Esketamine Nasal Spray for Rapid Reduction of... — Research Summary & Context

Abstract

Objective

To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation.

Methods

This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate.

Results

Greater improvement in MADRS total score was observed with esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: −3.8 [1.39]; 95% CI, −6.56 to −1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [−1.00 to 0.00]; 2-sided P = .107). The most common adverse events among esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence.

Conclusions

These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent.

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Research Summary of 'Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I)'

Introduction

Depression is a common, disabling disorder that carries substantial suicide-related morbidity and mortality. Patients with major depressive disorder (MDD) who have active suicidal ideation with intent represent a particularly severe subgroup, with more pronounced depressive symptoms and poorer treatment response than those without suicidal ideation. Current standard management for such patients typically includes initiation or optimisation of oral antidepressants and inpatient care, but conventional antidepressants often take four or more weeks to reach full effect and there were, until recently, no approved pharmacological treatments specifically for rapid reduction of depressive symptoms in this high-risk population. Ionescu and colleagues describe a global clinical development programme comprising two identically designed Phase III trials (ASPIRE I and ASPIRE II) intended to test whether adding esketamine nasal spray to comprehensive standard of care produces a more rapid reduction in depressive symptoms than placebo plus standard of care. The study reported in this paper (identified in the text as ASPIRE II) set out to determine if esketamine plus standard of care would significantly reduce Montgomery–Åsberg Depression Rating Scale (MADRS) total score at 24 hours post first dose compared with placebo plus standard of care, and to characterise safety in this acutely suicidal population.

Methods

This was a double-blind, randomised, placebo-controlled, multicentre study conducted between June 2017 and April 2019 at 47 sites across multiple countries. The study comprised a screening phase (within 48 hours before first dose), a 25-day double-blind treatment phase, and a 9-week follow-up phase (days 26–90). Eligible adults were 18–64 years old, met DSM‑5 criteria for MDD without psychosis based on the Mini International Neuropsychiatric Interview, had a baseline MADRS total score >28, and had active suicidal ideation with intent as determined by affirmative responses to MINI items assessing current suicidal thoughts and intent. Key exclusions included selected concurrent psychiatric diagnoses (for example bipolar disorder or psychotic disorders), recent moderate-to-severe substance/alcohol use disorder, and positive urine tests for certain illicit substances unless medically prescribed. Patients were randomised 1:1 by computer-generated permuted blocks and stratified by site and type of standard-of-care antidepressant (monotherapy or antidepressant plus augmentation). Blinding measures included addition of a bittering agent to placebo and identical nasal spray devices; efficacy raters were separate from safety raters and not involved in patient care. Intranasal study drug was self-administered under supervision twice weekly for 4 weeks: each nominal 84 mg dose comprised three devices delivering a total of 84 mg esketamine base (or matching placebo), with a protocol‑permitted one-time dose reduction to 56 mg for intolerance. Comprehensive standard of care was provided to all patients and consisted of recommended inpatient psychiatric hospitalisation (≥5 days; in some EU countries 14 days) and a newly initiated or optimised oral antidepressant regimen (monotherapy or antidepressant plus augmenting agent); antidepressant doses could be adjusted during the first 2 weeks. The primary efficacy endpoint was change in MADRS total score from baseline to 24 hours after the first dose (day 2). The key secondary endpoint was change in Clinical Global Impression‑Severity of Suicidality‑revised (CGI‑SS‑r) over the same interval. MADRS assessments were performed pre-dose and at 4 and 24 hours after the first dose, pre-dose at subsequent visits, and at multiple points during follow-up. Suicidality was assessed with a computerized Suicide Ideation and Behavior Assessment Tool including CGI‑SS‑r, CGI of Imminent Suicide Risk (CGI‑SR‑I), and Frequency of Suicidal Thinking (FoST). Safety monitoring included adverse events, vital signs, the Clinician Administered Dissociative States Scale (CADSS), and the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) at dosing visits. The primary analysis used ANCOVA on last observation carried forward (LOCF) data with factors for treatment, analysis centre, and standard‑of‑care antidepressant type, and baseline MADRS as a covariate; CGI‑SS‑r change was analysed with ANCOVA on ranks. A mixed model for repeated measures (MMRM) was used to assess treatment effect over time on observed cases. Multiplicity was controlled by a fixed-sequence testing procedure. The planned sample size (~112 per arm) was estimated to provide 90% power to detect a standardised effect size of 0.45 on the primary endpoint with a 2‑sided α=0.05.

