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)

This placebo-controlled, double-blind study, phase 3 study (n=226) compared esketamine (84mg, nasal, 2xp/w for 4w) with a placebo spray and found esketamine to be effective in lowering depression scores (MADRS) for those suffering from depression (MDD) and suicidal ideation (SI). Scores on a measure of SI was, however, not significantly different between the two groups.

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.

Authors: Dong-Jing Fu, Dawn F. Ionescu, Xiang Li, Rosanne Lane, Pilar Lim, Gerard Sanacora, David Hough, Husseini Manji, Wayne C. Drevets & Carla M. Canuso

Summary

ABSTRACT

This phase 3, double-blind, multicenter study enrolled 226 adults with major depressive disorder, 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.

Esketamine + standard-of-care was more effective than placebo + standard-of-care at improving MADRS total score at 24 hours, as well as at earlier and later time points during 4-week double-blind treatment.

Depression is the leading cause of disability worldwide and a major contributor to the overall global burden of disease. Patients with major depressive disorder who have active suicidal ideation with intent constitute a psychiatric emergency and are often hospitalized to protect themselves from self-harm.

Esketamine nasal spray, an NMDA receptor antagonist, was recently approved in the United States and European Union for treating treatment-resistant depression. A phase 2 double-blind, proof-of-concept study found that esketamine nasal spray significantly reduced depressive symptoms in depressed patients at imminent risk for suicide.

Ethical Practices

Independent Review Boards and Ethics Committees approved the study protocol, which was conducted in accordance with Good Clinical Practices and applicable regulatory requirements.

Study Population

Adults with MDD without psychotic features were enrolled in the study. They had to think about suicide within 24 hours of presenting to the emergency department or inpatient psychiatric unit, and have a MADRS total score > 28 predose on day 1.

The criteria for inclusion were obsessive-compulsive disorder, antisocial personality disorder, borderline personality disorder, moderate-to-severe substance use disorder, and psychotic disorder.

Study Design

Patients were initially hospitalized for 5 days, followed by 4 weeks of double-blind treatment and 9 weeks of posttreatment follow-up.

Patients were randomized to receive esketamine or placebo nasal spray, administered twice weekly, based on a computer-generated randomization schedule.

Study Drug and Standard-of-Care Antidepressant Therapy

Intranasal study drugs were administered in disposable nasal spray devices to patients twice weekly for 4 weeks. Patients self-administered study drug, under the supervision of a site staff member.

Standard-of-care oral antidepressant(s) was initiated or optimized at the time of randomization on day 1, and doses were to remain stable. Esketamine nasal spray was used to treat patients with depression who had active suicidal ideation with intent.

Efficacy Assessments

Depressive symptom severity was assessed using the Structured Interview Guide for MADRS24 on day 1, day 2, day 24, day 25, and at all visits during the follow-up phase.

The Suicide Ideation and Behavior Assessment Tool (SIBAT) was used to assess efficacy in patients with suicidal ideation and behavior during the double-blind and follow-up phases.

Safety Assessments

Adverse events were monitored throughout the study, and the SIBAT was utilized as a safety outcome.

Statistical Methods

All patients who received at least 1 dose of double-blind study medication were included in the safety analysis set.

Efficacy Endpoints and Analyses

Statistical analysis was conducted at a 2-sided .050 significance level to adjust for multiplicity and control type I error.

The primary efficacy endpoint was change in MADRS total score from baseline to 24 hours post-first dose using analysis of covariance (ANCOVA) and mixed model for repeated measures (MMRM).

The primary endpoint was changed in CGI-SS-r score from baseline to 24 hours after the first dose. The key secondary endpoint was changed in CGI-SR-I, clinician- and patient-rated FoST, MADRS suicide item.

Patients and Treatment

A total of 226 patients were randomized to esketamine + standard-of-care or placebo + standard-of-care, and the mean MADRS total score was measured at day 2. Only 1 patient had missing data at baseline.

89.5% of patients completed the study; 192 entered the follow-up phase; 164 completed the day 90 follow-up visit.

The treatment groups were similar with respect to demographic and baseline clinical characteristics, standard-of-care antidepressant use, and concomitant use of benzodiazepines. Most patients were moderately to extremely suicidal.

Efficacy Results

Patients in both groups improved over the double-blind treatment phase, with esketamine significantly improving MADRS total score from baseline to 24 hours after the first dose. The difference between treatment groups generally remained over time through day 25.

At the end of double-blind treatment, patients in both treatment groups experienced improvement in the severity of their suicidality as measured by CGI-SS-r, though there was no statistically significant difference between treatment groups.

Safety Results

Most adverse events occurred on intranasal dosing days and resolved on the same day in the esketamine + standard-of-care group and 85.7% in the placebo + standard-of-care group, respectively.

One patient in the esketamine 84 mg + standard-of-care group had missing CGI-SS-r data at baseline, and one patient in the esketamine 84 mg + standard-of-care group had missing SIBAT data at baseline.

The study site investigator considered all depression- and suicide-related adverse events as unrelated to esketamine, and all suicide attempts and deaths by suicide were dispersed, without pattern or signal of rebound.

Esketamine + standard-of-care group had more patients with MOAA/S score 3 than placebo + standard-of-care group, and none of these patients required medical intervention.

