A Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression

NCT03434041 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: CR108418ESKETINTRD3006
• Study Type: interventional
• Target: 252
• Locations: 2 countries
• Sites: 30

Brief Summary

The purpose of this study is to evaluate the efficacy of switching adult participants with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine (56 milligram \[mg\] or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms. Efficacy will be assessed by the change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score from Day 1 (before randomization) to the end of the 4-week double-blind treatment phase.

Conditions

Depressive Disorder, Treatment-Resistant

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score to the End of Double-blind Treatment Phase (Day 28)

  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 (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

  Baseline up to end of the double-blind treatment phase (Day 28)

Secondary Outcomes (11)

• Change From Baseline in Depressive Symptoms as Measured by the MADRS Total Score to 24 Hours Post First Dose (Day 2)

  Baseline (Day 1: predose) to 24 hours post first dose (Day 2)

• Change From Baseline in Sheehan Disability Scale (SDS) Total Score to the End of Double-blind Treatment Phase (Day 28)

  Baseline up to end of the double-blind treatment phase (Day 28)

• Percentage of Participants With Onset of Clinical Response

  Day 2 up to Day 28

• Percentage of Responders at the End of Double-blind Treatment Phase (Day 28)

  Day 28

• Percentage of Participants in Remission at the End of Double-blind Treatment Phase (Day 28)

  Day 28

Study Arms (2)

Intranasal Esketamine plus Oral Antidepressant

EXPERIMENTAL

Eligible participants will self-administer esketamine (56 mg or 84 mg) intranasally twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Treatment Phase. All participants will start at a dose of 56 milligram (mg) on Day 1. The dose may be increased to 84 mg or maintained at 56 mg per investigator's discretion. In addition, participants will simultaneously initiate a new, open-label 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of the 4-week Double-Blind Treatment Phase.

Drug: Esketamine 56 mg; Drug: Esketamine 84 mg; Drug: Duloxetine (Oral Antidepressant); Drug: Escitalopram (Oral Antidepressant); Drug: Sertraline (Oral Antidepressant); Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant)

Oral Antidepressant plus Intranasal Placebo

ACTIVE COMPARATOR

Eligible Participants will self-administer matching placebo intranasally twice per week for 4 weeks in Double-Blind Treatment Phase. In addition, participants will simultaneously initiate a new, open-label oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Treatment Phase.

Drug: Placebo; Drug: Duloxetine (Oral Antidepressant); Drug: Escitalopram (Oral Antidepressant); Drug: Sertraline (Oral Antidepressant); Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant)

Interventions

Esketamine 56 mg DRUG

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

Intranasal Esketamine plus Oral Antidepressant

Esketamine 84 mg DRUG

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

Intranasal Esketamine plus Oral Antidepressant

Placebo DRUG

Participants will self-administer matching placebo as intranasal spray.

Oral Antidepressant plus Intranasal Placebo

Duloxetine (Oral Antidepressant) DRUG

Duloxetine can be selected as the oral antidepressant medication based on investigator's discretion. The minimum therapeutic dose is 60 milligram per day (mg/day).

Intranasal Esketamine plus Oral Antidepressant; Oral Antidepressant plus Intranasal Placebo

Escitalopram (Oral Antidepressant) DRUG

Escitalopram can be selected as the oral antidepressant medication based on investigator's discretion. Escitalopram will be started at a dose of 10 mg/day and up-titrated to a maximum dose of 20 mg/day.

Intranasal Esketamine plus Oral Antidepressant; Oral Antidepressant plus Intranasal Placebo

Sertraline (Oral Antidepressant) DRUG

Sertraline can be selected as the oral antidepressant medication based on investigator's discretion. Sertraline will be started at a dose of 50 mg/day and up-titrated to a maximum dose of 200 mg/day.

Intranasal Esketamine plus Oral Antidepressant; Oral Antidepressant plus Intranasal Placebo

Venlafaxine Extended Release (XR) (Oral Antidepressant) DRUG

Venlafaxine XR can be selected as the oral antidepressant medication based on investigator's discretion. Venlafaxine XR will be started at a dose of 75 mg/day and up-titrated to a maximum dose of 225 mg/day.