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INTRODUCTION

Depression is a common, disabling, and costly psychiatric illness that can have a devastating impact on all aspects of life; affected individuals are often unable to continue with ordinary family, social, or work activities and may feel that life is not worth living. Moreover, suicide-related morbidity and mortality in patients with major depressive disorder (MDD) are major public health concerns. Between 10% and 20% of patients with MDD attempt suicide over their lifetime, with an estimated lifetime risk of 3.4% for completed suicide. Depression with suicidal ideation is a particularly severe form of MDD; these patients show more severe depressive symptomsand worse response to treatmentcompared with MDD patients without suicidal ideation. Nearly all patients with MDD who attempt or complete suicide have suicidal ideation prior to the event. Thus, patients with MDD who have active suicidal ideation with intent require prompt intervention to protect them from self-harm. Current standard of care includes initiation or optimization of oral antidepressants and, frequently, hospitalization (American Psychiatric. However, there are no approved pharmacological treatments for the rapid reduction of depressive symptoms in this patient population, and standard antidepressants often take 4 or more weeks for optimal effect. Furthermore, the benefits of hospitalization are short-lived; the risks for attempted and completed suicide remain high in the weeks immediately after discharge. Esketamine nasal spray was approved in 2019 in the United States and European Union for treatment-resistant depression in adults (Spravato Summary of Product Characteristics 2019; Spravato Prescribing Information 2020). The primary mechanism of esketamine, an N-methyl-D-aspartate receptor antagonist, is distinct from that of conventional monoaminergic antidepressants. Rapid, robust, clinically meaningful reduction in depressive symptoms has been demonstrated in phase 2/3 studies of treatment-resistant depressionand in a phase 2, proof-of-concept study of depressed patients at imminent risk for suicide, suggesting a role for esketamine nasal spray in the urgent care of patients with MDD who have active suicide ideation with intent. The first clinical development program, consisting of 2 identically designed, phase 3 global studies (ASPIRE I and ASPIRE II), was launched to confirm the antidepressant benefits of esketamine in this population. These studies, which were conducted to determine if treatment with esketamine nasal spray plus standard of care would significantly reduce Montgomery-Asberg Depression Rating Scale (MADRS) total score at 24 hours, compared to placebo plus standard of care, formed the basis for esketamine's approval in 2020 in the United States for the treatment of depressive symptoms in adult MDD patients with acute suicidal ideation or behavior (Spravato Prescribing Information 2020). The results of ASPIRE II are reported herein.

Study Details

Study Type
individual
Population
humans
Characteristics
placebo controlleddouble blindparallel group
Journal
Journal of Clinical Psychiatry
Compounds
Esketamine Ketamine
Topics
Depressive Disorders Suicidality

