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 (TRANSFORM-1)
Randomized, double-blind, active-controlled Phase III study (n=346) comparing fixed-dose intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant versus intranasal placebo plus a newly initiated oral antidepressant in adults with treatment-resistant depression.
Detailed Description
This multicenter, randomized, double-blind, active-controlled study enrolled adults with treatment-resistant major depressive disorder to assess efficacy and safety of fixed doses of intranasal esketamine (56 mg or 84 mg) administered twice weekly plus a newly initiated oral antidepressant versus matching intranasal placebo plus a newly initiated oral antidepressant.
The trial included a screening/prospective observational phase (4–7 weeks), a 4-week double-blind induction phase (twice-weekly dosing), and a 24-week follow-up; primary outcome was change in MADRS total score at Week 4. Safety monitoring included adverse events, vital signs, and assessments per protocol.
Study Protocol
Preparation
Dosing
Integration
Study Arms & Interventions
Esketamine 84 mg
experimentalIntranasal esketamine 84 mg administered twice weekly plus a newly initiated oral antidepressant during 4-week double-blind induction.
Interventions
- Esketamine84 mgvia Other• twice per week• 8 doses total
Day 1 56 mg then 84 mg from Day 4 onwards per protocol titration.
- Compound• daily
Open-label oral antidepressant (duloxetine 60 mg/day; escitalopram up to 20 mg/day; sertraline up to 200 mg/day; venlafaxine XR up to 225 mg/day).
Esketamine 56 mg
experimentalIntranasal esketamine 56 mg administered twice weekly plus a newly initiated oral antidepressant during 4-week double-blind induction.
Interventions
- Esketamine56 mgvia Other• twice per week• 8 doses total
Fixed 56 mg dosing twice weekly.
- Compound• daily
Open-label oral antidepressant (duloxetine 60 mg/day; escitalopram up to 20 mg/day; sertraline up to 200 mg/day; venlafaxine XR up to 225 mg/day).
Placebo plus oral antidepressant
active comparatorMatching intranasal placebo twice weekly plus a newly initiated oral antidepressant during 4-week double-blind induction.
Interventions
- Placebo• twice per week• 8 doses total
Matching intranasal placebo.
- Compound• daily
Open-label oral antidepressant (duloxetine 60 mg/day; escitalopram up to 20 mg/day; sertraline up to 200 mg/day; venlafaxine XR up to 225 mg/day).
Participants
Inclusion Criteria
- Inclusion Criteria:
- At the time of signing the informed consent form (ICF), participant must be a man or woman 18 to 64 years of age, inclusive
- At the start of the screening/prospective observational phase, participant must meet DSM-5 diagnostic criteria for single-episode MDD (if single-episode MDD, duration must be >= 2 years) or recurrent MDD, without psychotic features, confirmed by MINI
- At the start of the screening/prospective observational phase, participant must have an IDS-C30 total score >= 34
- At the start of the screening/prospective observational phase, participants must have had non-response (<=25% improvement) to >=1 and <=5 oral antidepressant treatments taken at adequate dosage and duration in the current episode, as assessed by MGH-ATRQ
- Participant is taking a different oral antidepressant on the MGH-ATRQ for at least the previous 2 weeks at or above the minimum therapeutic dose
- Current major depressive episode and Week 1 MADRS total score >=28 must be confirmed using a Site Independent Qualification Assessment
Exclusion Criteria
- Exclusion Criteria:
- Prior nonresponse of depressive symptoms to esketamine or ketamine in the current episode, to all 4 oral antidepressant options available for induction (duloxetine, escitalopram, sertraline, venlafaxine XR) in the current episode, or an adequate course of ECT (>=7 treatments) in the current episode
- Participant has received VNS or DBS in the current episode of depression
- Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders, current OCD, intellectual disability, autism spectrum disorder, borderline personality disorder, antisocial, histrionic, or narcissistic personality disorder
- Participant has homicidal ideation/intent per investigator judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of screening/prospective observational phase (per investigator judgment or 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 Enrollment346 participants
- TimelineStart: 2015-08-10End: 2018-02-20
- Compounds
- Topic