Speaker 3: Christina Kurre Olsen, Denmark

Abstract

Background: Esketamine and ketamine have been shown to produce rapid antidepressant action in patients with treatmentresistant depression (TRD).The aim of the current study was to assess the efficacy, safety and dose response of intranasal esketamine in patients with TRD.Methods: This was a 2-Panel, doubly-randomized, double-blind, placebo-controlled, multicenter study.Panel A was conducted in the United States and Belgium and Panel B is currently ongoing in Japan.In both panels, each subject participated in up to 4 phases: a screening phase of up to 4 weeks, a double-blind treatment phase which included two 1-week periods (Periods 1 and 2), a 9-week optional open-label treatment phase and an 8-week posttreatment follow-up phase.Only Panel A double blind phase data are available, and will be presented at this time.The primary efficacy endpoint was the change from baseline to Day 8 in each period in the Montgomery-Asberg Depression Rating Scale (MADRS) total score combined.Safety and secondary efficacy endpoints were also assessed.Results: A total of 67 subjects with TRD were randomly assigned in a 3:1:1:1 ratio to one of four treatment groups: placebo (n=33), esketamine 28 mg (n=11), esketamine 56 mg (n=11), or esketamine 84 mg (n=12) in Period 1.In Period 2, 28 placebo subjects who were eligible for re-randomization at the end of Period 1 were randomly assigned to placebo (n=6), esketamine 28 mg (n=8), esketamine 56 mg (n=9), or esketamine 84 mg (n=5) in a 1:1:1:1 ratio.Subjects were eligible for re-randomization if the patient-rated 16 item Quick Inventory of Depressive Symptomatology (QIDS-SR16) total score was ≥11 at the end of Period 1.The analysis of Period 1 and Period 2, combined using the weighted combination test, showed that the mean change in MADRS total score in all three esketamine groups was statistically superior to that obtained under placebo, based on a one-sided 0.05 significance level (p=0.021,p=0.001 and p<0.001 for esketamine 28 mg, 56 mg and 84 mg respectively).The mean differences (SE) from placebo (after one week of treatment) were -4.2(2.09) for esketamine 28 mg, -6.3(2.07) for esketamine 56 mg, and -9.0(2.13) for esketamine 84 mg.The magnitude of effect size in Period 1 increases from a low Cohen's D effect size in the 28 mg dose group (0.43) to a high Cohen's D effect size for the 56 (0.92) and 84 mg (1.19) dose groups.The most common TEAEs during the double-blind phase (≥10% of subjects in any group) were: dizziness, dissociation, headache, dysgeusia, nasal discomfort, nausea, hypoaesthesia oral, dissociative symptoms, tunnel vision, oropharyngeal pain, throat irritation, blurred vision, hypersomnia, feeling abnormal, insomnia, hypertension, vertigo, polyuria and sedation.No death was reported.Transient elevation in blood pressure and heart rate was also observed on dosing days.The perceptual changes and dissociative symptoms measured by the Clinician administered Dissociative Symptom Scale (CADSS), suggest onset of these symptoms occurred shortly after the start of intranasal dosing and resolved by 2 hours postdose, and with repeated dosing these symptoms reduced significantly.Conclusions: Intranasal esketamine administered in doses of 28, 56 and 84 mg across the study period showed statistically and clinically significant improvement of depressive symptoms in subjects with TRD, as demonstrated by the mean changes in the MADRS total score for the combined analysis of both periods.The doses evaluated were well tolerated and adverse events were similar to what has been observed previously with IV ketamine and eskatamine.