Results

Of 273 patients screened, 230 were randomised (115 per arm); 227 received at least one dose and were included in efficacy and safety analyses. Completion of the 4‑week double‑blind phase occurred in most patients (esketamine: 90/115, 78.3%; placebo: 94/115, 81.7%); 183 entered follow‑up and 166 completed day 90. Baseline clinical severity was high (mean MADRS 39.7, SD 5.48), 91.2% were rated moderately to extremely suicidal on CGI‑SS‑r, and 66.1% had a prior suicide attempt. A somewhat higher proportion randomised to esketamine had a recent (within 1 month) suicide attempt (31.6% vs 21.2%). Concomitant benzodiazepine use during double‑blind treatment occurred in 67.4% of patients. On the primary endpoint, MADRS total score decreased in both groups at 24 hours, with a significantly greater reduction in the esketamine plus standard‑of‑care group. Mean change from baseline to 24 hours was −15.7 (SD 11.56) with esketamine and −12.4 (SD 10.43) with placebo; the least‑squares mean difference was −3.9 (SE 1.39), 95% CI −6.60 to −1.11, 2‑sided P = .006. A significant advantage for esketamine was already evident at 4 hours (LS mean difference −4.2, 95% CI −6.38 to −1.94). The treatment benefit generally persisted across the double‑blind phase and was statistically significant at day 25 pre‑dose (LS mean difference −3.7, 95% CI −7.09 to −0.38). Remission (MADRS ≤12) rates were numerically higher with esketamine at most timepoints; the between‑group difference in remission was 11.3% (95% CI 1.83 to 20.80) at 24 hours. Response rates (≥50% MADRS improvement) generally favoured esketamine over placebo, except at the day 25 4‑hour post‑dose assessment. Subgroup analyses showed the primary treatment effect was observed in most subgroups, including patients with prior suicide attempts and those with more severe baseline depressive symptoms. Suicidality as measured by CGI‑SS‑r decreased rapidly in both groups (median change −1.0 at 24 hours), but the between‑group difference was not statistically significant (P = .379). Similar improvements in suicidality were observed by other indices and remained low during follow‑up; at day 90, among observed cases, 86.3% (69/80) of esketamine‑treated and 76.7% (66/86) of placebo‑treated patients had CGI‑SS‑r scores of 0 or 1. Adverse events commonly reported with esketamine during the double‑blind phase included dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. Most adverse events occurred on dosing days and resolved the same day. Thirteen (11.4%) esketamine‑treated patients required a dose reduction to 56 mg for intolerance. No deaths occurred. Events potentially related to suicidality during the double‑blind phase were balanced between groups (10 patients per group; 3 patients per group reported a suicide attempt). During follow‑up, nine patients in each group reported suicidality‑related events; four patients previously treated with esketamine and one previously treated with placebo attempted suicide in follow‑up. Dissociative symptoms (CADSS) and blood pressure increases began shortly after dosing, peaked at about 40 minutes, and generally resolved by 1.5 hours post‑dose; the highest mean CADSS post‑first dose was 15.9 (SD 12.8) with esketamine versus 1.9 in placebo. Sedation of moderate or greater severity (MOAA/S ≤3 at any time) occurred in 21/114 (18.4%) esketamine‑treated versus 3/113 (2.7%) placebo‑treated patients; none required medical intervention or showed respiratory depression.

Discussion

Ionescu and colleagues report that, in this acutely suicidal MDD population, esketamine nasal spray added to comprehensive standard of care produced a statistically significant and clinically meaningful greater reduction in depressive symptoms at 24 hours compared with placebo plus standard of care. Rapid improvements were observed as early as 4 hours after the first dose, and the advantage for esketamine generally persisted throughout the 4‑week double‑blind treatment phase, with statistical significance at the final pre‑dose assessment. The authors note that these Phase III results confirm findings from the other identically designed trial in the programme. With respect to suicidality, severity decreased rapidly in both groups but the key secondary endpoint (CGI‑SS‑r at 24 hours) did not show a significant between‑group difference. The investigators suggest several possible explanations: the therapeutic effect of comprehensive standard‑of‑care interventions (including inpatient hospitalisation and initiation/optimisation of oral antidepressants), the intensive clinical contact inherent in trial participation, and concomitant benzodiazepine use may have mitigated suicidality in both arms. Safety findings were consistent with the known profile of esketamine; dissociation, transient sedation, and transient blood pressure elevations occurred primarily in the immediate post‑dose period and resolved within about 1.5 hours. No completed suicides were observed during the study period, and adverse events potentially related to suicidality were balanced between groups. The authors acknowledge methodological challenges inherent to trials in a high‑risk suicidal population. Conducting the study within comprehensive standard‑of‑care was necessary for safety and ethics but complicates attribution of effects solely to the investigational drug. Functional unblinding due to esketamine's acute dissociative effects could have biased clinical care decisions, although measures were implemented to separate efficacy raters from care providers. Additional limitations cited include the substantial placebo response seen in antidepressant trials, potential regional variation in standard‑of‑care practices (notably hospitalisation duration), and the influence of protocol‑specified hospitalisation requirements on outcomes. The investigators conclude that, while further research is warranted to understand real‑world implementation, these trials provide evidence that esketamine nasal spray may address an unmet need for a rapid‑acting antidepressant in adults with MDD and active suicidal ideation with intent.

