EFFICACY AND SAFETY OF ESKETAMINE NASAL SPRAY PLUS AN ORAL ANTIDEPRESSANT IN ELDERLY PATIENTS WITH TREATMENT-RESISTANT DEPRESSION

Abstract

Introduction Estimates of 18-40% of elderly patients with depression suffer from treatment-resistant depression (TRD), defined as non-response to at least two antidepressants. Elderly patients experience greater disability and functional decline, decreased quality of life, and greater mortality from suicide than younger patients. Esketamine nasal spray is being investigated for treatment of TRD. We evaluated the efficacy, safety, and tolerability of flexibly dosed esketamine nasal spray (ESK) (28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant (AD), compared with AD plus placebo nasal spray (PBO), for the treatment of TRD in elderly patients. Post hoc analyses, performed to better assess the data from this first large clinical trial of TRD in the elderly, are presented in the companion abstract. Methods Patients ≥ 65 years of age (N=138) in this phase 3, double-blind, multicenter, active-controlled study (NCT02422186) were randomized (1:1) to either ESK + AD (n=72) or AD + PBO (n=66). The primary endpoint was the change in the Montgomery–Asberg Depression Rating Scale (MADRS) total score from day 1 (baseline) to the end of a 4-week double-blind treatment phase. Statistical analysis employed mixed-effects model for repeated measures (MMRM), with a weighted combination test to account for an interim analysis for sample size re-estimation, using a one-sided 0.025 significance level. Pre-specified subgroup analyses were performed for ages 65-74 years (n=116) and ≥75 years (n=21). Remote raters, blinded to the treatment arm, conducted the MADRS assessments by telephone. Results The mean (SD) patient age was 70.0 (4.52) years and mean (SD) baseline MADRS total score was 35.2 (6.16). The mean (SD) change in MADRS total scores from baseline to day 28 was -10.0 (12.74) for ESK + AD and -6.3 (8.86) for AD + PBO. Based on MMRM analysis, the median-unbiased estimate of the difference between ESK + AD and AD + PBO was -3.6 (95% CI: -7.20, 0.07; one-sided p=0.029). A treatment difference favoring ESK+AD was seen for the 65-74 years subgroup. The difference in LS mean (SE) change at day 28 was -4.9 (2.04) for 65-74 years (one-sided p=0.009) and -0.4 (5.02) for ≥75 years (one-sided p=0.465). The most common treatment-emergent adverse events (TEAEs) in the ESK + AD group were dizziness (20.8%), nausea (18.1%), headache, fatigue, increased blood pressure, dissociation (12.5% each) and vertigo (11.1%). The most common TEAEs in the AD + PBO group were anxiety, dizziness and fatigue (7.7% each). Conclusions While treatment with ESK + AD did not demonstrate a statistically significant difference vs treatment with AD + PBO using the weighted combination test on the primary outcome, a statistically significant treatment effect was observed for patients aged 65-74 years, but not for the limited number of patients aged ≥75 years. Safety results were consistent with previous studies in younger adult populations; no new safety concerns were identified. This study was funded by Janssen Research & Development, LLC. This research was funded by Janssen Research & Development, LLC