Clinical trial NCT02497287: A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression
Official title: An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Treatment-resistant Depression
Keywords: Treatment-resistant Depression
Esketamine
Oral Antidepressant
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-07-14
Enrollment: 802
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to End of Follow up Phase (Week 56)
measure: Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders
timeFrame: Up to End of Follow up Phase (Week 56)
measure: Change From Baseline in Cognitive Test Battery: Detection Test (DET) Score
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of Optimization/Maintenance [OP/MA] Phase)
measure: Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
measure: Change From Baseline in Cognitive Test Battery: One Card Learning Test (OCL) Score
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
measure: Change From Baseline in Cognitive Test Battery: One Back Test (ONB) Score
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
measure: Change From Baseline in Cognitive Test Battery: Groton Maze Learning Test (GMLT) Score
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
measure: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Total Recall
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
measure: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Delayed Recall
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
measure: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Number of Words Recalled
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
measure: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Recognition Discrimination Index
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Secondary outcomes:
measure: Change From Baseline to Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score During Induction (IND) Phase
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
measure: Change From Baseline to Endpoint in MADRS Total Score During Optimization/Maintenance (OP/MA) Phase
timeFrame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
measure: Change From Baseline to Endpoint in Patient Health Questionnaire - 9 (PHQ-9) Total Score During IND Phase
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
measure: Change From Baseline to Endpoint in PHQ-9 Total Score During OP/MA Phase
timeFrame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
measure: Change From Baseline to Endpoint in Clinical Global Impression of Severity (CGI-S) Scale Score During IND Phase
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
measure: Change From Baseline to Endpoint in CGI-S Scale Score During OP/MA Phase
timeFrame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
measure: Change From Baseline to Endpoint in Generalized Anxiety Disorder (GAD-7) Total Score During IND Phase
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
measure: Change From Baseline to Endpoint in GAD-7 Total Score During OP/MA Phase
timeFrame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
measure: Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During IND Phase: Sum Score
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
measure: Change From Baseline to Endpoint in EQ-5D-5L Score During IND Phase: EQ-VAS
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
measure: Change From Baseline to Endpoint in EQ-5D-5L Scale Score During IND Phase: Health Status Index
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
measure: Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During OP/MA Phase: Sum Score
timeFrame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
measure: Change From Baseline to Endpoint in EQ-5D-5L Score During OP/MA Phase: EQ-VAS
timeFrame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
measure: Change From Baseline to Endpoint in EQ-5D-5L Scale Score During OP/MA Phase: Health Status Index
timeFrame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
measure: Change From Baseline in Sheehan Disability Scale (SDS) Total Score During IND Phase
timeFrame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND Phase)
measure: Change From Baseline in Sheehan Disability Scale Total Score During OP/MA Phase
timeFrame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
measure: Percentage of Participants With Response as Assessed by MADRS Total Score During IND Phase
timeFrame: Days 8, 15, 22 and Endpoint (last post-baseline assessment during 4 weeks of IND phase)
measure: Percentage of Participants With Response as Assessed by PHQ-9 Total Score During IND Phase
timeFrame: Day 15 and Endpoint (last post-baseline assessment value during 4 Week IND phase)
measure: Percentage of Participants With Remission as Assessed by MADRS Total Score During IND Phase
timeFrame: Days 8, 15, 22 and Endpoint (last post-baseline assessment value during 4 weeks of IND Phase)
measure: Percentage of Participants With Remission as Assessed by PHQ-9 Total Score During IND Phase
timeFrame: Day 15 and Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
