Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1)

Abstract

Background: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression.

Methods: This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested.

Results: Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache.

Conclusions: Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression.

Trial registration: ClinicalTrials.gov identifier: NCT02417064.

Keywords: esketamine; ketamine; s-ketamine; treatment-resistant depression.

Figure 1.

Disposition of patients. AE, adverse event; LOE, lack of efficacy; LTFU, lost to follow-up; MADRS, Montgomery-Asberg Depression Rating Scale; OTH,  other reason for withdrawal; PV, protocol violation; TRD, treatment-resistant depression; WBP, withdrawal by patient; WDDB, withdrawal from double-blind phase; WDFU, withdrawn from follow-up phase. 3008 entered Janssen-sponsored Study TRD3008 (NCT02782104). aPatients with nonresponse to ≥2 oral antidepressants, 1 observed prospectively, prior to randomization were eligible to participate in the study. bResponders (defined as ≥50% reduction in MADRS total score from baseline to end of the 28-day double-blind phase) were eligible to continue to Janssen-sponsored Study ESKETINTRD3003 (NCT02493868).

Figure 2.

Least squares mean change (±SE) in Montgomery-Asberg Depression Rating Scale (MADRS) total score over time in double-blind phase (observed cases mixed model for repeated measures [MMRM]). LS, least squares; SE, standard error. LS mean and SE were based on MMRM with change from baseline as the response variable and the fixed effect model terms for treatment (esketamine 56 mg/antidepressant, esketamine 84 mg/antidepressant, antidepressant/placebo), day, region, class of oral antidepressant, and treatment-by-day, and baseline value as a covariate. Results are not adjusted for multiple comparisons or sample size reestimation. Negative change in score indicates improvement.

Figure 3.

Least squares mean changes (±SE) in Montgomery-Asberg Depression Rating Scale (MADRS) total score over time (observed case) by stage in double-blind phase. SE, standard error. LS mean and SE were based on mixed model for repeated measures (MMRM) with change from baseline as the response variable and the fixed effect model terms for treatment (esketamine 56 mg/oral antidepressant, esketamine 84 mg/oral antidepressant, oral antidepressant/placebo), day, region, class of oral AD, stage, treatment-by-day, treatment-by-stage, and treatment-by-day-by-stage, and baseline value as a covariate. Results are not adjusted for multiple comparisons or sample size reestimation. Negative change in score indicates improvement.

Figure 4.

Forest plot for Montgomery-Asberg Depression Rating Scale (MADRS) total score: least squares mean treatment difference of change from baseline (95% CI) to day 28 mixed model for repeated measures (MMRM) by subgroup in double-blind phase. CI , confidence interval. aNumber of antidepressants taken with nonresponse in addition to 1 prospective antidepressant.

Figure 5.

Mean (±SE) Clinician-Assessed Dissociative Symptom Scale (CADSS) total score over time in the double-blind phase. SE, standard error.

Figure 6.

Mean (±SE) blood pressure over time in the double-blind phase. SE, standard error.