A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder (ESCAPE-TRD)
This Phase III interventional trial (n=676) evaluated flexibly dosed esketamine nasal spray versus quetiapine XR, both with a continuing SSRI/SNRI, in participants with treatment-resistant major depressive disorder.
Detailed Description
Randomized, parallel-group Phase III trial comparing flexibly dosed esketamine nasal spray (28/56/84 mg) plus continuing SSRI/SNRI against quetiapine XR augmentation of SSRI/SNRI in adults with treatment-resistant major depressive disorder.
Treatment included an 8-week acute phase (induction: twice-weekly dosing initially) followed by a 24-week maintenance phase with once-weekly or once-every-2-weeks dosing; safety assessments included AEs/SAEs, vitals, ECG, labs and C-SSRS monitoring.
Primary objective was efficacy for remission in participants with TRD; background SSRI/SNRI was continued and could be optimised per SmPC throughout the study.
Study Arms & Interventions
Esketamine
experimentalFlexibly dosed esketamine nasal spray plus continuing SSRI/SNRI; induction then maintenance schedule.
Interventions
- Esketamine56 - 84 mgvia Other• twice-weekly (Day1–Week4), then weekly (Week5–8), then weekly or every 2 weeks (Week9–32)
Nasal spray; doses 28, 56, or 84 mg; 28 mg initial option for elderly/Japanese ancestry; flexible uptitration per protocol.
- Compoundvia Other• daily
Continuing SSRI/SNRI (background treatment; dose optimised per SmPC).
Quetiapine XR
active comparatorQuetiapine XR augmentation of continuing SSRI/SNRI per SmPC versus esketamine arm.
Interventions
- Placebovia Other• daily
Quetiapine XR 50→150 mg (adults) with possible increase to 300 mg/day per investigator; elderly schedule differs; encoded as active comparator (name/doses in notes).
- Compoundvia Other• daily
Continuing SSRI/SNRI (background treatment; dose optimised per SmPC).
Participants
Inclusion Criteria
- At screening, participant must meet DSM-5 criteria for single-episode MDD or recurrent MDD without psychotic features confirmed by MINI.
- IDS-C30 total score >=34 at screening and baseline.
- On current SSRI/SNRI at screening with documented nonresponse (<25% improvement) after adequate dose/duration (>=6 weeks) and showing minimal clinical improvement at screening.
- Current antidepressant treatment preceded by nonresponse to 1–5 different consecutive adequate AD treatments within current episode.
- Treated with at least 2 different antidepressant substance classes at adequate dose/duration resulting in nonresponse in current episode.
- Must be on a single oral SSRI/SNRI on Day 1 prior to randomization.
Exclusion Criteria
- Received esketamine or ketamine in current episode.
- Received quetiapine extended- or immediate-release >50 mg/day in current episode.
- Depressive symptoms in current episode previously nonresponsive to adequate ECT course (>=7 unilateral/bilateral ECT treatments).
- No signs of clinical improvement on current SSRI/SNRI as determined at screening.
- Received vagal nerve stimulation or deep brain stimulation in current episode.
- 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/narcissistic personality disorder.
- Age at onset of first MDD episode >=55 years.
- Homicidal ideation or intent per investigator; suicidal ideation with some intent within 1 month prior to screening or C-SSRS Item 4 or 5 positive, or suicidal behaviour within past year.
Primary Results(2 publications)
Participants
Response Rates
Remission at Week 8 defined as MADRS total score <=8
Remission at Week 8 defined as MADRS total score <=12
Relapse-free through Week 32 after achieving remission at Week 8; remission defined as MADRS total score <=10
Relapse-free through Week 32 after achieving remission at Week 8; remission defined as MADRS total score <=8
Relapse-free through Week 32 after achieving remission at Week 8; remission defined as MADRS total score <=12
Remission without treatment discontinuation; MADRS total score <=10
Relapse-free through week 32 after remission at week 8 without treatment discontinuation
Response; >=50% reduction in MADRS total score or MADRS total score <=10
Remission; MADRS total score <=12
Remission; MADRS total score <=8
Remission; MADRS total score <=10
Remission at any point within the first 8 weeks; MADRS total score <=10
Remission without treatment discontinuation; MADRS total score <=12
Relapse-free through week 32 after remission at week 8 without treatment discontinuation; MADRS total score <=12
Relapse-free through week 32 after remission at week 8 without treatment discontinuation; MADRS total score <=8
Relapse-free through week 32 after remission at week 8 without treatment discontinuation; CGI-S total score >=5 as relapse definition
Adverse Events (from all publications)
| Arm / Group | n | Any TEAE | Severe | Serious | Discont. |
|---|---|---|---|---|---|
| Esketamineexperimental | 336 | — | — | — | — |
| Quetiapine XRactive_comparator | 340 | — | — | — | — |
| Esketamineexperimental | 314 | 289(92.0%) | — | — | 14(4.5%) |
| Quetiapine XRactive_comparator | 316 | 248(78.5%) | — | — | 32(10.1%) |
* This paper reports efficacy sensitivity analyses and does not provide treatment-emergent adverse event summary counts for the esketamine arm in the extracted text. Safety was mentioned as an evaluated outcome, but no AE table/counts were included here.
* This paper reports efficacy sensitivity analyses and does not provide treatment-emergent adverse event summary counts for the quetiapine XR arm in the extracted text. Safety was mentioned as an evaluated outcome, but no AE table/counts were included here.
* Safety analysis set. TEAE defined as starting after first dose and on or before 14 days after last dose; serious AEs counted as TEAEs if within 30 days after last dose. Discontinuation due to TEAEs was 4.5% (n=14/314), derived from text.
* Safety analysis set. TEAE defined as starting after first dose and on or before 14 days after last dose; serious AEs counted as TEAEs if within 30 days after last dose. Discontinuation due to TEAEs was 10.1% (n=32/316), derived from text.
Study Details
- StatusCompleted
- PhasePhase III
- Typeinterventional
- DesignRandomized
- Target Enrollment676 participants
- TimelineStart: 2020-08-21End: 2022-07-15
- Compounds
- Topic
Study Team
Sponsors & Collaborators
- Janssen Research & DevelopmentPrimary Sponsor