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
Overview
- Phase
- Phase 3
- Intervention
- Esketamine
- Conditions
- Treatment-resistant Depression
- Sponsor
- Janssen Research & Development, LLC
- Enrollment
- 346
- Primary Endpoint
- 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
- Status
- Completed
- Last Updated
- last year
Overview
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.
Investigators
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
Arms & Interventions
Intranasal Esketamine 84mg plus Oral Antidepressant
As part of an initial titration, participants will self-administer 56 milligrams (mg) of esketamine intranasally on Day 1, and then 84 mg from Day 4 onwards, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Esketamine
Intranasal Esketamine 84mg plus Oral Antidepressant
As part of an initial titration, participants will self-administer 56 milligrams (mg) of esketamine intranasally on Day 1, and then 84 mg from Day 4 onwards, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Duloxetine (Oral Antidepressant)
Intranasal Esketamine 84mg plus Oral Antidepressant
As part of an initial titration, participants will self-administer 56 milligrams (mg) of esketamine intranasally on Day 1, and then 84 mg from Day 4 onwards, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Escitalopram (Oral antidepressant)
Intranasal Esketamine 84mg plus Oral Antidepressant
As part of an initial titration, participants will self-administer 56 milligrams (mg) of esketamine intranasally on Day 1, and then 84 mg from Day 4 onwards, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Sertraline (Oral Antidepressant)
Intranasal Esketamine 84mg plus Oral Antidepressant
As part of an initial titration, participants will self-administer 56 milligrams (mg) of esketamine intranasally on Day 1, and then 84 mg from Day 4 onwards, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Venlafaxine Extended Release (XR) (Oral Antidepressant)
Esketamine 56 mg plus Oral Antidepressant
Starting from Day 1, participants will self-administer 56 mg of esketamine, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Esketamine
Esketamine 56 mg plus Oral Antidepressant
Starting from Day 1, participants will self-administer 56 mg of esketamine, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Duloxetine (Oral Antidepressant)
Esketamine 56 mg plus Oral Antidepressant
Starting from Day 1, participants will self-administer 56 mg of esketamine, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Escitalopram (Oral antidepressant)
Esketamine 56 mg plus Oral Antidepressant
Starting from Day 1, participants will self-administer 56 mg of esketamine, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Sertraline (Oral Antidepressant)
Esketamine 56 mg plus Oral Antidepressant
Starting from Day 1, participants will self-administer 56 mg of esketamine, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Venlafaxine Extended Release (XR) (Oral Antidepressant)
Placebo plus Oral Antidepressant
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Placebo
Placebo plus Oral Antidepressant
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Duloxetine (Oral Antidepressant)
Placebo plus Oral Antidepressant
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Escitalopram (Oral antidepressant)
Placebo plus Oral Antidepressant
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Sertraline (Oral Antidepressant)
Placebo plus Oral Antidepressant
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Intervention: Venlafaxine Extended Release (XR) (Oral Antidepressant)
Outcomes
Primary Outcomes
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
Time Frame: Baseline up to Day 28 of Double-blind Induction Phase
MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
Time Frame: Baseline up to Double-blind Endpoint (Day 28)
MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using Last Observation Carried Forward (LOCF) method and last post baseline observation during double-blind induction phase was carried forward as "End Point" for that phase.
Secondary Outcomes
- 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)(At Day 28 of Double-blind Induction phase)
- Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis(Baseline up to Day 28 of Double-blind Induction phase)
- 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)(At Day 28 (Double-blind Endpoint))
- Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis(Baseline up to Double-blind Endpoint (Day 28))
- Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis(Baseline up to Double-blind Endpoint (Day 28))
- Percentage of Participants in Remission (MADRS<=12) at Day 28 of Double-blind Induction Phase (Observed Data)(At Day 28 of Double-blind Induction Phase)
- Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8(Day 2 up to Day 28 and Day 8 up to Day 28)
- Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis(Baseline up to Day 28 of Double-blind Induction phase)
- Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis (LOCF Data)(At Day 28 (Double-blind Endpoint))
- Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint (Double-blind Induction Phase [Day 28])(Baseline up to Double-blind Endpoint (Day 28))
- Change From Baseline in Generalized Anxiety Disorder-7 Item (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])(Baseline up to Double-blind Endpoint (Day 28))
- 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(Baseline up to End of Double-blind Induction Phase (Day 28))
- Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): EQ-VAS(Baseline up to end of Double-blind induction phase (Day 28))
- Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Sum Score(Baseline up to end of Double-blind Induction phase (Day 28))