A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression (SUSTAIN-2)

An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression

The purpose of this open-label, multicenter study is to assess the long term safety and efficacy of intranasal esketamine plus an oral antidepressant in participants with treatment-resistant depression (TRD).

Study Overview

• Status: Completed
• Conditions: Treatment-resistant Depression
• Intervention / Treatment: Drug: Duloxetine (Oral Antidepressant); Drug: Esketamine (Intranasal Spray); Drug: Escitalopram (Oral Antidepressant); Drug: Sertraline (Oral Antidepressant); Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant)

Detailed Description

This is an open-label (the researchers and participants know the treatment the participant is receiving), multicenter (more than 1 study site), long-term safety and efficacy study of intranasal esketamine plus an oral antidepressant in participants with treatment-resistant depression (TRD). Participants will enter the study either directly (direct-entry participants) or after completing the Double-Blind Induction Phase of ESKETINTRD3005 (transferred-entry participants). The study consists of 4 phases: Screening Phase (4 weeks), Open-Label Induction Phase (4 weeks), Open-Label Optimization/Maintenance phase (48 weeks), and Follow up Phase (4 weeks). Transferred entry non-responders in the ESKETINTRD3005 may enter study at the Open-Label Induction Phase and responders in the ESKETINTRD3005 may enter Optimization/Maintenance phase. In the Open-Label Induction Phase, participants will self-administer flexibly-dosed intranasal esketamine (participants who are less than (<) 65 years old self-administer 56 mg or 84 mg dose, participants who are greater than or equal to (>=) 65 years old self-administer 28 mg, 56 mg or 84 mg dose) twice weekly for 4 weeks. The starting dose for all participants >= 65 years old will be 28 mg. In addition, each direct-entry participants will be assigned to receive 1 of 4 selected oral antidepressant medications (escitalopram or sertraline or duloxetine or venlafaxine extended release [XR]), initiated on Day 1 of the open-label induction phase and continued through the duration of the study. Transferred-entry participants will continue their same antidepressant from ESKETINTRD3005 through the duration of this study. Participants who are responders at the end of the Open-Label Induction phase and transferred-entry responder participants (from study ESKETINTRD3005) will enter the Optimization/Maintenance Phase where intranasal esketamine treatment sessions will be reduced from that in the induction phase (twice weekly) to weekly for the first 4 weeks of this phase, and then individualized to either once weekly or once every other week based on the severity of depressive symptoms. Participants' safety and depressive symptoms will be assessed and monitored throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 802
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Banfield, Argentina
  • Buenos Aires, Argentina
  • Ciudad Autonoma de Buenos Aires, Argentina
  • Cordoba, Argentina
  • La Plata, Argentina
  • Mendoza, Argentina
  • Rosario, Argentina
• Australia
  • Adelaide, Australia
  • Caulfield, Australia
  • Frankston, Australia
  • Melbourne, Australia
• Austria
  • Innsbruck, Austria
  • Vienna, Austria
• Belgium
  • Brugge, Belgium
  • Hasselt, Belgium
• Brazil
  • Belo Horizonte, Brazil
  • Fortaleza, Brazil
  • Recife, Brazil
  • Rio de Janeiro, Brazil
  • Santo André, Brazil
  • São José do Rio Preto, Brazil
  • São Paulo, Brazil
• Bulgaria
  • Bourgas, Bulgaria
  • Kardzhali, Bulgaria
  • Kazanlak, Bulgaria
  • Pazardzhik, Bulgaria
  • Pleven, Bulgaria
  • Plovdiv, Bulgaria
  • Rousse, Bulgaria
  • Sofia, Bulgaria
  • Varna, Bulgaria
• Finland
  • Helsinki, Finland
  • Kuopio, Finland
• France
  • Paris, France
  • Poitiers, France
  • TOURS cedex 9, France
  • Toulon, France
• Germany
  • Berlin, Germany
  • Bochum, Germany
  • Oranienburg-Sachsenhausen, Germany
• Korea, Republic of
  • Ansan-si, Korea, Republic of
  • Gwangju, Korea, Republic of
  • Seoul, Korea, Republic of
• Lithuania
  • Kaunas, Lithuania
  • Silute, Lithuania
  • Vilnius, Lithuania
• Malaysia
  • Ipoh, Malaysia
  • Johor Bahru, Malaysia
  • Kuala Lumpur, Malaysia
• Mexico
  • Acapulco, Mexico
  • Durango, Mexico
  • Mexico, Mexico
  • Mexico City, Mexico
  • Monterrey, Mexico
• Poland
  • Gdansk, Poland
• South Africa
  • Cape Town, South Africa
  • Garsfontein, South Africa
  • Pretoria, South Africa
• Spain
  • Badajoz, Spain
  • Bilbao, Spain
  • Madrid, Spain
  • Ourense, Spain
  • Oviedo, Spain
  • Sant Boi de Llobregat, Spain
  • Torrevieja, Spain
  • Valencia, Spain
  • Zamora, Spain
• Sweden
  • Goteborg, Sweden
  • Halmstad, Sweden
  • Lund, Sweden
  • Skovde, Sweden
  • Solna, Sweden
  • Stockholm, Sweden
  • Umea, Sweden
• Taiwan
  • Kaohsiung, Taiwan
  • New Taipei City, Taiwan
  • Taichung, Taiwan
  • Tainan, Taiwan
  • Taipei, Taiwan
  • Taoyuan County, Taiwan
• Turkey
  • Ankara, Turkey
  • Bursa, Turkey
  • Gaziantep, Turkey
  • Istanbul, Turkey
  • Kocaeli, Turkey
  • Manisa, Turkey
• United Kingdom
  • Bristol, United Kingdom
  • Chesterfield, United Kingdom
  • Derby, United Kingdom
  • London, United Kingdom
  • Middlesbrough, United Kingdom
  • Northampton, United Kingdom
  • Oxford, United Kingdom
  • Preston, United Kingdom
• United States
  • Connecticut
    • New Haven, Connecticut, United States
  • Florida
    • Miami, Florida, United States
  • Georgia
    • Marietta, Georgia, United States
  • Iowa
    • Iowa City, Iowa, United States
  • Kansas
    • Wichita, Kansas, United States
  • Maryland
    • Baltimore, Maryland, United States
  • Massachusetts
    • Watertown, Massachusetts, United States
  • New York
    • Cedarhurst, New York, United States
    • New York, New York, United States
    • Staten Island, New York, United States
  • Ohio
    • Cincinnati, Ohio, United States
  • Pennsylvania
    • Allentown, Pennsylvania, United States
  • South Carolina
    • Charleston, South Carolina, United States
  • Texas
    • Dallas, Texas, United States
    • Wichita Falls, Texas, United States
  • Washington
    • Richland, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

