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

Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program

“…The largest mean maximum SBP/DBP increases from predose at any postdose timepoint across all intranasal dosing days were 13.3/8.7 mmHg for esketamine/antidepressant and 6.1/4.9 mmHg for antidepressant/placebo in the two 4-week studies of patients aged 18-64 years (Fig. 2) Table 3 Summary of increased blood pressure-related adverse events in esketamine nasal spray phase II/III clinical development studies CI confidence interval, TRD treatment-resistant depression a Includes safety evaluable patients from studies cited in Daly et al [4,7], Fedgchin et al [5], Popova et al [6], and Ochs-Ross et al [9] b Includes safety evaluable patients from studies cited in references Daly et al [4,7], Fedgchin et al [5], Popova et al [6], Wajs et al [8], and Ochs-Ross et al [9] c Includes all patients who had ≥ 1 occurrences of an adverse event that coded to the MedDRA ® preferred terms grouped under 'Increased Blood Pressure-related Events'; the patient is counted only once regardless of the number of events or the number of occurrences d The two-sided exact 95% CI in odds ratio of esketamine + oral antidepressant to oral antidepressant + placebo for All Randomized, Blinded Trials TRD Population e One event was severe and serious; 2 events in the All Clinical Trials TRD Population were severe and non-serious f Event was severe and serious g The total number of distinct preferred terms (i.e., preferred terms that refer to separate adverse events reported by individual patients) in the 'Increased Blood Pressure-related Events' group by seriousness/outcome and also by severity and 16.0/9.5 and 11.1/6.8 mmHg, respectively, in the elderly study (TRANSFORM-3). The percentage of patients (age 18-64 years) with markedly abnormal BP elevation (SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg) ranged 2.0-4.9% in esketamine/antidepressant group versus 0-0.9% in antidepressant/placebo group across studies/phases and was higher in patients with (5.5-7.6%) versus without (4.1-4.3%) a history of hypertension.…”

“…Safety data were analyzed in an All Randomized, Blinded Trials TRD Population [4][5][6][7]9] and in an All Clinical Trials TRD Population [4][5][6][7][8][9], both including patients who received at least one dose of intranasal study drug.…”

“…and one open-label phase III study of esketamine nasal spray in adults with TRD (Table 1 [4][5][6][7][8][9]).…”

“…Eligible patients received esketamine nasal spray (28 mg (only for patients 65 years and older) to 84 mg twice weekly, once weekly, or every other week; Table 1) in combination with an oral antidepressant for 4-52 weeks. In the phase III studies [5][6][7][8][9], patients received a new oral antidepressant [one of the following options: a selective serotonin reuptake inhibitor (SSRI: escitalopram or sertraline) or a serotonin and norepinephrine reuptake inhibitor (SNRI: duloxetine or venlafaxine extended release)], which was initiated at the start of the induction phase, whereas in the adjunctive phase II study [4], no new antidepressant was initiated and patients were permitted to continue their ongoing oral antidepressant treatment. In the placebo-controlled studies, patients randomized to placebo received intranasal study drug [i.e., water for injection with bittering agent (to imitate the bitter taste of esketamine) and a preservative] that was provided in a disposable nasal spray device with identical appearance and packaging to that of esketamine nasal spray.…”

“…Ketamine, an antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor (an ionotropic glutamate receptor), was shown to exhibit rapid onset and robust, short-term antidepressant effect in patients with treatmentresistant depression (TRD) [1][2][3]. Esketamine, the S-enantiomer of ketamine racemate, was recently approved by the United States (US) Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) as an intranasal formulation for adults with TRD based on efficacy and safety findings from short-term phase II/III studies [4][5][6][7][8][9] and longer-term phase III studies [7,8].…”