INTRANASAL STUDY DRUG AND STANDARD-OF-CARE ORAL ANTIDEPRESSANT THERAPY

The intranasal study drugs were administered via identical, disposable nasal spray devices. Each device delivered 2 sprays of either esketamine (total of 28 mg of esketamine base) or placebo. Patients self-administered intranasal study drug twice weekly for 4 weeks; intranasal study drug dosing occurred at the study site and was supervised by a site healthcare professional. After the first dose, a protocolpermitted 1-time dose reduction of esketamine (or corresponding placebo) from 84 mg to 56 mg was allowed for patients who experienced intolerance; patients who required a dose reduction continued 56 mg dosing thereafter. Standard-of-care oral antidepressant(s) (monotherapy or antidepressant plus an augmenting agent [e.g., second antidepressant, an atypical antipsychotic, or a mood stabilizer]) was initiated or optimized at randomization by investigators based on their clinical judgment and practice guidelines. The dose of standard-of-care antidepressant(s) could be titrated/ adjusted, if needed, during the first 2 weeks of double-blind treatment but not thereafter. Patients also received standard-ofcare antidepressant(s) during the follow-up phase; antidepressant drug and dosage were based on the clinical judgment of investigators. The first dose of study drug was administered in an emergency department or in an inpatient psychiatric unit, where study patients were to remain for a recommended 5 days (14 days in 7 countries in the European Union based on health authority request during the clinical trial approval); shorter or longer periods of hospitalization were permitted, if clinically necessary, per local standard practice. Benzodiazepines at an equivalent dosage to lorazepam ≤6 mg/d were allowed during the study but prohibited within 8 hours before each intranasal study drug dose, and none were to be used within 4 hours after the first dose of intranasal study drug and within 8 hours of day 2 assessments. Psychotherapy was permitted, but electroconvulsive therapy was restricted during the study.

EFFICACY ENDPOINTS AND ANALYSES

Statistical analyses were conducted at a 2-sided .05 level of significance. Multiplicity with regard to testing multiple endpoints (primary and key secondary) was controlled by a fixed sequence Downloaded fromby guest on 10 July 2021 testing procedure (i.e., the key secondary efficacy endpoint was to be tested only after the null hypothesis for the primary endpoint was rejected). The primary efficacy endpoint was change in MADRS total score from baseline (day 1, pre-dose) to 24 hours after the first dose (day 2). The primary endpoint was analyzed on last observation carried forward (LOCF) data using ANCOVA with treatment, analysis center, and standard-of-care antidepressant as randomized (monotherapy or antidepressant plus augmentation therapy) as factors, and baseline MADRS total score as a continuous covariate. Five patients (3 patients in the esketamine plus standard-of-care group and 2 patients in the placebo plus standard-of-care group) did not have a day 2 MADRS total score for analysis of the primary endpoint; the MADRS total score from 4 hours post-first dose was carried forward to day 2 (i.e., LOCF) for these 5 patients. One additional patient in the esketamine plus standard-of-care group was missing day 1, 4 hours post-dose, and day 2 values and was not included in the primary analysis on LOCF data using ANCOVA. Treatment effect over time for MADRS total score during the double-blind and follow-up phases was analyzed using a mixed model for repeated measures based on observed case data. The model included baseline MADRS total score as a continuous covariate; day, treatment, analysis center, standard-of-care antidepressant treatment as randomized, and day-by-treatment interaction as fixed effects, and a random patient effect. The key secondary efficacy endpoint, change in CGI-SS-r from baseline to 24 hours after the first dose, was analyzed using an ANCOVA model on the ranks of change with the same factors used for the primary endpoint and unranked baseline score as a covariate. Subgroup analyses were performed according to the ANCOVA model used for the primary efficacy endpoint and key secondary efficacy endpoint (unranked data); the subgroups are shown in supplementary Figureand supplementary Figure, respectively. The percentage of patients in remission (defined as MADRS total score ≤12) and response rate (≥50% improvement in MADRS total score) over time were summarized, and estimates of the treatment difference in proportions and 95% CIs were calculated. Differences in least square (LS) means and 95% CIs were calculated for other indices of suicidality (MADRS suicide item, CGI-SR-I, clinician-and patient-rated FoST) based on ANCOVA modeling similar to that described for the primary endpoint analysis. Frequency distributions or descriptive statistics were provided for adverse events, vital signs, CADSS, and MOAA/S. Adverse events potentially related to suicidality (MedDRA preferred terms presented in the online supplement) were summarized.