A). 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)
• At the start of the screening 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 screening, participant must have a MADRS total score of >=22
• At the start of the screening phase, participants must have had nonresponse to >=2 oral antidepressant treatments in the current episode of depression, as assessed using the the MGHATRQ and confirmed by documented records (example medical/pharmacy/prescription records or a letter from treating a physician, etc,) B). For Transferred-entry Participants
• All participants who completed the double-blind induction phase of ESKETINTRD3005 study, regardless of their response status, will be eligible to participate in this study, if they meet the study specific eligibility criteria

Exclusion Criteria:

A). For Direct-Entry Participants

• Participant's depressive symptoms have previously not responded to: Esketamine or ketamine in the current major depressive episode per clinical judgment or All of the 4 oral antidepressant treatment options available in the respective country for the open-label induction phase (that is, duloxetine, escitalopram, sertraline, and venlafaxine XR) in the current major depressive episode (based on Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire [ MGH-ATRQ])
• 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 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
• Participants who has a Mini Mental State Examination (MMSE) <25; Has neurodegenerative disorder (example, Alzheimer's disease, vascular dementia, Parkinson's disease), or evidence of mild cognitive impairment (MCI) B). Transferred-Entry Participants
• Participant has taken any prohibited therapies that would not permit dosing on Day 1

