A Long-Term Extension Study for Participants With Treatment-resistant Major Depressive Disorder Who Are Continuing Esketamine Nasal Spray Treatment

Open-label Long-Term Extension Study for Participants With Treatment-Resistant Major Depressive Disorder Who Are Continuing Esketamine Nasal Spray Treatment From Study 54135419TRD3013

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04829318

Acronym

ESCAPE-LTE

Enrollment

183

Registered

2021-04-02

Start date

2021-04-26

Completion date

2024-07-22

Last updated

2025-09-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Depressive Disorder, Major

Keywords

Treatment resistant depression

Brief summary

The primary purpose of this study is to assess the long-term safety and tolerability of esketamine nasal spray in combination with a selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) in participants who have completed 32 weeks of esketamine nasal spray treatment in Study 54135419TRD3013 (NCT04338321).

Interventions

DRUGEsketamine

Esketamine will be self-administered as nasal spray.

DRUGSSRI/SNRI

Participants will continue to take SSRI/SNRI that is approved for use in depression in their country of participation; off-label use of any SSRI/SNRI is not permitted. The continuing SSRI/SNRI dosage may be optimized throughout the study, at the investigator's discretion and based on the summary of product characteristics (SmPC) (or local equivalent, if applicable). During this LTE study, investigators will be allowed to switch individual participant's SSRI/SNRI for tolerability issues.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 74 Years

Healthy volunteers

Inclusion criteria

* Completed the maintenance phase (Week 32) of Study 54135419TRD3013 (NCT04338321) and had esketamine nasal spray in combination with continuing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) administered through Week 30 (every 2 week dosing) or Week 31 (once weekly dosing) of Study 54135419TRD3013, and continues to be willing to be treated with esketamine nasal spray * Must, in the opinion of the investigator, be benefiting from continuation of esketamine nasal spray in combination with their current SSRI/SNRI based on efficacy and tolerability assessed on Day 1 of this study * Must be medically stable based on the investigator's judgment * A woman of childbearing potential must have a negative urine pregnancy test on Day 1 * Male participants who are sexually active with a woman of childbearing potential must agree to the following during the intervention period and for at least 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study intervention (that is, esketamine nasal spray), must fulfill the following criteria: must be practicing a highly effective method of contraception with his female partner, must use a condom if his partner is pregnant, and must agree not to donate sperm

Exclusion criteria

* Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (example, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments * Completed Study 54135419TRD3013 while presenting adverse events deemed clinically relevant by the investigator, and which may interfere with safety and well-being of the participant * Has developed during participation in Study 54135419TRD3013 any of the following cardiovascular-related conditions where an increase in blood pressure or intracranial pressure poses a serious risk: cerebrovascular disease following stroke or transient ischemic attack, aneurysmal vascular disease (including intracranial, thoracic, or abdominal aorta, or peripheral arterial vessels), intracerebral hemorrhage, coronary artery disease following myocardial infarction, unstable angina, or revascularization procedure (example, coronary angioplasty or bypass graft surgery), uncontrolled brady- or tachyarrhythmias that lead to hemodynamic instability, hemodynamically significant valvular heart disease such as mitral regurgitation, aortic stenosis, or aortic regurgitation or heart failure (New York Heart Association \[NYHA\] Class III-IV) of any etiology * Significant pulmonary insufficiency, including chronic obstructive pulmonary disease * Has homicidal ideation or intent, per the investigator's clinical judgment; or has suicidal ideation with some intent to act within 1 month prior to Day 1, per the investigator's clinical judgment; or based on the Columbia-suicide severity rating scale (C-SSRS) performed at Week 32 visit of Study 54135419TRD3013, 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 * Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 90 days after the last dose of study intervention

