Clinical trial NCT02417064: A Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression
Official title: A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Treatment-resistant Depression
Keywords: Treatment-resistant Depression
Esketamine
Placebo
Oral Antidepressant
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-04-15
Enrollment: 346
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) participants 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.

Detailed description: This is a randomized, double-blind (neither the researchers nor the participants know what treatment the participant is receiving), active-controlled, multicenter study (more than 1 study site) in participants with TRD to assess the efficacy, safety, and tolerability of fixed doses of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. The study will consist of 3 phases: Screening/Prospective Observational Phase (4-7 weeks), Double-blind Induction Phase (4-weeks), Follow-up Phase (24-weeks). Participants who rollover into a long-term maintenance study will not participate in the Follow-up Phase. At the start of the screening/prospective observational phase, the participant must have had documented non-response to at least 1 antidepressant treatment (based on Massachusetts General Hospital - Antidepressant Treatment Response Questionnair \[MGH-ATRQ\]) in the current episode of depression, and 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. This antidepressant treatment, as well as any other ongoing medications being taken for depression at screening (including adjunctive/ augmentation therapies), will continue from the start of Week 1 through the end of Week 4 of the screening/prospective observational phase. Participants will be randomly assigned to receive Intranasal esketamine (56 milligrams \[mg\]), Intranasal esketamine (84 mg), or Intranasal placebo. In addition, each participant will be assigned to receive 1 of 4 oral antidepressant medications from 2 different classes of antidepressant treatments, a Selective Serotonin Reuptake Inhibitor (SSRI) (escitalopram or sertraline) or a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) (duloxetine or venlafaxine extended release \[XR\]), initiated on Day 1 and continued through the double-blind induction phase. Participants will be primarily evaluated for improvement in depressive symptoms as assessed by change in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 4. Participants' safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* At the time of signing the informed consent form (ICF), participant must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than \[\>\]18) to 64 years of age, inclusive
* 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 (\>=) 34
* At the start of the screening/prospective observational phase, participants must have had non-response (less than or equal to \[\<=25\] percent \[%\] improvement) to \>=1 but less than or equal to (\<=) 5 (if current episode is \>2 years, upper limit is applicable to only the last 2 years) 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 by medical history and pharmacy/prescription records, for the current episode of depression.

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 MADRS total score \>=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Site Independent Qualification Assessment

Exclusion Criteria:

* Participants who have previously demonstrated nonresponse of depressive symptoms to esketamine or ketamine in the current major depressive episode, to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (i.e, 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/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 317, 318.0, 318.1, 318.2, 315.8, 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)
* Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria

