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

NCT02422186 | Completed Phase 3 Results DMC

• 3 other identifiers: CR107129ESKETINTRD30052014-004588-19
• Study Type: interventional
• Target: 139
• Locations: 12 countries
• Sites: 69

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of switching elderly participants with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.

Conditions

Depressive Disorder, Treatment-Resistant

Keywords

Depressive Disorder, Treatment-Resistant; Esketamine; Oral Antidepressant; Elderly Participants

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis

  The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items (to evaluates 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 0-60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

  Baseline up to Endpoint (Double-blind Induction Phase[Day 28])

• Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis

  The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items (to evaluates 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 0-60. Higher scores represent a more severe condition. Negative change in score indicates improvement. Missing data was imputed using Last Observation Carried Forward (LOCF) method and last post baseline observation during the double-blind induction phase was carried forward as the "End Point" for that phase.

  Baseline and Endpoint (Double-blind Induction Phase [Day 28])

Secondary Outcomes (6)

• Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)

  At Endpoint-Double-blind Induction Phase [Day 28]

• Percentage of Participants in Remission (MADRS<=12) at Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)

  At Endpoint-Double-blind Induction Phase [Day 28]

• Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis on Ranks

  Baseline and Endpoint (Double-blind Induction Phase [Day 28])

• Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): Health Status Index

  Baseline and Endpoint (Double-blind Induction Phase [Day 28])

• Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): EQ-VAS

  Baseline and Endpoint (Double-blind Induction Phase [Day 28])

Study Arms (2)

Intranasal Esketamine plus Oral Antidepressant

EXPERIMENTAL

Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Induction Phase. All participants will start with first dose (Day 1 as 28 milligram \[mg\]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability. In addition participants will simultaneously initiate a new, open-label oral antidepressant (Duloxetine, Escitalopram, Sertraline, or Venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.

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

Placebo plus Oral Antidepressant

ACTIVE COMPARATOR

Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a flexible dose regimen in Double-Blind Induction Phase using the same titration as Esketamine. In addition participants will simultaneously initiate a new, open-label oral antidepressant (Duloxetine, Escitalopram, Sertraline, or Venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.

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

Interventions

Esketamine DRUG

All participants will start with first dose (Day 1 as 28 milligram \[mg\]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability.

Intranasal Esketamine plus Oral Antidepressant

Placebo DRUG

Participants will self-administer matching placebo, intranasally, twice per week for 4-weeks as a flexible dose regimen in the Double-Blind Induction Phase.

Placebo plus Oral Antidepressant

Duloxetine (Oral Antidepressant) DRUG

Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital -Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).

Intranasal Esketamine plus Oral Antidepressant; Placebo plus Oral Antidepressant

Escitalopram (Oral Antidepressant) DRUG

Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be given at a dose of 10 mg/day throughout the Double-Blind Induction Phase. This dose (10 mg/day) is the also the minimum therapeutic dose.

Intranasal Esketamine plus Oral Antidepressant; Placebo plus Oral Antidepressant

Sertraline (Oral Antidepressant) DRUG

Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.

Intranasal Esketamine plus Oral Antidepressant; Placebo plus Oral Antidepressant

Venlafaxine Extended Release (XR) (New Antidepressant) DRUG

Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 75 mg/day.

Intranasal Esketamine plus Oral Antidepressant; Placebo plus Oral Antidepressant

Eligibility Criteria

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

You may qualify if:

• At the time of signing the informed consent form (ICF), participant must be a man or woman 65 years of age or older
• At the start of the Screening/prospective observational 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 the start of the Screening/Prospective observational Phase, participant must have an Inventory of Depressive Symptomatology-Clinician rated (IDS-C30) total score of greater than or equal to (\>=) 31
• At the start of the Screening/Prospective observational Phase, participants must have had nonresponse (less than or equal to 25% improvement) to \>=1 but less than or equal to (\<=) 8 oral antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented records by medical and pharmacy/prescription records, or a letter from the treating physician, for the current episode of depression
• Participant must be taking one of the oral antidepressant treatment with nonresponse that is documented on the MGH-ATRQ at the start of the screening/prospective observational phase
• The participant's current major depressive episode, depression symptom severity (Week 1 MADRS total score greater than or equal to 24 required) and treatment response to antidepressant treatments used in the current depressive episode (retrospectively assessed) must be confirmed for participation in a clinical study based on a Site-Independent Qualification Assessment
• Participant must be medically stable on the basis of clinical laboratory tests performed in the screening/prospective observational phase

You may not qualify if:

• The participant's depressive symptoms have previously demonstrated nonresponse to: Esketamine or ketamine in the current major depressive episode per clinical judgment, or all of the 4 oral antidepressant treatment options available for the double-blind induction Phase (Duloxetine, Escitalopram, Sertraline, and Venlafaxine extended release \[XR\]) 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 ECT
• Participants who has received vagal nerve stimulation (VNS) or who 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 psychosis, bipolar or related disorders (confirmed by the MINI), obsessive compulsive disorder (current episode only), intellectual disability ( intellectual disability \[DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319\]), 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) and also includes history of suicidal behavior within the past year prior to start of the screening/prospective observational phase
• Participant has a history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder\\
• Participant has a Mini Mental State Examination (MMSE) \< 25 or \<22 for those participants with less than an equivalent of high school education
• Participant has neurodegenerative disorder (eg, Alzheimer's Disease, Vascular dementia, Parkinson's disease with clinical evidence of cognitive impairment) or evidence of mild cognitive impairment (MCI)
• Participant has a history of uncontrolled hypertension; current or past history of significant pulmonary insufficiency/condition;clinically significant ECG abnormalities; current or past history of seizures; clinically significant cardiovascular disorders including cerebral and cardiac vascular disease

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead

Study Sites (69)

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San Diego, California, United States

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New Haven, Connecticut, United States

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Miami, Florida, United States

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Marietta, Georgia, United States

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Iowa City, Iowa, United States

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Baltimore, Maryland, United States

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Watertown, Massachusetts, United States

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New York, New York, United States

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Staten Island, New York, United States

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Cincinnati, Ohio, United States

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Allentown, Pennsylvania, United States

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Dallas, Texas, United States

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Wichita Falls, Texas, United States

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Charlottesville, Virginia, United States

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Richland, Washington, United States

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Aalst, Belgium

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Bruges, Belgium

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Brussels, Belgium

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Hasselt, Belgium

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Heusden-Zolder, Belgium

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Liège, Belgium

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Belo Horizonte, Brazil

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Fortaleza, Brazil

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Rio de Janeiro, Brazil

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Santo André, Brazil

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São José do Rio Preto, Brazil

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São Paulo, Brazil

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Burgas, Bulgaria

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Kardzhali, Bulgaria

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Sofia, Bulgaria

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Varna, Bulgaria

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Helsinki, Finland

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Kuopio, Finland

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Issy-les-Moulineaux, France

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La Tronche, France

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Nice, France

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Nîmes, France

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Paris, France

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Poitiers, France

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Toulon, France

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Toulouse, France

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Tours, France

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Kaunas, Lithuania

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Šilutė, Lithuania

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Vilnius, Lithuania

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Bełchatów, Poland

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Bydgoszcz, Poland

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Gdansk, Poland

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Torun, Poland

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Tuszyn, Poland

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Cape Town, South Africa

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Garsfontein, South Africa

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Pretoria, South Africa

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Badajoz, Spain

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Bilbao, Spain

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Madrid, Spain

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Ourense, Spain

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Sant Boi de Llobregat, Spain

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Torrevieja, Spain

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Zamora, Spain

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Gothenburg, Sweden

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Halmstad, Sweden

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Lund, Sweden

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Skövde, Sweden

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Solna, Sweden

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Stockholm, Sweden

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Derbyshire, United Kingdom

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Oxford, United Kingdom

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Preston, United Kingdom

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Related Publications (3)

• Doty RL, Popova V, Wylie C, Fedgchin M, Daly E, Janik A, Ochs-Ross R, Lane R, Lim P, Cooper K, Melkote R, Jamieson C, Singh J, Drevets WC. Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies. CNS Drugs. 2021 Jul;35(7):781-794. doi: 10.1007/s40263-021-00826-9. Epub 2021 Jul 7.

  PMID: 34235612 DERIVED

• Perez-Ruixo C, Rossenu S, Zannikos P, Nandy P, Singh J, Drevets WC, Perez-Ruixo JJ. Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression. Clin Pharmacokinet. 2021 Apr;60(4):501-516. doi: 10.1007/s40262-020-00953-4. Epub 2020 Oct 31.

  PMID: 33128208 DERIVED

• Katz EG, Hough D, Doherty T, Lane R, Singh J, Levitan B. Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression. Clin Pharmacol Ther. 2021 Feb;109(2):536-546. doi: 10.1002/cpt.2024. Epub 2020 Oct 13.

  PMID: 32860422 DERIVED

Related Links

• Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Subjects with Treatment-resistant Depression

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

Results Point of Contact

• Title: Senior Director
• 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

Study Record Dates

• First Submitted: April 16, 2015
• First Posted: April 21, 2015
• Study Start: August 20, 2015
• Primary Completion: August 10, 2017
• Study Completion: August 10, 2017
• Last Updated: April 29, 2025
• Results First Posted: April 24, 2019

Record last verified: 2025-04

Locations

SE (6); BE (6); BU (4); FI (2); ZA (3); ES (7); US (15); PL (5); GB (3); LI (3); BR (6); FR (9)