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intranasal Esketamine plus oral antidepressant; Open-Label Induction Phase: Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen (56 mg or 84 mg). Participants greater than or equal to (>=) 65 will start at a dose of 28 mg on Day 1. Direct-entry participants will initiate a new, open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1; transferred-entry participants will continue the same oral antidepressant from ESKETINTRD3005. Optimization/Maintenance Phase: Participants will self-administer esketamine (56mg or 84mg for those < 65 years; 28 mg, 56 mg or 84 mg for those >= 65 years) intranasally once per week for 4 weeks; transferred entry responder subjects from ESKETINTRD3005 will start at a dose of 28 mg in the first week. All participants will continue their same oral antidepressant during this 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 (Intranasal Spray); Open-Label Induction Phase: Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen (56 mg or 84 mg for those < 65 years; 28 mg, 56 mg or 84 mg for those >= 65 years). Participants >= 65 years old will start at a dose of 28 mg on Day 1. Optimization/Maintenance Phase: Participants will self-administer esketamine intranasally (56 mg or 84 mg for those < 65 years; 28 mg, 56 mg or 84 mg for those >= 65 years) once weekly then individualized to either once weekly or once every other week based on the severity of depressive symptoms. Transferred-entry responder participants from ESKETINTRD3005 >= 65 years old will start at a dose of 28 mg in Week 5.; 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. The minimum therapeutic dose is 10 mg/day. Participants >= 65 years of age will be titrated up to 20 mg/day, but can lower the dose to 10 mg/day for tolerability.; 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 up to a dose of 150 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 for participants < 65 years of age up to a dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day. For participants >= 65, it can be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 75 mg/day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)	An adverse event is any untoward medical occurrence in a clinical study participants who administered a medicinal (investigational or non-investigational) product and does not necessarily have a causal relationship with the treatment. A TEAE defined as an event that was new in onset or increased in severity following treatment initiation.	Up to End of Follow up Phase (Week 56)
Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders	Percentage of participants with cystitis, urinary tract infections, renal and urinary tract symptoms, renal and urinary disorders were evaluated. Cystitis and urinary tract infections are selected MedDRA preferred terms, "renal and urinary tract symptoms" refers to any preferred term (PT) in the group of selected PTs; and "renal and urinary disorders" refers to a MedDRA System Organ Class (SOC).	Up to End of Follow up Phase (Week 56)
Change From Baseline in Cognitive Test Battery: Detection Test (DET) Score	This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. The DET is a measure of psychomotor function and uses a well-validated simple reaction time. In this outcome measure, speed of performance of participants (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Total score ranges from 2 to 3.3 log 10 milliseconds (msec). Lower score indicates better performance. Higher change from baseline indicates better performance.	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of Optimization/Maintenance [OP/MA] Phase)
Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score	This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. IDN test is a measure of visual attention (choice reaction time) and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Total score ranges from 2 to 3.3 log 10 msec. Lower score indicates better performance. Higher change from baseline indicates better performance.	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Change From Baseline in Cognitive Test Battery: One Card Learning Test (OCL) Score	This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses (CR). The range for OCL is 0 to 100 percent (%) accuracy; presented as an arcsin transformation, the range is 0 to 1.57. Higher score indicates better performance. Higher change from baseline indicates better performance.	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Change From Baseline in Cognitive Test Battery: One Back Test (ONB) Score	The ONB is a measure of working memory and scored for speed of correct response (mean of the log10-transformed reaction times for correct responses). Total score ranges from 2 to 3.54 log10 msec. Lower score indicates better performance. Higher change from baseline indicates better performance.	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Change From Baseline in Cognitive Test Battery: Groton Maze Learning Test (GMLT) Score	This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. GMLT measures executive function; maze/sequencing test, scored for total number of errors. Total score ranges from 0 to 999 number of errors. Lower score indicates better performance. Higher change from baseline indicates better performance.	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Total Recall	Hopkins Verbal Learning Test (HVLT) measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Delayed Recall	HVLT measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Number of Words Recalled	HVLT measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Recognition Discrimination Index	HVLT measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score During Induction (IND) Phase	MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using last observation carried forward (LOCF) method, last post baseline observation during the phase was carried forward as the "Endpoint".	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Change From Baseline to Endpoint in MADRS Total Score During Optimization/Maintenance (OP/MA) Phase	MADRS measure depression severity, detects changes due to AD treatment. It evaluates 10 items: apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Change From Baseline to Endpoint in Patient Health Questionnaire - 9 (PHQ-9) Total Score During IND Phase	PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. A higher score indicates greater severity of depression. Severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Change From Baseline to Endpoint in PHQ-9 Total Score During OP/MA Phase	PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. A higher score indicates greater severity of depression. severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Change From Baseline to Endpoint in Clinical Global Impression of Severity (CGI-S) Scale Score During IND Phase	CGI-S measures severity of participant's illness that include knowledge of participant's history, psychosocial circumstances, symptoms, behavior, impact of symptoms on participant's ability to function. CGI-S evaluates severity of psychopathology on a scale range from 0 - 7, where 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. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as "Endpoint".	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Change From Baseline to Endpoint in CGI-S Scale Score During OP/MA Phase	The CGI-S measures the severity of the participant's illness that include 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, where 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. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Change From Baseline to Endpoint in Generalized Anxiety Disorder (GAD-7) Total Score During IND Phase	GAD-7 is brief, validated 7-item self-reported assessment of overall anxiety. Participant's responded to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield total score ranges from 0 to 21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of GAD-7 is categorized as: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Missing data was imputed using LOCF method, last post baseline observation during the phase was carried forward as "Endpoint".	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Change From Baseline to Endpoint in GAD-7 Total Score During OP/MA Phase	GAD-7 is brief and validated 7-item self-reported assessment of overall anxiety. Participants respond to each item using a 4 point scale with response categories: 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 ranges from 0 to 21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During IND Phase: Sum Score	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 -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (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 (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Change From Baseline to Endpoint in EQ-5D-5L Score During IND Phase: EQ-VAS	EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. 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).	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Change From Baseline to Endpoint in EQ-5D-5L Scale Score During IND Phase: Health Status Index	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 -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health).	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During OP/MA Phase: Sum Score	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 Health Status Index (HSI). HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (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 (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Change From Baseline to Endpoint in EQ-5D-5L Score During OP/MA Phase: EQ-VAS	EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. 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).	Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Change From Baseline to Endpoint in EQ-5D-5L Scale Score During OP/MA Phase: Health Status Index	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 -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health).	Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Change From Baseline in Sheehan Disability Scale (SDS) Total Score During IND Phase	SDS was a 5 item questionnaire used for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, (3) family life/home responsibilities using a 0 to 10 rating scale. Score for the first three items are summed to create a total score of 0 to 30, higher score indicates greater impairment and a negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND Phase)
Change From Baseline in Sheehan Disability Scale Total Score During OP/MA Phase	SDS was a participant-reported outcome measure and was a 5 item questionnaire used for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0 to 10 rating scale. The score for the first three items are summed to create a total score of 0 to 30 where a higher score indicates greater impairment and a negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Percentage of Participants With Response as Assessed by MADRS Total Score During IND Phase	Response is defined as greater than or equal to (>=) 50 % reduction from baseline in the MADRS total score. MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Days 8, 15, 22 and Endpoint (last post-baseline assessment during 4 weeks of IND phase)
Percentage of Participants With Response as Assessed by PHQ-9 Total Score During IND Phase	Response is defined as >= 50 % reduction from baseline (IND phase) in PHQ-9 total score. PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The scores are summed for a total score ranging from 0-27. A higher score indicates greater severity of depression. Severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Day 15 and Endpoint (last post-baseline assessment value during 4 Week IND phase)
Percentage of Participants With Remission as Assessed by MADRS Total Score During IND Phase	Remission is defined as MADRS total score less than or equal to (<=) 12. MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Days 8, 15, 22 and Endpoint (last post-baseline assessment value during 4 weeks of IND Phase)
Percentage of Participants With Remission as Assessed by PHQ-9 Total Score During IND Phase	Remission is defined as PHQ-9 total score <= 4. PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The scores are summed for a total score ranging from 0-27. A higher score indicates greater severity of depression. severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the "Endpoint".	Day 15 and Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Percentage of Participants With an Increase Score From Predose at Any Time in Clinician-Administered Dissociative States Scale (CADSS) Total Score During IND Phase	The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = "Not at all", 1 = "Mild", 2 = "Moderate", 3 = 'Severe" and 4 = "Extreme"). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition.	Predose, up to 1.5 hours postdose (up to end of IND phase [Week 4])
Percentage of Participants With an Increase Score From Predose at Any Time in CADSS Total Score During OP/MA Phase	The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = "Not at all", 1 = "Mild", 2 = "Moderate", 3 = 'Severe" and 4 = "Extreme"). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition.	Predose, up to 1.5 hours postdose (up to end of OP/MA phase [Week 52])
Percentage of Participants With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases	Percentage of participants with treatment-emergent acute hypertension (Systolic Blood Pressure >=180 millimeters of mercury [mm Hg] or Diastolic Blood Pressure >= 110 mm Hg) during IND and OP/MA Phases were evaluated.	Up to End of OP/MA phase (Week 52)