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Suicidal Ideation and Behavior in Study 54135419TRD4010 as Assessed by Columbia-suicide Severity Rating Scale (C-SSRS) Score	Baseline (Day 1 of Study 54135419TRD3013) up to Week 104 of study 54135419TRD4010 (up to Week 136)	Number of participants with suicidal ideation and behavior in study 54135419TRD4010 as assessed by C-SSRS score were reported. C-SSRS score: an assessment tool that evaluated suicidal ideation and behavior. Suicidal ideation (5 items): wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intention to act, active suicidal ideation with some intent to act without specific plan, and active suicidal ideation with specific plan and intent. Suicidal behavior (5 items): preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt (non-fatal), and suicide. Total score from 10 categories was summarized into 3 categories: No suicidal ideation or behavior (0), Suicidal ideation (1 to 5), Suicidal behavior (6 to 10). Total score ranged from 0 to 10. Higher scores indicated more severe suicidal ideation and behavior.
Incidence Rate of Treatment-emergent Adverse Events (TEAEs)	From Day 1 of study 54135419TRD4010 up to 30 days after last dose of study drug at Week 104 (up to Week 108)	Incidence rate of TEAEs were reported. AE Incidence rate was defined as incidence rate per 100 patient-months = (number of participants with AE divided by sum of days at risk for AE) \* 100\*365.25/12. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurring at or after the initial administration of study intervention up to 30 days after last dose in Study 54135419TRD4010 was considered to be treatment emergent. TEAEs included both serious and non-serious adverse events.
Percentage of Participants With Treatment-emergent Serious Adverse Events (TESAEs)	From Day 1 of study 54135419TRD4010 up to 30 days after last dose of study drug at Week 104 (up to Week 108)	Percentage of participants with TESAEs were reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurring at or after the initial administration of study intervention up to 30 days after last dose in Study 54135419TRD4010 was considered to be treatment emergent.
Incidence Rate of Treatment-emergent Serious Adverse Events (TESAEs)	From Day 1 of study 54135419TRD4010 up to 30 days after last dose of study drug at Week 104 (up to Week 108)	Incidence rate of with TESAEs were reported. AE Incidence rate was defined as incidence rate per 100 patient-months = (number of participants with AE divided by sum of days at risk for AE) \* 100\*365.25/12. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurring at or after the initial administration of study intervention up to 30 days after last dose in Study 54135419TRD4010 was considered to be treatment emergent.
Percentage of of Participants With TEAEs Leading to Death	From Day 1 of study 54135419TRD4010 up to 30 days after last dose of study drug at Week 104 (up to Week 108)	Percentage of participants with TEAEs leading to death were reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurring at or after the initial administration of study intervention up to 30 days after last dose in Study 54135419TRD4010 was considered to be treatment emergent. TEAEs included both serious and non-serious adverse events.
Incidence Rate of TEAEs Leading to Death	From Day 1 of study 54135419TRD4010 up to 30 days after last dose of study drug at Week 104 (up to Week 108)	Incidence rate of TEAEs leading to death were reported. AE Incidence rate was defined as incidence rate per 100 patient-months = (number of participants with AE divided by sum of days at risk for AE) \* 100\*365.25/12. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurring at or after the initial administration of study intervention up to 30 days after last dose in Study 54135419TRD4010 was considered to be treatment emergent. TEAEs included both serious and non-serious adverse events.
Percentage of Participants With Treatment-emergent AEs of Special Interest (AESIs)	From Day 1 of study 54135419TRD4010 up to 30 days after last dose of study drug at Week 104 (up to Week 108)	Percentage of participants with TEAEs of special interest were reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with intervention. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurring at or after the initial administration of study intervention up to 30 days after last dose in Study 54135419TRD4010 was considered to be treatment emergent. TEAEs included both serious and non-serious AEs. AEs of special interest were separately grouped by categories sedation, dissociation, suicidality, suggestive of abuse potential, cystitis and hepatic impairment.
Incidence Rate of Treatment-emergent AEs of Special Interest (AESIs)	From Day 1 of study 54135419TRD4010 up to 30 days after last dose of study drug at Week 104 (up to Week 108)	AE Incidence rate: incidence rate per 100 patient-months=(number of participants with AE divided by sum of days at risk for AE)\* 100\*365.25/12. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with intervention. SAE: AE resulting in any following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurring at or after the initial intervention administration up to 30 days after last dose in Study 54135419TRD4010 was considered to be treatment emergent. TEAEs included both serious and non-serious AEs. AEs of special interest were grouped as categories sedation, dissociation, suicidality, suggestive of abuse potential, cystitis and hepatic impairment.
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	From Day 1 of study 54135419TRD4010 up to 30 days after last dose of study drug at Week 104 (up to Week 108)	Percentage of participants with TEAEs were reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurring at or after the initial administration of study intervention up to 30 days after last dose in Study 54135419TRD4010 was considered to be treatment emergent. TEAEs included both serious and non-serious adverse events.