Intranasal Esketamine plus Oral Antidepressant; Oral Antidepressant plus Intranasal Placebo

Eligibility Criteria

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

You may qualify if:

• At the start of the screening/prospective observational phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) diagnostic criteria for recurrent major depressive disorder (MDD) or single-episode MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (mental status questionnaire) (MINI)
• At the start of the screening/prospective observational phase, participant must have had non-response (less than or equal to \[\<=\] 25 percent \[%\] improvement) to \>=1 but \<=5 (if current episode is greater than (\>) 2 years or not definable, upper limit is applicable to only the last 2 years) 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 letter from a treating physician). In addition, the participant is taking a different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose
• The participant's current major depressive episode, depression symptom severity (Week 1 Montgomery-Asberg Depression Rating Scale \[MADRS\] total score \>=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Clinical-Validation Inventory for Study Admission (C-VISA)

You may not qualify if:

• Participant must be medically stable on the basis of clinical laboratory tests performed in the screening/prospective observational phase. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialed or signed by the investigator
• The participant's depressive symptoms have previously demonstrated non-response to:
• Esketamine or ketamine in the current major depressive episode per clinical judgment, or
• All of the oral antidepressant treatment options available in the respective country for the double-blind phase (that is, duloxetine, escitalopram, sertraline, and venlafaxine XR) in the current major depressive episode (based on MGH-ATRQ), or
• An adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT
• Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression
• 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 315.8, 317, 318.0, 318.1, 318.2 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/prospective observational 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/prospective observational 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 (30)

Atlanta Center for Medical Research

Atlanta, Georgia, 30331, United States

Location

Biomedical Research Foundation of Northwest Louisiana

Shreveport, Louisiana, 71104-2136, United States

Location

CBH Health

Gaithersburg, Maryland, 20877, United States

Location

Adams Clinical

Watertown, Massachusetts, 02472, United States

Location

The Medical Research Network, LLC

New York, New York, 10128, United States

Location

IPS Research Company

Oklahoma City, Oklahoma, 73106, United States

Location

Beijing Anding Hospital of Capital Medical University

Beijing, 100088, China

Location

Beijing HuiLong Guan Hospital

Beijing, 100096, China

Location

Peking University Sixth Hospital

Beijing, 100191, China

Location

The Second People's Hospital of Hunan Province / Brian Hospital of Hunan Province

Changsha, 410007, China

Location

The second Xiangya Hospital of Central South University

Changsha, 410011, China

Location

West China Hospital Sichuan University

Chengdu, 610041, China

Location

Chongqing Mental Health Center

Chongqing, 401147, China

Location

the 3rd Affiliated Hospital,Sun Yansen University

Guangzhou, 510000, China

Location

Guangdong Provincial People's Hospital

Guangzhou, 510100, China

Location

Hangzhou Seventh People's Hospital

Hangzhou, 310000, China

Location

First Hospital, Zhejiang University Medical College

Hangzhou, 310003, China

Location

The Second Affiliated Hospital of Zhejiang University

Hangzhou, 310009, China

Location

Huzhou third people's Hospital

Huzhou, 313000, China

Location

First Affiliated Hospital of Kunming Medical Unversity

Kunming, 650032, China

Location

Nanjing Brain Hospital Affilicated to Nanjing Medical University

Nanjing, 210000, China

Location

The First Hospital of Hebei Medical University

Shijiazhuang, 050031, China

Location

Tianjin Anding Hospital

Tianjin, 300222, China

Location

Urumqi fourth Hospital

Ürümqi, 830000, China

Location

The first affiliated hospital of Xinjiang medical university

Ürümqi, 830054, China

Location

Renmin Hospital of Wuhan University

Wuhan, 430060, China

Location

The First Affiliated Hospital of Xian Jiaotong University

Xi'an, 710061, China

Location

Xi'an Mental Health Center

Xi'an, 710061, China

Location

Xiamen Xianyue Hospital

Xiamen, 361012, China

Location

The First Affiliated Hospital of Zhengzhou University

Zhengzhou, 450052, China

Location

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant

Interventions

Esketamine; Duloxetine Hydrochloride; Antidepressive Agents; Escitalopram; Sertraline

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Psychotropic Drugs; Central Nervous System Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Propylamines; Amines; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; 1-Naphthylamine; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Limitations and Caveats

As esketamine has known transient dissociative effects that are difficult to blind, these specific treatment-emergent events could have biased the staff who provided and observed the dosing. Therefore, to ensure an unbiased efficacy evaluation, independent, remote (by telephone), blinded MADRS raters were used to assess the treatment response.

Results Point of Contact

• Title: DIRECTOR CLINICAL LEADER
• Organization: Janssen Research & Development, LLC

ClinicalTrialDisclosure@its.jnj.com

844-434-4210

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

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
• Expanded Access: Yes

Study Record Dates

• First Submitted: February 9, 2018
• First Posted: February 15, 2018
• Study Start: May 25, 2018
• Primary Completion: April 13, 2021
• Study Completion: April 13, 2021
• Last Updated: April 29, 2025
• Results First Posted: May 24, 2022

Record last verified: 2025-04

Locations

CN (24); US (6)