A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression
Condition: Depressive Disorder, Treatment-Resistant
MeSH terms: Recurrence; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Intervention: Esketamine; Placebo; Duloxetine (Oral Antidepressant); Escitalopram (Oral antidepressant); Sertraline (Oral Antidepressant); Venlafaxine Extended Release (XR) (Oral Antidepressant)
Intervention description: Open-label induction phase: Direct entry participants start at a dose of 56 mg on Day 1. On Day 4, the dose may be increased to 84 mg or remain at 56 mg. From Day 8 to 22, dose may be increased to 84 mg, remain the same or be reduced to 56 mg from 84 mg per protocol, at investigator's discretion based on efficacy and/or tolerability. On Day 25, a dose reduction from 84 mg to 56 mg is permitted but no dose increase is permitted. Optimization Phase: Direct-entry and transferred-entry participants will self-administer intranasal esketamine (same dose) for first 4 weeks, then individualized to either once weekly or once every other week based on depressive symptoms. Maintenance Phase: All participants assigned to esketamine will self-administer intranasal esketamine once weekly or once every other week based on depressive symptoms.; Optimization Phase: Transferred-entry participant will self-administer intranasal placebo at weekly treatment sessions for the first 4 weeks of this phase, then individualized to either once weekly or once every other week based on depressive symptoms. Maintenance Phase: Direct-entry and transferred-entry participants assigned to placebo will self-administer matching intranasal placebo once weekly or once based on depressive symptoms.; 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).; 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 titrated upto a maximum dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.; 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 will be titrated upto a maximum dose of 200 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.; 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 will be titrated upto a maximum dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day.
Intervention MeSH terms: Duloxetine Hydrochloride; Venlafaxine Hydrochloride; Sertraline; Antidepressive Agents; Esketamine; Escitalopram
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 719.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: Treatment-resistant Depression; Esketamine; Placebo; Oral Antidepressant; Relapse prevention

Summary:

      The purpose of this study is to assess the efficacy of intranasal esketamine plus an oral
      antidepressant compared with an oral antidepressant (active comparator) plus intranasal
      placebo in delaying relapse of depressive symptoms in participants with treatment-resistant
      depression (TRD) who are in stable remission after an induction and optimization course of
      intranasal esketamine plus an oral antidepressant.
    

Eligibility criteria:

        Inclusion Criteria:

        For Direct-Entry Participants

          -  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 nonresponse (less than or equal to 25 percent [%] improvement) to greater than or
             equal to (>=1) but less than or equal to (<=) 5 oral antidepressant treatments taken
             at adequate dosage and for adequate duration, as assessed using the Massachusetts
             General Hospital (MGH-ATRQ )

          -  MGH-ATRQ and documented by medical history and pharmacy/prescription records, for the
             current episode of depression. In addition, the participant is taking different
             ongoing oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2
             weeks at or above the minimal therapeutic dose

          -  The participant's current major depressive episode, depression symptom severity (Week
             1 MADRS total score >=28 required), and treatment response to antidepressant
             treatments used in the current depressive episode (retrospectively assessed) must be
             deemed valid for participation in a clinical study based on a Site-Independent
             Qualification Assessment For Transferred-Entry Participants

          -  The participant must have completed the double-blind induction phase in ESKETINTRD3001
             or ESKETINTRD3002 and must have demonstrated response at the end of that phase (>=50%
             reduction in the MADRS total score from baseline [Day 1 pre-randomization] at the end
             of the 4-week double-blind induction phase)

        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 (ie,
             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