Secondary

Measure	Time frame	Description
Change From Baseline of Study 54135419TRD3013 in Clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS) Total Score	Baseline (Day 1 of study 54135419TRD3013) up to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104 of study 54135419TRD4010	Change from baseline of study 54135419TRD3013 in Clinician-rated MADRS total score were reported. MADRS was a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items , scored from 0 (item is not present or normal) to 6 (severe or continuous presence of symptoms), summed up for a total possible score range of 0 to 60. Higher scores represented a more severe condition. The MADRS evaluated reported sadness, apparent sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts.
Change From Baseline of Study 54135419TRD3013 in Clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS) Score Individual Items	Baseline (Day 1 of study 54135419TRD3013) up to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104 of study 54135419TRD4010	Change from Baseline of Study 54135419TRD3013 in Clinician-rated MADRS Score Individual Items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts) were reported. MADRS was a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed up for a total possible score range of 0 to 60. Higher scores represent a more severe condition.
Change From Baseline of Study 54135419TRD3013 in Clinical Global Impression -Severity (CGI-S) Scale Score	Baseline (Day 1 of study 54135419TRD3013) up to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104 of study 54135419TRD4010	Change from Baseline of Study 54135419TRD3013 in CGI-S scale score were reported. The CGI-S provided an overall clinician-determined summary measure of the severity of the participant's illness that took into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluated the severity of psychopathology on a scale of 1 to 7: where, 1 = normal (not ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participant's. Negative change in score indicated improvement. Participant's with a score of zero were considered missing.
Change From Baseline of Study 54135419TRD3013 in Patient Health Questionnaire (PHQ) 9-item Total Score	Baseline (Day 1 of study 54135419TRD3013) up to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104 of study 54135419TRD4010	Change from Baseline of Study 54135419TRD3013 in PHQ 9-item total score were reported. The PHQ-9 was a validated 9-item, patient-reported outcome (PRO) measure to assess depressive symptoms. Each item was rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses were summed to a total score with a range of 0 to 27. Higher scores indicated greater severity of depressive symptoms.
Change From Baseline of Study 54135419TRD3013 in European Quality of Life (EuroQol) 5 Dimension 5-Level (EQ-5D-5L): Health Status Index	Baseline (Day 1 of Study 54135419TRD3013) up to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104 of study 54135419TRD4010	Change from baseline of Study 54135419TRD3013 in EQ-5D-5LQuestionnaire Score: health status index were reported. The EQ-5D-5L descriptive system comprised the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions were divided into 5 levels of perceived problems (level 1 = no problem, level 2 = slight problems, level 3 = moderate problems, level 4 = severe problems, level 5 = extreme problems). The participant selected an answer for each of the 5 dimensions considering a response that best matched participant's health today. Responses were used to generate health status index ranged from -0.594 to 1 (where 1 represents full health and negative values represent health states considered worse than dead). Positive change in score indicated improvement.
Change From Baseline of Study 54135419TRD3013 in European Quality of Life (EuroQol) 5 Dimension 5-Level (EQ-5D-5L): Visual Analogue Scale (VAS)	Baseline (Day 1 of Study 54135419TRD3013) up to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104 of study 54135419TRD4010	Change from baseline of Study 54135419TRD3013 in EQ-5D-5L: visual analogue scale were reported. EQ-VAS self-rating recorded the participant's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Positive change in score indicated improvement.
Percentage of Participants With No Relapse and Without Discontinuation Until the End of the Prospective Observation Period at Week 104	Baseline (Day 1 of Study 54135419TRD3013) up to Week 104 of study 54135419TRD4010 (up to Week 136)	Relapse was defined by any of the following: a) Worsening of depressive symptoms as indicated by Montgomery-Asberg Depression Rating Scale (MADRS) total score \>=22 confirmed by 1 additional assessment of MADRS total score \>=22 within the next 5 to 31 days. b) Any psychiatric hospitalization for: 1) worsening of depression, 2) suicide prevention or due to a suicide attempt for any of these events. c) Suicide attempt, completed suicide, or any other clinically relevant event determined per investigator's clinical judgment to be indicative of relapse of depressive illness, but for which participant was not hospitalized. MADRS scale consisted of 10 items, scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 0 to 60. Higher scores represented a more severe condition.

