and associated disability. The first 3 items assess disruption of 1: work/school 2: social life 3: family life/home responsibilities using a 0-10 rating scale. It also has one item on days lost from school or work and one item on days when underproductive. The score for the first 3 items are summed to create a total score of 0-30 where a higher score indicates greater impairment. The recall period is 7 days. Scores <= 4 for each item and <= 12 for the total score are considered response. Scores <= 2 for each item and <= 6 for the total score are considered remission. The change from baseline in SDS total Score, (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.	Baseline and Endpoint (Up to 92 Weeks)

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Investigators: Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): February 15, 2018
• Study Completion (Actual): February 16, 2018

Study Registration Dates

• First Submitted: May 13, 2015
• First Submitted That Met QC Criteria: July 7, 2015
• First Posted (Estimated): July 10, 2015

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

• Keywords: Relapse prevention; Placebo; Esketamine; Treatment-resistant Depression; Oral Antidepressant
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Disease Attributes; Behavioral Symptoms; Mood Disorders; Recurrence; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Serotonin and Noradrenaline Reuptake Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Sensory System Agents; Analgesics; Neurotransmitter Agents; Membrane Transport Modulators; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Dopamine Agents; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Antidepressive Agents, Second-Generation; Duloxetine Hydrochloride; Esketamine; Venlafaxine Hydrochloride; Escitalopram; Antidepressive Agents; Sertraline
• Other Study ID Numbers: CR107128; ESKETINTRD3003 (Other Identifier: Janssen Research & Development, LLC); 2014-004586-24 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No