EFFICACY RESULTS

MADRS total score decreased from baseline to 24 hours after the first dose (day 2) in both the esketamine plus standard-of-care group (mean [SD]: -15.7 [11.56]) and the placebo plus standardof-care group), with significantly greater improvement in depressive symptoms with esketamine (LS mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). The treatment effect of esketamine was observed in most subgroups (supplementary Figure), importantly among patients who had attempted suicide) and patients with more severe depressive symptoms (i.e., MADRS total score > median)). The difference between treatment groups was evident at 4 hours (LS mean difference -4.2, 95% CI: -6.38; -1.94) and generally remained over the double-blind treatment phase (after the 24-hour assessment, significant only at day 25 pre-dose [-3.7, 95% CI: -7.09; -0.38]; Figure). Among the patients who completed double-blind treatment and entered the follow-up phase, MADRS total scores remained low throughout follow-up (supplementary Figure). The percentage of patients who achieved remission (MADRS total score ≤12) was numerically greater for the esketamine plus standard-of-care group than the placebo plus standard-of-care group at all time points during double-blind treatment, except on day 18 (Figure). The treatment difference (95% CI) in remission between study arms was 11.3% (1.83, 20.80) 24 hours post-first dose on day 2 and 10.2%4 hours postdose on day 25. Response rates directionally favored esketamine plus standard of care over placebo plus standard of care at all timepoints but the day 25, 4-hour post-dose timepoint (supplementary Figure). Patients in both treatment groups experienced rapid reduction in the severity of their suicidality as measured by the CGI-SS-r (median change from baseline at 24 hours post-first dose: -1.0 point); the between-group difference was not statistically significant (2-sided P = .379). At the 24-hour time point, the treatment difference (LS mean difference, 95% CI) observed in the subgroup of patients with a history of prior suicide attempt was -0.22 (-0.64, 0.19) and in the subgroup of patients with more severe depressive symptoms was -0.31 (-0.79, -0.18) (supplementary Figure). Severity of suicidality also improved in both treatment groups at the end of double-blind treatment (Figure). Severity of suicidality was low at the end of the follow-up phase for most patients in both treatment groups. Among patients who completed the double-blind treatment and entered the follow-up phase (observed cases), 86.3% (69/80) of patients in the esketamine plus standard-of-care group and 76.7% (66/86) of patients in the placebo plus standard-of-care group had a CGI-SS-r score of 0 or 1 at day 90, indicating the patient was normal/ questionably suicidal. Results for other indices of suicidality are presented in supplementary Figure.

