A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression (TRANSFORM-2)
The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) subjects 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
Randomized, double-blind, active-controlled, multicentre Phase III study in adults with treatment-resistant major depressive disorder comparing flexible-dose intranasal esketamine plus a new oral antidepressant versus intranasal placebo plus a new oral antidepressant.
Double-blind induction phase: 4 weeks with intranasal dosing twice weekly (start 56 mg, may increase to 84 mg per protocol) and initiation of one of four open-label oral antidepressants; safety and efficacy assessed acutely and during a 24-week follow-up for non-rollover participants.
Primary outcomes assess antidepressant efficacy in TRD; safety monitoring includes adverse events, vital signs, and tolerability with specified dose adjustments for tolerability through Day 15.
Study Protocol
Preparation
Dosing
Integration
Study Arms & Interventions
Esketamine + oral antidepressant
experimentalIntranasal esketamine (flexible 56 or 84 mg) twice weekly for 4 weeks plus a newly initiated oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR).
Interventions
- Esketamine56 - 84 mgvia Other• twice per week• 8 doses total
Intranasal; start 56 mg Day 1; may increase to 84 mg on Day 4 and on Days 8/11; dose may be reduced for tolerability; stable after Day 15.
- Compound mg/dayvia Other• daily
New oral antidepressant started Day 1 (duloxetine 60 mg/day minimum; escitalopram up to 20 mg/day, min 10 mg; sertraline up to 150 mg/day, min 50 mg; venlafaxine XR up to 225 mg/day, min 150 mg).
Placebo + oral antidepressant
active comparatorMatching intranasal placebo twice weekly for 4 weeks plus a newly initiated oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR).
Interventions
- Placebovia Other• twice per week• 8 doses total
Matching intranasal placebo, administered on same schedule.
- Compound mg/dayvia Other• daily
New oral antidepressant started Day 1 (duloxetine, escitalopram, sertraline, or venlafaxine XR) per investigator selection; titration per protocol.
Participants
Inclusion 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, participant must have had non-response (greater 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 in the current episode of depression, 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. 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 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
- 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 psychosis, bipolar or related disorders (confirmed by the MINI), comorbid obsessive compulsive disorder, 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)
- Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria
Study Details
- StatusCompleted
- PhasePhase III
- Typeinterventional
- DesignRandomizeddouble Blind
- Target Enrollment236 participants
- TimelineStart: 2015-08-07End: 2017-11-06
- Compounds
- Topic