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC

Publications and helpful links

General Publications

• 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.
• Ochs-Ross R, Wajs E, Daly EJ, Zhang Y, Lane R, Lim P, Drevets WC, Steffens DC, Sanacora G, Jamieson C, Hough D, Manji H, Singh JB. Comparison of Long-Term Efficacy and Safety of Esketamine Nasal Spray Plus Oral Antidepressant in Younger Versus Older Patients With Treatment-Resistant Depression: Post-Hoc Analysis of SUSTAIN-2, a Long-Term Open-Label Phase 3 Safety and Efficacy Study. Am J Geriatr Psychiatry. 2022 May;30(5):541-556. doi: 10.1016/j.jagp.2021.09.014. Epub 2021 Oct 6.
• Wajs E, Aluisio L, Holder R, Daly EJ, Lane R, Lim P, George JE, Morrison RL, Sanacora G, Young AH, Kasper S, Sulaiman AH, Li CT, Paik JW, Manji H, Hough D, Grunfeld J, Jeon HJ, Wilkinson ST, Drevets WC, Singh JB. Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2). J Clin Psychiatry. 2020 Apr 28;81(3):19m12891. doi: 10.4088/JCP.19m12891.
• Nijs M, Wajs E, Aluisio L, Turkoz I, Daly E, Janik A, Borentain S, Singh JB, DiBernardo A, Wiegand F. Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data. Int J Neuropsychopharmacol. 2020 Jul 29;23(7):426-433. doi: 10.1093/ijnp/pyaa027.

Helpful Links

• An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2015
• Primary Completion (Actual): October 28, 2017
• Study Completion (Actual): October 28, 2017

Study Registration Dates

• First Submitted: May 18, 2015
• First Submitted That Met QC Criteria: July 10, 2015
• First Posted (Estimate): July 14, 2015

Study Record Updates

• Last Update Posted (Actual): May 6, 2020
• Last Update Submitted That Met QC Criteria: April 27, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Esketamine; Treatment-resistant Depression; Oral Antidepressant
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Dopamine Agents; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Sertraline; Duloxetine Hydrochloride; Citalopram; Esketamine; Venlafaxine Hydrochloride; Antidepressive Agents
• Other Study ID Numbers: CR107148; ESKETINTRD3004 (Other Identifier: Janssen Research & Development, LLC); 2014-004587-38 (EudraCT Number)

Drug and device information, study documents

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