A Study of Esketamine Nasal Spray Versus Placebo Spray in Adult Participants With Treatment-resistant Depression

Official title

A Randomized, Double-blind, Multicenter, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant Depression

Overview

The purpose of this study is to evaluate how well each individual dose of esketamine (56 milligrams \[mg\] and 84 mg) works when compared with placebo in improving depressive symptoms in participants with treatment resistant depression (individuals with major depressive disorder \[MDD\] who have not responded to at least 2 different antidepressant treatments given at an adequate dose for an adequate duration in the current episode of depression).

Interventions

• Drug Esketamine 56 mg
  Participants will self-administer 56 mg of esketamine as intranasal spray into each nostril.
• Drug Esketamine 84 mg
  Participants will self-administer 84 mg of esketamine as intranasal spray into each nostril.
• Drug Placebo
  Participants will self-administer placebo as intranasal spray into each nostril.

Primary outcome measures

• Double-Blind (DB) Treatment Phase: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Day 1 to the End of the 4-Week Double-Blind Treatment Phase [Time frame: Baseline (Day 1 [prerandomization]) up to end of the 4-Week DB treatment phase (Day 28)]

Secondary outcome measures (12)

• DB Treatment Phase: Change From Baseline in MADRS Total Score From Day 1 to Day 2 [Time frame: Baseline (Day 1 [prerandomization]) up to Day 2 (approximately 24 hours after the first dose)]
• DB Treatment Phase: Percentage of Responders in MADRS Over Time to the End of the 4-Week DB Treatment Phase [Time frame: Up to end of the 4-Week DB treatment phase (Day 28)]
• DB Treatment Phase: Percentage of Participants in Remission in MADRS Over Time to the End of the 4-Week DB Treatment Phase [Time frame: Up to end of the 4-Week DB treatment phase (Day 28)]
• DB Treatment Phase: Change From Baseline in Clinical Global Impression-Severity (CGI-S) Over Time to the End of the 4-Week DB Treatment Phase [Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)]
• DB Treatment Phase: Change From Baseline in MADRS Total Score Over Time to the End of the 4-Week DB Treatment Phase [Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)]
• DB Treatment Phase: Change From Baseline in Individual MADRS Item Scores Over Time to the End of the 4-Week DB Treatment Phase [Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)]
• DB Treatment Phase: Change From Baseline in Anhedonia Symptoms Over Time to the End of the 4-Week DB Treatment Phase As Assessed by MADRS Anhedonia Factor Score [Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)]
• DB Treatment Phase: Change From Baseline in Patient-Reported Anhedonia Symptoms Over Time to the End of the 4-Week DB Treatment Phase As Assessed by Patient Health Questionnaire 9-item (PHQ-9) Item 1 Score [Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)]
• DB Treatment Phase: Change From Baseline in PHQ-9 Total Score Over Time to the End of the 4-Week DB Treatment Phase [Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)]
• DB Treatment Phase: Percentage of Responders in PHQ-9 Over Time to the End of the 4-Week DB Treatment Phase [Time frame: Up to end of the 4-Week DB treatment phase (Day 28)]
• DB Treatment Phase: Percentage of Participants in Remission in PHQ-9 Over Time to the End of the 4-Week DB Treatment Phase [Time frame: Up to end of the 4-Week DB treatment phase (Day 28)]
• Open-Label (OL) Treatment Phase: Percentage of Responders in MADRS Over Time to the End of the OL Treatment Phase [Time frame: Up to 12 Weeks]

Eligibility criteria

Inclusion criteria

• Participant must meet the diagnostic and statistical manual of mental disorders (5th edition) (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single episode MDD, the duration of the episode must be greater than or equal to \[>=\] 12 months) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the mini international neuropsychiatric interview (MINI) as the primary diagnosis. Participant must have had the first onset of depression prior to 55 years of age
• Participant must have had nonresponse (less than or equal to \[<=\] 25 percent \[%\] improvement) to >=2 oral antidepressant treatments in the current episode of depression, assessed using the massachusetts general hospital-antidepressant treatment response questionnaire (MGH-ATRQ), and confirmed by documented records (for example, medical/pharmacy/prescription records or a letter from a treating physician)
• The participant's current major depressive episode, depression symptom severity, and antidepressant treatment response in the current depressive episode, must be confirmed by the state versus trait, assessability, face validity, ecological validity, rule of three P's (SAFER) Interview
• Participant must be comfortable with self-administration of nasal spray medication and be able to follow the nasal spray administration instructions provided
• A female participant of childbearing potential must have a negative highly sensitive serum (β-human chorionic gonadotropin \[β-hCG\]) at the start of screening and a negative urine pregnancy test must be obtained before the first dose of study drug on Day 1, prior to randomization

Exclusion criteria

• The participant has used ketamine/esketamine (lifetime)
• The participant's depressive symptoms have demonstrated nonresponse in the current major depressive episode to an adequate course of treatment with electroconvulsive therapy (ECT), defined as at least 7 treatments with unilateral/bilateral ECT, or to adequate course of treatment with transcranial magnetic stimulation (TMS), defined as at least 4 weeks of treatment with 5 sessions per week
• Participant has received vagal nerve stimulation (VNS) or deep brain stimulation (DBS) in the current episode of depression
• Participant has homicidal ideation/intent, per the investigator's clinical judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of the screening phase, per the investigator's clinical judgment or based on the columbia suicide severity rating scale (C-SSRS), corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or a history of suicidal behavior within the past year prior to the start of the screening phase. Participants reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the double-blind treatment phase should be excluded
• Participant has a history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria, except nicotine or caffeine, within 6 months before the start of the screening phase. a. A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is exclusionary
• Participant has a current or history of seizures (uncomplicated childhood febrile seizures with no sequelae are not exclusionary)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 2 centers

• Psychiatric Medicine Associates LLC — Skokie
• The Medical Research Network, LLC — New York

Taiwan · 2 centers

• Taipei Medical University — Taipei
• Linkou Chang Gung Memorial Hospital — Taoyuan

Identifiers

NCT: NCT07716098 · 54135419TRD3015

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