measure: Percentage of Participants With an Increase Score From Predose at Any Time in Clinician-Administered Dissociative States Scale (CADSS) Total Score During IND Phase
timeFrame: Predose, up to 1.5 hours postdose (up to end of IND phase [Week 4])
measure: Percentage of Participants With an Increase Score From Predose at Any Time in CADSS Total Score During OP/MA Phase
timeFrame: Predose, up to 1.5 hours postdose (up to end of OP/MA phase [Week 52])
measure: Percentage of Participants With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases
timeFrame: Up to End of OP/MA phase (Week 52)
Other outcomes:
Locations:
city: New Haven
country: United States
state: Connecticut
city: Miami
country: United States
state: Florida
city: Marietta
country: United States
state: Georgia
city: Iowa City
country: United States
state: Iowa
city: Wichita
country: United States
state: Kansas
city: Baltimore
country: United States
state: Maryland
city: Watertown
country: United States
state: Massachusetts
city: Cedarhurst
country: United States
state: New York
city: New York
country: United States
state: New York
city: Staten Island
country: United States
state: New York
city: Cincinnati
country: United States
state: Ohio
city: Allentown
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Dallas
country: United States
state: Texas
city: Wichita Falls
country: United States
state: Texas
city: Richland
country: United States
state: Washington
city: Banfield
country: Argentina
city: Buenos Aires
country: Argentina
city: Ciudad Autonoma de Buenos Aires
country: Argentina
city: Cordoba
country: Argentina
city: La Plata
country: Argentina
city: Mendoza
country: Argentina
city: Rosario
country: Argentina
city: Adelaide
country: Australia
city: Caulfield
country: Australia
city: Frankston
country: Australia
city: Melbourne
country: Australia
city: Innsbruck
country: Austria
city: Vienna
country: Austria
city: Brugge
country: Belgium
city: Hasselt
country: Belgium
city: Belo Horizonte
country: Brazil
city: Fortaleza
country: Brazil
city: Recife
country: Brazil
city: Rio de Janeiro
country: Brazil
city: Santo André
country: Brazil
city: Sao Jose do Rio Preto
country: Brazil
city: São Paulo
country: Brazil
city: Bourgas
country: Bulgaria
city: Kardzhali
country: Bulgaria
city: Kazanlak
country: Bulgaria
city: Pazardzhik
country: Bulgaria
city: Pleven
country: Bulgaria
city: Plovdiv
country: Bulgaria
city: Rousse
country: Bulgaria
city: Sofia
country: Bulgaria
city: Varna
country: Bulgaria
city: Helsinki
country: Finland
city: Kuopio
country: Finland
city: Paris
country: France
city: Poitiers
country: France
city: Toulon
country: France
city: TOURS cedex 9
country: France
city: Berlin
country: Germany
city: Bochum
country: Germany
city: Oranienburg-Sachsenhausen
country: Germany
city: Gwangju
country: Korea, Republic of
city: Gyeonggi-do
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Kaunas
country: Lithuania
city: Silute
country: Lithuania
city: Vilnius
country: Lithuania
city: Ipoh
country: Malaysia
city: Johor Bahru
country: Malaysia
city: Kuala Lumpur
country: Malaysia
city: Acapulco
country: Mexico
city: Durango
country: Mexico
city: Mexico City
country: Mexico
city: Mexico
country: Mexico
city: Monterrey
country: Mexico
city: Gdansk
country: Poland
city: Cape Town
country: South Africa
city: Garsfontein
country: South Africa
city: Pretoria
country: South Africa
city: Badajoz
country: Spain
city: Bilbao
country: Spain
city: Madrid
country: Spain
city: Ourense
country: Spain
city: Oviedo
country: Spain
city: Sant Boi de Llobregat
country: Spain
city: Torrevieja
country: Spain
city: Valencia
country: Spain
city: Zamora
country: Spain
city: Goteborg
country: Sweden
city: Halmstad
country: Sweden
city: Lund
country: Sweden
city: Skovde
country: Sweden
city: Solna
country: Sweden
city: Stockholm
country: Sweden
city: Umea
country: Sweden
city: Kaohsiung
country: Taiwan
city: New Taipei City
country: Taiwan
city: Taichung
country: Taiwan
city: Tainan
country: Taiwan
city: Taipei
country: Taiwan
city: Taoyuan County
country: Taiwan
city: Ankara
country: Turkey
city: Bursa
country: Turkey
city: Gaziantep
country: Turkey
city: Istanbul
country: Turkey
city: Kocaeli
country: Turkey
city: Manisa
country: Turkey
city: Bristol
country: United Kingdom
city: Chesterfield
country: United Kingdom
city: Derby
country: United Kingdom
city: London
country: United Kingdom
city: Middlesbrough
country: United Kingdom
city: Northampton
country: United Kingdom
city: Oxford
country: United Kingdom
city: Preston
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Williamson DJ, Gogate JP, Kern Sliwa JK, Manera LS, Preskorn SH, Winokur A, Starr HL, Daly EJ. Longitudinal Course of Adverse Events With Esketamine Nasal Spray: A Post Hoc Analysis of Pooled Data From Phase 3 Trials in Patients With Treatment-Resistant Depression. J Clin Psychiatry. 2022 Sep 19;83(6):21m14318. doi: 10.4088/JCP.21m14318.
citation: 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.
citation: 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.
citation: 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.