SAFETY RESULTS

The most frequently reported adverse events are listed in Table(reported during the double-blind treatment phase) and supplementary Table(reported during the follow-up phase). The majority of events in the esketamine plus standard-of-care group (89.1%) and placebo plus standard-of-care group (68.0%) occurred on intranasal dosing days, and most of these events (94.9% and 84.9%, respectively) resolved on the same day they began. Thirteen esketamine-treated patients (11.4%) had a dose reduction to 56 mg due to intolerance. No deaths were reported during the study. Serious adverse events (supplementary Tablesand) and events leading to discontinuation of study drug are summarized in the online supplement. The numbers of patients who reported adverse events potentially related to suicidality during the double-blind treatment phase were balanced between the treatment groups (10 patients in each treatment group; 3 patients per group who reported a suicide attempt). During the follow-up phase when patients were only receiving standard of care and not study medication, 9 patients in each treatment group reported events related to phase and either entered the follow-up phase or had adverse events evaluated after the double-blind treatment phase. Note: Three patients were not included in the efficacy analysis dataset due to discontinuing prior to receiving study drug or not providing postbaseline efficacy data. suicidality. Four patients previously treated with esketamine plus standard of care and 1 patient previously treated with placebo plus standard of care attempted suicide in the follow-up phase. The occurrence of these suicide attempts in the follow-up phase was dispersed over the follow-up phase without an apparent pattern suggestive of a rebound effect. Six of the 11 patients who attempted suicide during the study had a history of a prior suicide attempt. Note: CGI-SS-r (score ranges from 0-6; a higher score indicates a more severe condition): "Considering your total clinical experience with suicidal patients and all information now available to you, how suicidal is this patient at this time?" Downloaded fromby guest on 10 July 2021 Dissociative symptoms and transient perceptual effects measured by the CADSS total score (supplementary Figure) began shortly after the start of esketamine dosing, peaked at the 40-minute post-dose assessment, and generally resolved by 1.5 hours post-dose. The highest (mean [SD]) CADSS total score post-first dose was 15.9 [12.8] in the esketamine plus standardof-care group and 1.9in the placebo plus standard-of-care group (supplemental Figure). No symptoms or adverse events of psychosis were reported during treatment with intranasal study drug. No symptoms or adverse events consistent with withdrawal or abuse were reported during the follow-up period. Blood pressure increased following esketamine dosing, peaking at 40 minutes post dose, and generally returning to baseline by 1.5 hours post dose (supplementary Figure). More patients in the esketamine plus standard-of-care group (21/114 [18.4%]) had a MOAA/S score ≤3 (indicating moderate or greater sedation) at any time during the double-blind phase vs patients in the placebo plus standard-of-care group (3/113 [2.7%]). None of these patients required medical intervention or manifested respiratory depression.

