A Study of Esketamine Nasal Spray Plus a New Standard-of-care Oral Antidepressant or Placebo Nasal Spray Plus a New Standard-of-care Oral Antidepressant in Adult and Elderly Participants With Treatment-resistant Depression

NCT ID: NCT03852160

Last Updated: 2025-04-27

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE3
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-12-01
• Study Completion Date: 2021-07-25

Brief Summary

The purpose of this study is to evaluate the efficacy of treating participants with treatment-resistant depression (TRD) who have failed at least 2 (and no more than 6) prior antidepressant (AD) treatments in the current moderate to severe depressive episode with flexibly-dosed esketamine nasal spray plus a newly initiated oral standard-of-care AD compared with placebo nasal spray plus a newly-initiated standard-of-care oral AD, in achieving remission and staying relapse-free after remission.

Detailed Description

Depression is a major cause of morbidity and mortality, with global estimates of 300 million treated and untreated individuals worldwide. In its severe forms, depression is the most common diagnosis associated with suicide. Esketamine (S-ketamine) is the S-enantiomer of ketamine. Ketamine profoundly affects fast excitatory glutamate transmission, increases brain-derived neurotrophic factor release, and stimulates synaptogenesis, in contrast to conventional antidepressants (ADs) which are modulatory transmitters. The goal of any new antidepressant (AD) treatment would be the rapid and long-lasting relief of depressive symptoms. The study includes screening phase (2 weeks, with possible extension up to 4 weeks), Induction phase (Week 1 to Week 4), Maintenance once-weekly phase (Week 5 to Week 8), Maintenance flexible-frequency phase (Week 9 to Week 32) and Follow-up phase (2 Weeks Duration). Total duration of study will be approximately up to 36 weeks. The safety will be monitored throughout the study.

Conditions

Depressive Disorder, Treatment-Resistant

Study Design

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

Study Groups

Esketamine + Oral Antidepressants

Participants will receive esketamine as nasal spray (28 milligram \[mg\] \[initial dose for elderly participants 65-74 years of age\] on Day 1 and then uptitrated to 56 mg on Day 4, 56 mg \[initial dose for adult participants aged 18-64 years and may be used for all age groups throughout the study\] or 84 mg \[maximum uptitrated esketamine dose\]) twice-weekly with a flexible dose regimen from Day 1 until Day 28 (Week 4), once weekly from Week 5 to Week 8 and once-weekly or once every other week from Week 9 to Week 32. The dose may be increased/decreased at any visit or may remain the same as determined by the investigator based on efficacy and tolerability. In addition, participants will initiate a new standard-of-care oral anti depressants (AD) (escitalopram, sertraline, duloxetine, agomelatine, mirtazapine, bupropion or trazodone prolonged release) on Day 1, taken daily for the duration of the study.

Group Type: EXPERIMENTAL

Esketamine 28 mg

Intervention Type: DRUG

Participants will receive 28 mg esketamine as nasal spray (Initial dose for elderly participants with 65-74 years of age on Day 1 and then uptitrated to 56 mg on Day 4).

Esketamine 56 mg

Intervention Type: DRUG

Participants will receive 56 mg esketamine as nasal spray (Initial dose for participants with 18-64 years of age) on Day 1. The dose may be increased/may remain same based on the efficacy and tolerability. Participants with 65 to 74 years of age will receive esketamine 56 mg from Day 4 onwards.

Esketamine 84 mg

Intervention Type: DRUG

Participants may receive 84 mg (maximum uptitrated esketamine dose). The dose may be decreased/may remain same based on the efficacy and tolerability.

Escitalopram

Intervention Type: DRUG

Escitalopram can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for escitalopram is 5 mg once daily (for elderly participants) and 10 mg once daily (for adults). The dose may be increased to 10 mg (for elderly participants) and 20 mg (for adults) once daily at the discretion of treating physician/investigator.

Sertraline

Intervention Type: DRUG

Sertraline can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for sertraline is 50 mg once daily and may be increased up to 200 mg once daily.