Primary outcomes:
measure: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 of Double- Blind Induction Phase- Mixed- Effects Model Using Repeated Measures (MMRM) Analysis
timeFrame: Baseline up to Day 28 of Double-blind Induction Phase
measure: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
timeFrame: Baseline up to Double-blind Endpoint (Day 28)
Secondary outcomes:
measure: Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8
timeFrame: Day 2 up to Day 28 and Day 8 up to Day 28
measure: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
timeFrame: Baseline up to Day 28 of Double-blind Induction phase
measure: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
timeFrame: Baseline up to Double-blind Endpoint (Day 28)
measure: Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
timeFrame: Baseline up to Day 28 of Double-blind Induction phase
measure: Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
timeFrame: Baseline up to Double-blind Endpoint (Day 28)
measure: Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at Day 28 of Double-blind Induction Phase (Observed Data)
timeFrame: At Day 28 of Double-blind Induction phase
measure: Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)
timeFrame: At Day 28 (Double-blind Endpoint)
measure: Percentage of Participants in Remission (MADRS<=12) at Day 28 of Double-blind Induction Phase (Observed Data)
timeFrame: At Day 28 of Double-blind Induction Phase
measure: Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis (LOCF Data)
timeFrame: At Day 28 (Double-blind Endpoint)
measure: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint (Double-blind Induction Phase [Day 28])
timeFrame: Baseline up to Double-blind Endpoint (Day 28)
measure: Change From Baseline in Generalized Anxiety Disorder-7 Item (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
timeFrame: Baseline up to Double-blind Endpoint (Day 28)
measure: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Health Status Index
timeFrame: Baseline up to End of Double-blind Induction Phase (Day 28)
measure: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): EQ-VAS
timeFrame: Baseline up to end of Double-blind induction phase (Day 28)
measure: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Sum Score
timeFrame: Baseline up to end of Double-blind Induction phase (Day 28)
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Little Rock
country: United States
state: Arkansas
city: Garden Grove
country: United States
state: California
city: Orange
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Marcos
country: United States
state: California
city: San Rafael
country: United States
state: California
city: Bradenton
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Hoffman Estates
country: United States
state: Illinois
city: Maywood
country: United States
state: Illinois
city: Schaumburg
country: United States
state: Illinois
city: Wichita
country: United States
state: Kansas
city: Gaithersburg
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Quincy
country: United States
state: Massachusetts
city: Watertown
country: United States
state: Massachusetts
city: Worcester
country: United States
state: Massachusetts
city: Minneapolis
country: United States
state: Minnesota
city: O'Fallon
country: United States
state: Missouri
city: Saint Charles
country: United States
state: Missouri
city: Omaha
country: United States
state: Nebraska
city: New York
country: United States
state: New York
city: Durham
country: United States
state: North Carolina
city: Dayton
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Media
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Lincoln
country: United States
state: Rhode Island
city: Austin
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Woodstock
country: United States
state: Vermont
city: Bothell
country: United States
state: Washington
city: Middleton
country: United States
state: Wisconsin
city: Aalst
country: Belgium
city: Brugge
country: Belgium
city: Brussel
country: Belgium
city: Bruxelles
country: Belgium
city: Gent
country: Belgium
city: Hasselt
country: Belgium
city: Heusden-Zolder
country: Belgium
city: Liège
country: Belgium
city: Spa
country: Belgium
city: Yvoir
country: Belgium
city: Belo Horizonte
country: Brazil
city: Curitiba
country: Brazil
city: Fortaleza
country: Brazil
city: Passo Fundo
country: Brazil
city: Porto Alegre
country: Brazil
city: Rio de Janeiro
country: Brazil
city: Santo André
country: Brazil
city: Calgary
country: Canada
state: Alberta
city: Vancouver
country: Canada
state: British Columbia
city: Kingston
country: Canada
state: Ontario
city: Ottawa
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Parnu
country: Estonia
city: Tallinn
country: Estonia
city: Tartu
country: Estonia
city: BESANCON Cedex
country: France
city: Clermont Ferrand
country: France
city: Douai
country: France
city: Issy-les-Moulineaux
country: France
city: La Tronche
country: France
city: Lille
country: France
city: Limoges
country: France
city: Montpellier Cedex 5
country: France
city: Nantes
country: France
city: Neuilly sur Marne
country: France
city: Nimes Cedex 9
country: France
city: Paris
country: France
city: Poitiers
country: France
city: Toulon
country: France
city: TOURS cedex 9
country: France
city: Budapest
country: Hungary
city: Vác
country: Hungary
city: Guadalajara
country: Mexico
city: Leon
country: Mexico
city: Mazatlan
country: Mexico
city: Mexico City
country: Mexico
city: Monterrey
country: Mexico
city: San Luis Potosi
country: Mexico
city: San Luis Potosí
country: Mexico
city: Bratislava
country: Slovakia
city: Liptovsky Mikulas
country: Slovakia
city: Rimavska Sobota
country: Slovakia
city: Roznava
country: Slovakia
city: Svidnik
country: Slovakia
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Jha MK, Williamson DJ, Magharehabed G, Turkoz I, Daly EJ, Trivedi MH. Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability. J Affect Disord. 2023 Jan 15;321:153-160. doi: 10.1016/j.jad.2022.10.020. Epub 2022 Oct 20.
citation: Chen G, Chen L, Zhang Y, Li X, Lane R, Lim P, Daly EJ, Furey ML, Fedgchin M, Popova V, Singh JB, Drevets WC. Relationship Between Dissociation and Antidepressant Effects of Esketamine Nasal Spray in Patients With Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2022 Apr 19;25(4):269-279. doi: 10.1093/ijnp/pyab084.
citation: Jones RR, Freeman MP, Kornstein SG, Cooper K, Daly EJ, Canuso CM, Nicholson S. Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials. Arch Womens Ment Health. 2022 Apr;25(2):313-326. doi: 10.1007/s00737-021-01185-6. Epub 2022 Jan 1.
citation: Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021 Sep 12;9(9):CD011612. doi: 10.1002/14651858.CD011612.pub3.
citation: Turkoz I, Daly E, Singh J, Lin X, Tymofyeyev Y, Williamson D, Salvadore G, Nash AI, Macaluso M, Wilkinson ST, Nelson JC. Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies. J Clin Psychiatry. 2021 Jul 20;82(4):20m13800. doi: 10.4088/JCP.20m13800.
citation: 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.
citation: 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.
citation: 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.
citation: Saad Z, Hibar D, Fedgchin M, Popova V, Furey ML, Singh JB, Kolb H, Drevets WC, Chen G. Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials. Int J Neuropsychopharmacol. 2020 Dec 3;23(9):549-558. doi: 10.1093/ijnp/pyaa030.
citation: Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, Vitagliano D, Blier P, Fava M, Liebowitz M, Ravindran A, Gaillard R, Ameele HVD, Preskorn S, Manji H, Hough D, Drevets WC, Singh JB. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019 Oct 1;22(10):616-630. doi: 10.1093/ijnp/pyz039.