DISCUSSION

This study demonstrated that esketamine nasal spray rapidly reduces depressive symptoms in patients with MDD and active suicidal ideation with intent, a population typically excluded from antidepressant treatment trials. Esketamine was also associated with a rapid reduction in suicidality, but the difference between treatment groups was not statistically significant.

At baseline, 1 patient had missing MADRS data and another patient had missing CGI-SS-r data.

Intravenous ketamine has been reported to rapidly reduce suicidal ideation, but the results were not confirmed in this phase 3 study. One patient died by suicide during the follow-up phase, but this was the only completed suicide across the entire clinical development program.

Methodological challenges were inevitable in this study of a high-risk patient population, including parsing the benefits of hospitalization and the care, attention, and expectancy bias that accompanies participation in research.

CONCLUSIONS

Authors: Drs Fu, Canuso, Li, Lim, and Ionescu; Drs Hough, Drevets, Manji, and Sanacora; Ms Lane. All authors meet ICMJE criteria.

Drs F u , Ionescu, Li, Lim, Hough, Drevets and Canuso, Ms Lane, and Dr Manji are employees of Janssen Research & Development, LLC, and Dr Sanacora is an employee of Janssen Research & Development, LLC and a co-inventor on a patent for glutamate agents in the treatment of mental disorders. Dr Sanacora’s employer, Yale University, has put multiple measures in place to mitigate a conflict of interest with Janssen Pharmaceuticals.

Anna Duca, Valerie Joanny, Susan Katz, and Christine Pinter, MS, provided operational support for study execution, Sandra Norris, PharmD, provided medical writing assistance, and Ellen Baum, PhD, provided additional editorial support. The following principal investigators participated in the study.

The World Health Organization (WHO) reports that 1 in 5 people with depression will attempt suicide during their lifetime. The risk of suicide is higher for women than men and is higher within two weeks of discharge from psychiatric inpatient care. The duration of the suicidal process is a measure of the time between consideration and accomplishment of a suicide attempt. Paroxetine reduces suicidal thoughts and attempts in patients starting depression treatment with medications or psychotherapy.

Ketamine has been shown to reduce suicidal ideation in clinical trials with a rapid-acting antidepressant. Please contact Philippe Courtet, MD, PhD, at [email protected] to submit a paper for consideration as a part of our Focus on Suicide section.

The Mini-International Neuropsychiatric Interview (M.I.N.I.) is a structured diagnostic psychiatric interview for DSM-IV and ICD -10 that was developed and validated by Sheehan DV, Lecrubier Y, Sheehan KH, et al.

The Clinician-Administered Dissociative States Scale (CADSS) is a validated measure of dissociative states that can be used in clinical trials. It is also a valid measure of alertness and sedation and can be used in the assessment of suicidal ideation.

Inclusion Criteria

Subjects must meet DSM-5 criteria for MDD, without psychotic features, and have current suicidal ideation with intent. They must also agree to be hospitalized voluntarily for a recommended period of 5 days after randomization, and take prescribed noninvestigational antidepressant therapy(ies) for at least the duration of the double-blind treatment phase (Day 25). Subjects must be medically stable, with no significant abnormalities on physical examination, medical history, vital signs, or 12-lead ECG.

Subjects must be medically stable on the basis of clinical laboratory tests performed by the local laboratory at screening. Any abnormalities must be deemed not clinically significant by the investigator. Contraceptive use by men and women must be consistent with local regulation regarding the use of contraceptive methods for subject participating in clinical studies. This includes being postmenopausal, permanently sterilized, or incapable of pregnancy, and practicing a highly effective method of contraception.

For a minimum of 1 spermatogenesis cycle after receiving the last dose of study drug, a man must use a highly effective method of contraception with his female partner.

Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, and must sign an informed consent form.

Subjects with borderline personality disorder, autism, dementia, intellectual disability, psychotic disorder, substance use disorder, or a history of ketamine, phencyclidine, PCP, lysergic acid diethylamide, or 3, 4-methylenedioxy-methamphetamine-related use disorder should be excluded from the study. Subjects with uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg) are excluded, as well as those with unstable heart failure, severe cardiovascular disease, recent cerebral injury, increased intracranial pressure or acute stroke. Subjects who have a positive urine test result(s) for phencyclidine, cocaine, or amphetamines may be eligible for study participation. Subjects who have a positive test result(s) for heroin should be excluded from the study.

Subjects with a positive test result due to opiates, benzodiazepines, barbiturates, or psychostimulants taken in a suicide attempt may be eligible for study participation. Subjects with a positive test result due to prescribed psychostimulants may be eligible for study participation. Subjects who have received or used an investigational drug within 60 days before the planned first dose of study drug, are pregnant, breast-feeding, or planning to become pregnant, or have any other situation that would prevent, limit, or confound the protocol-specified assessments are not eligible to participate.

Standard antidepressant treatment was initiated or optimized on day 1, and patients were followed up after the double-blind phase.

The MADRS total score of 12 indicates remission. The remission rate on day 90 exceeded 45% in each treatment group.

Cases)

Ten patients discontinued intranasal study drug prematurely due to an adverse event: 5 patients in the esketamine+standard-of-care group and 5 patients in the placebo+standard-of-care group.

CADSS total score ranges from 0 to 92; a higher score indicates a more severe condition. Zero scores at 40 minutes postdose were carried forward to 1.5 hours postdose.