Duloxetine

Intervention Type: DRUG

Duloxetine can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for duloxetine is 60 mg once daily and may be increased to 120 mg once daily.

Mirtazapine

Intervention Type: DRUG

Mirtazapine can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for mirtazapine is 15 to 30 mg once daily and may be increased to 45 mg once daily.

Agomelatine

Intervention Type: DRUG

Agomelatine can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for agomelatine is 25 mg once daily and may be increased to 50 mg once daily after 2 weeks.

Bupropion

Intervention Type: DRUG

Bupropion can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for bupropion is 150 mg once daily and may be increased to 300 mg once daily after 4 weeks.

Trazodone Prolonged Release

Intervention Type: DRUG

Trazodone prolonged release can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for trazodone prolonged release is 75 to 150 mg once or twice daily and may be increased up to 450 mg (adults) and 300 mg (elderly).

Placebo + Oral Antidepressants

Participants will receive matching placebo as nasal spray twice-weekly with a flexible dose regimen from Day 1 until Day 28 (Week 4), once weekly from Week 5 to Week 8 and once-weekly or once every other week from Week 9 to Week 32. The dose may be increased/decreased at any visit or may remain the same as determined by the investigator based on efficacy and tolerability. In addition, participants will initiate a new standard-of-care oral AD (escitalopram, sertraline, duloxetine, agomelatine, mirtazapine, bupropion or trazodone prolonged release) on Day 1, taken daily for the duration of the study.

Group Type: ACTIVE_COMPARATOR

Placebo

Intervention Type: DRUG

Participants will receive matching placebo as nasal spray.

Escitalopram

Intervention Type: DRUG

Escitalopram can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for escitalopram is 5 mg once daily (for elderly participants) and 10 mg once daily (for adults). The dose may be increased to 10 mg (for elderly participants) and 20 mg (for adults) once daily at the discretion of treating physician/investigator.

Sertraline

Intervention Type: DRUG

Sertraline can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for sertraline is 50 mg once daily and may be increased up to 200 mg once daily.

Duloxetine

Intervention Type: DRUG

Duloxetine can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for duloxetine is 60 mg once daily and may be increased to 120 mg once daily.

Mirtazapine

Intervention Type: DRUG

Mirtazapine can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for mirtazapine is 15 to 30 mg once daily and may be increased to 45 mg once daily.

Agomelatine

Intervention Type: DRUG

Agomelatine can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for agomelatine is 25 mg once daily and may be increased to 50 mg once daily after 2 weeks.

Bupropion

Intervention Type: DRUG

Bupropion can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for bupropion is 150 mg once daily and may be increased to 300 mg once daily after 4 weeks.

Trazodone Prolonged Release

Intervention Type: DRUG

Trazodone prolonged release can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for trazodone prolonged release is 75 to 150 mg once or twice daily and may be increased up to 450 mg (adults) and 300 mg (elderly).

Interventions

Esketamine 28 mg

Participants will receive 28 mg esketamine as nasal spray (Initial dose for elderly participants with 65-74 years of age on Day 1 and then uptitrated to 56 mg on Day 4).

Intervention Type: DRUG

Esketamine 56 mg

Participants will receive 56 mg esketamine as nasal spray (Initial dose for participants with 18-64 years of age) on Day 1. The dose may be increased/may remain same based on the efficacy and tolerability. Participants with 65 to 74 years of age will receive esketamine 56 mg from Day 4 onwards.

Intervention Type: DRUG

Esketamine 84 mg

Participants may receive 84 mg (maximum uptitrated esketamine dose). The dose may be decreased/may remain same based on the efficacy and tolerability.

Intervention Type: DRUG

Placebo

Participants will receive matching placebo as nasal spray.

Intervention Type: DRUG

Escitalopram

Escitalopram can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for escitalopram is 5 mg once daily (for elderly participants) and 10 mg once daily (for adults). The dose may be increased to 10 mg (for elderly participants) and 20 mg (for adults) once daily at the discretion of treating physician/investigator.

