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
Condition: Depressive Disorder, Treatment-Resistant
MeSH terms: Depressive Disorder; Depressive Disorder, Treatment-Resistant
Intervention: Esketamine 56 mg; Esketamine 84 mg; Placebo; Duloxetine (Oral Antidepressant); Escitalopram (Oral Antidepressant); Sertraline (Oral Antidepressant); Venlafaxine Extended Release (XR) (Oral Antidepressant)
Intervention description: Participants will self-administer 56 mg of esketamine as intranasal spray.; Participants will self-administer 84 mg of esketamine as intranasal spray.; Participants will self-administer matching placebo as intranasal spray.; 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).; 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.; 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.; 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.
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: 252.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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)

          -  Participant must be medically stable on the basis of physical examination, medical
             history, vital signs (including blood pressure), pulse oximetry, and 12-lead
             electrocardiogram (ECG) performed in the screening/prospective observational phase. If
             there are any abnormalities that are not specified in the inclusion and exclusion
             criteria, they must be consistent with the underlying illness in the study population.
             This determination must be recorded in the participant's source documents and
             initialed or signed by the investigator

          -  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

        Exclusion Criteria:

          -  The participant's depressive symptoms have previously demonstrated non-response to:

               1. Esketamine or ketamine in the current major depressive episode per clinical
                  judgment, or

               2. 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

               3. 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

          -  Participant has a history of moderate or severe substance or alcohol use disorder
             according to DSM-5 criteria, except nicotine or caffeine, within 6 months before the
             start of screening/prospective observational phase a. A history (lifetime) of
             ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3,
             4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is
             exclusionary