A Study of Esketamine Nasal Spray Versus Placebo Spray in Adult Participants With Treatment-resistant Depression

NCT07716098 | Recruiting Phase 3 FDA Drug

• 1 other identifier: 54135419TRD3015
• Study Type: interventional
• Target: 348
• Locations: 2 countries
• Sites: 4

Brief Summary

The purpose of this study is to evaluate how well each individual dose of esketamine (56 milligrams \[mg\] and 84 mg) works when compared with placebo in improving depressive symptoms in participants with treatment resistant depression (individuals with major depressive disorder \[MDD\] who have not responded to at least 2 different antidepressant treatments given at an adequate dose for an adequate duration in the current episode of depression).

Conditions

Depressive Disorder, Treatment-Resistant

Outcome Measures

Primary Outcomes (1)

• Double-Blind (DB) Treatment Phase: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Day 1 to the End of the 4-Week Double-Blind Treatment Phase

  The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. 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), for a total possible score of 60. Higher scores represent a more severe condition.

  Baseline (Day 1 [prerandomization]) up to end of the 4-Week DB treatment phase (Day 28)

Secondary Outcomes (21)

• DB Treatment Phase: Change From Baseline in MADRS Total Score From Day 1 to Day 2

  Baseline (Day 1 [prerandomization]) up to Day 2 (approximately 24 hours after the first dose)

• DB Treatment Phase: Percentage of Responders in MADRS Over Time to the End of the 4-Week DB Treatment Phase

  Up to end of the 4-Week DB treatment phase (Day 28)

• DB Treatment Phase: Percentage of Participants in Remission in MADRS Over Time to the End of the 4-Week DB Treatment Phase

  Up to end of the 4-Week DB treatment phase (Day 28)

• DB Treatment Phase: Change From Baseline in Clinical Global Impression-Severity (CGI-S) Over Time to the End of the 4-Week DB Treatment Phase

  Baseline up to end of the 4-Week DB treatment phase (Day 28)

• DB Treatment Phase: Change From Baseline in MADRS Total Score Over Time to the End of the 4-Week DB Treatment Phase

  Baseline up to end of the 4-Week DB treatment phase (Day 28)

Other Outcomes (15)

• DB Treatment Phase: Number of Participants with Abnormalities in Blood Oxygen Saturation (SpO2)

  Up to end of the 4-Week DB treatment phase (Day 28)

• DB Treatment Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

  Up to end of the 4-Week DB treatment phase (Day 28)

• DB Treatment Phase: Suicidal Ideation and Behavior as Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS)

  Up to end of the 4-Week DB treatment phase (Day 28)

Study Arms (3)

Esketamine 56 milligram (mg)

EXPERIMENTAL

Participants will be randomized to receive double-blind (DB) treatment with esketamine 56 mg, twice a week for 4 weeks. Participants who complete the DB treatment phase on Day 28 may be eligible to participate in an open-label treatment phase and receive either esketamine 56 or 84 mg.

Drug: Esketamine 56 mg; Drug: Esketamine 84 mg

Esketamine 84 mg

EXPERIMENTAL

Participants will be randomized to receive DB treatment with esketamine 84 mg, twice a week for 4 weeks. Participants who complete the DB treatment phase on Day 28 may be eligible to participate in an open-label treatment phase and receive either esketamine 56 or 84 mg.

Drug: Esketamine 56 mg; Drug: Esketamine 84 mg

Placebo

PLACEBO COMPARATOR

Participants will be randomized to receive DB treatment with placebo twice a week for 4 weeks. Participants who complete the DB treatment phase on Day 28 may be eligible to participate in an open-label treatment phase and receive either esketamine 56 mg or 84 mg.

Drug: Esketamine 56 mg; Drug: Esketamine 84 mg; Drug: Placebo

Interventions

Esketamine 56 mg DRUG

Participants will self-administer 56 mg of esketamine as intranasal spray into each nostril.

Also known as: JNJ-54135419

Esketamine 56 milligram (mg); Esketamine 84 mg; Placebo

Esketamine 84 mg DRUG

Participants will self-administer 84 mg of esketamine as intranasal spray into each nostril.

Also known as: JNJ-54135419

Esketamine 56 milligram (mg); Esketamine 84 mg; Placebo

Placebo DRUG

Participants will self-administer placebo as intranasal spray into each nostril.

Placebo

Eligibility Criteria

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

You may qualify if:

• Participant must meet the diagnostic and statistical manual of mental disorders (5th edition) (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single episode MDD, the duration of the episode must be greater than or equal to \[\>=\] 12 months) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the mini international neuropsychiatric interview (MINI) as the primary diagnosis. Participant must have had the first onset of depression prior to 55 years of age
• Participant must have had nonresponse (less than or equal to \[\<=\] 25 percent \[%\] improvement) to \>=2 oral antidepressant treatments in the current episode of depression, assessed using the massachusetts general hospital-antidepressant treatment response questionnaire (MGH-ATRQ), and confirmed by documented records (for example, medical/pharmacy/prescription records or a letter from a treating physician)
• The participant's current major depressive episode, depression symptom severity, and antidepressant treatment response in the current depressive episode, must be confirmed by the state versus trait, assessability, face validity, ecological validity, rule of three P's (SAFER) Interview
• Participant must be comfortable with self-administration of nasal spray medication and be able to follow the nasal spray administration instructions provided
• A female participant of childbearing potential must have a negative highly sensitive serum (β-human chorionic gonadotropin \[β-hCG\]) at the start of screening and a negative urine pregnancy test must be obtained before the first dose of study drug on Day 1, prior to randomization

You may not qualify if:

• The participant has used ketamine/esketamine (lifetime)
• The participant's depressive symptoms have demonstrated nonresponse in the current major depressive episode to an adequate course of treatment with electroconvulsive therapy (ECT), defined as at least 7 treatments with unilateral/bilateral ECT, or to adequate course of treatment with transcranial magnetic stimulation (TMS), defined as at least 4 weeks of treatment with 5 sessions per week
• Participant has received vagal nerve stimulation (VNS) or deep brain stimulation (DBS) in the current episode of depression
• 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), 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 the start of the screening phase. Participants reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the double-blind treatment phase should be excluded

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead

Study Sites (4)

Psychiatric Medicine Associates LLC

Skokie, Illinois, 60076, United States

RECRUITING

The Medical Research Network, LLC

New York, New York, 10128, United States

RECRUITING

Taipei Medical University

Taipei, 110, Taiwan

RECRUITING

Linkou Chang Gung Memorial Hospital

Taoyuan, 333, Taiwan

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant

Interventions

Esketamine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Central Study Contacts

Study Contact

CONTACT

844-434-4210; Participate-In-This-Study1@its.jnj.com

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: July 15, 2026
• First Posted: July 21, 2026
• Study Start: July 27, 2026
• Primary Completion (Estimated): December 27, 2028
• Study Completion (Estimated): September 12, 2029
• Last Updated: July 31, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share

Locations

US (2); TW (2)