Intervention Type: DRUG

Sertraline

Sertraline can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for sertraline is 50 mg once daily and may be increased up to 200 mg once daily.

Intervention Type: DRUG

Duloxetine

Duloxetine can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for duloxetine is 60 mg once daily and may be increased to 120 mg once daily.

Intervention Type: DRUG

Mirtazapine

Mirtazapine can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for mirtazapine is 15 to 30 mg once daily and may be increased to 45 mg once daily.

Intervention Type: DRUG

Agomelatine

Agomelatine can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for agomelatine is 25 mg once daily and may be increased to 50 mg once daily after 2 weeks.

Intervention Type: DRUG

Bupropion

Bupropion can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for bupropion is 150 mg once daily and may be increased to 300 mg once daily after 4 weeks.

Intervention Type: DRUG

Trazodone Prolonged Release

Trazodone prolonged release can be selected as the oral antidepressant medication based on investigator's discretion. The initial dose for trazodone prolonged release is 75 to 150 mg once or twice daily and may be increased up to 450 mg (adults) and 300 mg (elderly).

Intervention Type: DRUG

Other Intervention Names

JNJ-54135419; JNJ-54135419; JNJ-54135419

Eligibility Criteria

Inclusion Criteria

• At screening, each participant must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria for single episode major depressive disorder (MDD) or recurrent MDD, without psychotic features, based on clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI)
• At baseline, each participant must have an Inventory of Depressive Symptomology Clinician-Rated 30 Items Scale (IDS-C30) total score of greater than or equal to (>= ) 34
• At screening, participants must have had a documented nonresponse to at least 2 but not more than 6 oral antidepressants (AD) treatments taken at adequate dosage and for adequate duration within the current episode of depression evaluated retrospectively. Nonresponse documentation at screening must include the sequence of retrospectively failed antidepressants and combination and or augmentation for retrospectively failed antidepressants

Exclusion Criteria

• Must be comfortable with self-administration of nasal medication and be able to follow the nasal administration instructions provided
• A woman of childbearing potential must have a negative highly sensitive serum (Beta human chorionic gonadotropin [Beta hCG]) at screening and a negative urine pregnancy test prior to the first dose of study intervention on Day 1 of the induction phase prior to randomization

• Depressive symptoms that have previously not responded to any of the following:

a Esketamine or ketamine in a major depressive episode per clinical judgment, or b All of the classes of oral ADs in the study or an adequate AD augmentation/combination therapy in the current major depressive episode, or c An adequate course of treatment with electroconvulsive therapy in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral electroconvulsive therapy

• Received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression
• 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), intellectual disability, autism spectrum disorder, borderline personality disorder, antisocial personality disorder
• Has homicidal ideation or intent, per the investigator's clinical judgment; or has suicidal ideation with some intent to act within 1 month prior to screening, per the investigator's clinical judgment; or based on the Columbia Suicide Severity Rating Scale (C-SSRS), corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C SSRS, or a history of suicidal behavior within the past year prior to screening. Participants reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the induction phase should also be excluded
• History of moderate or severe substance use disorder or severe alcohol use disorder according to DSM-5 criteria, except nicotine or caffeine, within 6 months before the start of the screening or current clinical signs
• Has other inflammatory diseases that might confound the evaluations of benefit of guselkumab therapy, including but not limited to Rheumatoid arthritis (RA), axial spondyloarthritis (this does not include a primary diagnosis of psoriatic spondylitis [PsA] with spondylitis), systemic lupus erythematosus, or Lyme disease

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen-Cilag International NV

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Janssen-Cilag International NV Clinical Trial

Role: STUDY_DIRECTOR

Janssen-Cilag International NV

Other Identifiers

2018-001890-26

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

54135419TRD3011

Identifier Type: OTHER

Identifier Source: secondary_id

CR108567

Identifier Type: -

Identifier Source: org_study_id