Countries

Argentina, Belgium, Bulgaria, Czechia, Finland, Germany, Greece, Hungary, Malaysia, Poland, South Africa, South Korea, Taiwan, Turkey (Türkiye)

Participant flow

Pre-assignment details

A total of 183 participants who completed the maintenance phase (Week 32) of study 54135419TRD3013 (NCT04338321) were enrolled and treated in this study.

Participants by arm

Arm	Count
Esketamine Nasal Spray + Oral Antidepressant (AD) Participants (who received esketamine nasal spray in study 54135419TRD3013 \[NCT04338321\] through Week 30 \[every 2 weeks dosing\] or Week 31 \[once weekly dosing\], and completed the maintenance phase at Week 32), received flexible dose of esketamine nasal spray 28 milligrams (mg) (one spray to each nostril at 0 minute), 56 mg (one spray to each nostril at 0 and 5 minutes) or 84 mg (one spray to each nostril at 0, 5 and 10 minutes) once weekly or every 2 weeks from Day 1 (Week 32 visit of study 54135419TRD3013 until week 104 along with oral AD, serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI) in this long-term extension (LTE) study. Time 0 minute signified time of first esketamine nasal spray administration to 1 nostril. Esketamine nasal devices contained a total of 28 mg esketamine per device (2 sprays). Only one device was used at a timepoint.	183
Total	183

Arm

Count

Esketamine Nasal Spray + Oral Antidepressant (AD)

Participants (who received esketamine nasal spray in study 54135419TRD3013 \[NCT04338321\] through Week 30 \[every 2 weeks dosing\] or Week 31 \[once weekly dosing\], and completed the maintenance phase at Week 32), received flexible dose of esketamine nasal spray 28 milligrams (mg) (one spray to each nostril at 0 minute), 56 mg (one spray to each nostril at 0 and 5 minutes) or 84 mg (one spray to each nostril at 0, 5 and 10 minutes) once weekly or every 2 weeks from Day 1 (Week 32 visit of study 54135419TRD3013 until week 104 along with oral AD, serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI) in this long-term extension (LTE) study. Time 0 minute signified time of first esketamine nasal spray administration to 1 nostril. Esketamine nasal devices contained a total of 28 mg esketamine per device (2 sprays). Only one device was used at a timepoint.

183

Total

183

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	6
Overall Study	Death	1
Overall Study	Lost to Follow-up	1
Overall Study	Other	1
Overall Study	Physician Decision	1
Overall Study	Site terminated by sponsor	1
Overall Study	Sponsor decision	5
Overall Study	Withdrawal by Subject	19

Baseline characteristics

Characteristic	Esketamine Nasal Spray + Oral Antidepressant (AD)
Age, Continuous	44.6 years STANDARD_DEVIATION 13.07
Age, Customized 18-64 years	174 Participants
Age, Customized >=65 years	9 Participants
Body mass index Normal 18.5 to <25 kg/m^2	63 Participants
Body mass index Obese >=30 kg/m^2	41 Participants
Body mass index Overweight 25 to <30 kg/m^2	46 Participants
Body mass index Underweight <18.5 kg/m^2	5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	12 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	60 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	6 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	66 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	0 Participants
Sex: Female, Male Female	128 Participants
Sex: Female, Male Male	55 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	1 / 183
other Total, other adverse events	145 / 183
serious Total, serious adverse events	11 / 183

Outcome results

Primary

Incidence Rate of TEAEs Leading to Death

Incidence rate of TEAEs leading to death were reported. AE Incidence rate was defined as incidence rate per 100 patient-months = (number of participants with AE divided by sum of days at risk for AE) \* 100\*365.25/12. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurring at or after the initial administration of study intervention up to 30 days after last dose in Study 54135419TRD4010 was considered to be treatment emergent. TEAEs included both serious and non-serious adverse events.

Time frame: From Day 1 of study 54135419TRD4010 up to 30 days after last dose of study drug at Week 104 (up to Week 108)