DISCUSSION

In this study of patients with MDD with suicidal ideation and intent-a particularly vulnerable patient population-treatment with esketamine plus standard of care resulted in a significantly greater improvement of depressive symptoms compared with placebo plus standard of care at the primary Downloaded fromby guest on 10 July 2021 endpoint (24 hours post-first dose). Given the substantial benefit of standard of care, consisting of initial inpatient psychiatric hospitalization and newly initiated or optimized oral antidepressant therapy, the additional treatment effects with esketamine are noteworthy. Rapid improvement in depressive symptoms was observed at 4 hours after the first dose. The advantage with esketamine continued until the end of 4-week double-blind treatment (LS mean treatment difference ranging from -1.2 to -3.7, statistically significant at day 25 predose), at which time oral antidepressant therapy putatively has sufficient time to exert its full effect. The findings of this phase 3 study confirm those from the identically designed study reported by, both showing that esketamine nasal spray rapidly reduces depressive symptoms in MDD patients having suicidal ideation with intent. The difference in the key secondary outcome, as measured by CGI-SS-r, did not reach the level of statistical significance at 24 hours between the 2 treatment groups. Several factors may have contributed to this finding. Psychiatric hospitalization may have played a role in mitigating the suicidal crisis among patients in both treatment groups. In addition, the rapid reduction of suicidality observed in both treatment groups may be at least partly related to the enhanced clinical contact associated with extensive study assessments and the use of benzodiazepines (as described in the Methods section) in both treatment arms. The adverse events observed in this study are consistent with the established safety profile of esketamine nasal spray (Spravato Summary of Product Characteristics 2019; Spravato Prescribing Information 2020). Dissociative symptoms (based on CADSS score), sedation (based on MOAA/S score), and blood pressure elevation associated with esketamine administration were, in general, confined to the immediate (1.5 hour) post-dosing period. No completed suicides were observed in either treatment group during the duration of the double-blind and follow-up phases. Overall, the number of patients who reported adverse events potentially related to suicidality was balanced between the treatment groups in both the double-blind treatment and follow-up phases and appear low in the context of published literature. For example, in a study of the emergence of suicidal ideation during post-discharge treatment of depressed patients, 70% of those with severe suicidality at index hospitalization exhibited recurrence of suicidal ideation after discharge and nearly 80% of patients with post-discharge suicidal ideation experienced suicidal thinking within 2 months of the hospitalization. Specifically, with regard to suicide attempts, 3 patients in each treatment group attempted suicide during the double-blind treatment. During the follow-up, among the 4 patients previously treated with esketamine who attempted suicide, 3 had a recent prior attempt. The 1 patient formerly treated with placebo who attempted suicide had a history of prior suicide attempt, though not within the past month. The fact that more patients randomized to esketamine had a history of recent (in the last month) suicide attempts compared with placebo (31.6% vs 21.2%), a known risk factor for subsequent suicidal behavior, may relate to the difference in the observed number of events in the follow-up phase. Indeed, in the phase 2 study, 3 patients in the group previously treated with placebo attempted suicide in the follow-up phase compared with 0 suicide attempts in the patients previously treated with esketamine plus standard of care; all 3 patients who attempted suicide in that study had a prior suicide attempt, 2 within the most recent month. Nonetheless, given the severity of suicidality of the studied population, the number of suicide attempts was low overall. Furthermore, severity of suicidality, based on CGI-SS-r scores, remained low during the follow-up phase of ASPIRE II. A population-based retrospective cohort study of US health claims was conducted to better understand suicide attempts in the period immediately following a psychiatric hospitalization. Among 121 065 adults with depression who were hospitalized for suicide ideation or attempt, the rate of re-hospitalizations due to suicidal ideation or suicidal attempt ranged from 8.0% to 11.2% (2.4%-3.3% for suicide attempt) within a year of discharge; the highest risk was reported during the first month, and nearly one-half of re-hospitalizations occurred within 3 months after initial hospitalization. Moreover, in a meta-analysis of 29 studies, Chung and associates reported a pooled suicide rate of 2060 per 100 000 person-years in the first month following discharge from a psychiatric hospital. Therefore, despite the severity of illness in our studied population, the rate of suicide attempts in the period immediately following psychiatric hospitalization is relatively low in this high-risk population and consistent with the literature. One of the study limitations relates to the unique methodological challenges of conducting clinical trials in a population of patients with MDD who have active suicidal ideation and intent. To study these patients in a safe and ethical manner, the study was conducted in the context of comprehensive standard of care, inclusive of initial hospitalization and optimized oral antidepressant therapy. Given difficulties in masking the dissociative side effects of esketamine, functional unblinding may have biased clinical decisions on patient care; however, potential bias on efficacy outcomes was mitigated by the protocol requirements that efficacy raters could not be involved in patient care and must have been different from safety raters. There is a well-known and substantial placebo response in antidepressant clinical trials due in large part to patient expectations and the intensity of therapeutic contacts). Potential regional differences in the standard-of-care treatment provided in this global study, particularly the regional differences in length of inpatient hospitalization, may also impact the study findings. Moreover, hospital duration was influenced by protocol requirements, and further research is needed to understand the impact of hospitalization in real-world practice. There is a clear unmet medical need for a novel treatment that can rapidly improve the depressive symptoms in patients with MDD who have active suicidal ideation with intent and bridge the efficacy gap created by the delayed onset of action of standard antidepressants. This study and another identically designed, phase 3 studyare pivotal to the first global clinical development program, to our knowledge, for this severely ill and vulnerable patient population and formed the basis for the FDA's recent approval of esketamine for these patients (Spravato Prescribing Information 2020). Evidence from this study suggests esketamine nasal spray may fulfill the unmet need for a rapid-acting antidepressant in patients undergoing an acute crisis of suicidal ideation and intent, addressing the limitation of delayed onset of antidepressant efficacy observed with existing pharmacological treatments.

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Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I)

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A Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Participants Assessed to be at Imminent Risk for Suicide (ASPIRE I)

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Abstract

Research Summary of 'Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I)'

Introduction

Methods

INTRODUCTION

Study Details

Results

Discussion

ETHICAL PRACTICES

PATIENTS

SIGNIFICANCE STATEMENT

STUDY DESIGN

RANDOMIZATION AND BLINDING

INTRANASAL STUDY DRUG AND STANDARD-OF-CARE ORAL ANTIDEPRESSANT THERAPY

EFFICACY AND SAFETY ASSESSMENTS

STATISTICAL METHODS

EFFICACY ENDPOINTS AND ANALYSES

SAMPLE SIZE DETERMINATION

PATIENTS AND TREATMENT

EFFICACY RESULTS

SAFETY RESULTS

DISCUSSION