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

NCT03852160 | Withdrawn Phase 3 FDA Drug

• 3 other identifiers: CR1085672018-001890-2654135419TRD3011
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Depressive Disorder, Treatment-Resistant

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants with Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) (Total Score of less than or Equal to [<=] 10) at the end of Week 8

  Percentage of participants with remission as assessed by the MADRS (total score of \<= 10) will be reported and compared between treatment arms. The MADRS is a clinician-rated scale designed to measure depression severity. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms).These item scores are summed up to yield a total score. The range of the total score is 0 to 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.

  Week 8

Secondary Outcomes (15)

• Percentage of Participants with Remission at Week 8 Without Relapse Until Week 32

  Week 32

• Change from Baseline in Clinician-reported MADRS Scale Score

  Baseline, up to 32 Week

• Change in MADRS Total Score from Baseline at Week 4

  Baseline, Week 4

• Change from Baseline in Patient Health Questionnaire (PHQ) 9-item Total Score

  Baseline, up to 32 Weeks

• Change from Baseline in Clinical Global Impression - Severity (CGI-S) Scale Score

  Baseline, up to 32 Weeks

Study Arms (2)

Esketamine + Oral Antidepressants

EXPERIMENTAL

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.

Drug: Esketamine 28 mg; Drug: Esketamine 56 mg; Drug: Esketamine 84 mg; Drug: Escitalopram; Drug: Sertraline; Drug: Duloxetine; Drug: Mirtazapine; Drug: Agomelatine; Drug: Bupropion; Drug: Trazodone Prolonged Release

Placebo + Oral Antidepressants

ACTIVE COMPARATOR

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.

Drug: Placebo; Drug: Escitalopram; Drug: Sertraline; Drug: Duloxetine; Drug: Mirtazapine; Drug: Agomelatine; Drug: Bupropion; Drug: Trazodone Prolonged Release

Interventions

Esketamine 28 mg 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).

Also known as: JNJ-54135419

Esketamine + Oral Antidepressants

Esketamine 56 mg 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.

Also known as: JNJ-54135419

Esketamine + Oral Antidepressants

Esketamine 84 mg DRUG

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

Also known as: JNJ-54135419

Esketamine + Oral Antidepressants

Placebo DRUG

Participants will receive matching placebo as nasal spray.

Placebo + Oral Antidepressants

Escitalopram 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.

Esketamine + Oral Antidepressants; Placebo + Oral Antidepressants

Sertraline 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.

Esketamine + Oral Antidepressants; Placebo + Oral Antidepressants

Duloxetine 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.

Esketamine + Oral Antidepressants; Placebo + Oral Antidepressants

Mirtazapine 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.

Esketamine + Oral Antidepressants; Placebo + Oral Antidepressants

Agomelatine 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.

Esketamine + Oral Antidepressants; Placebo + Oral Antidepressants

Bupropion 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.

Esketamine + Oral Antidepressants; Placebo + Oral Antidepressants

Trazodone Prolonged Release 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).

Esketamine + Oral Antidepressants; Placebo + Oral Antidepressants

Eligibility Criteria

• Age: 18 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Janssen-Cilag International NV: lead

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant

Interventions

Esketamine; Escitalopram; Sertraline; Duloxetine Hydrochloride; Mirtazapine; agomelatine; Bupropion

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; 1-Naphthylamine; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Thiophenes; Sulfur Compounds; Heterocyclic Compounds, 1-Ring; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Propiophenones; Ketones

Study Officials

• Janssen-Cilag International NV Clinical Trial

  Janssen-Cilag International NV

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2019
• First Posted: February 25, 2019
• Study Start: December 1, 2019
• Primary Completion: July 25, 2021
• Study Completion: July 25, 2021
• Last Updated: April 27, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share