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

Depressive Disorder, Treatment-Resistant Clinical Trial

— SUSTAIN-1  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02493868
• Other study ID #: CR107128
• Secondary ID: ESKETINTRD300320
• Status: Completed
• Phase: Phase 3
• Start date: October 1, 2015
• Est. completion date: February 16, 2018

Study information

• Verified date: May 2020
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 719
• Est. completion date: February 16, 2018
• Est. primary completion date: February 15, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

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

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Treatment-Resistant
• Recurrence

Intervention

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.
• 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.
• 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).
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Canada,  Czechia,  Estonia,  France,  Germany,  Hungary,  Mexico,  Poland,  Slovakia,  Spain,  Sweden,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

External Links

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