A Randomized, Open-label, Rater-Blinded, Active-Controlled, International, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Flexibly Dosed Esketamine Nasal Spray Compared With Quetiapine Extended-Release in Adult and Elderly Participants With Treatment-Resistant Major Depressive Disorder Who Are Continuing a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 676
- 试验地点
- 168
- 主要终点
- Percentage of Participants With Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) Score at Week 8
研究概览
简要总结
The primary purpose of this study is to evaluate the efficacy of flexibly dosed esketamine nasal spray compared with quetiapine extended-release (XR), both in combination with a continuing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI), in achieving remission in participants who have treatment-resistant major depressive disorder (MDD) with a current moderate to severe depressive episode.
详细描述
A depressive state with classical symptoms such as low (depressive/sad) mood, markedly diminished interest in activities, significant weight loss/gain, insomnia or hypersomnia, psychomotor agitation/retardation, excessive fatigue, inappropriate guilt, diminished concentration, and recurrent thoughts of death, persisting for more than 2 weeks is classified as major depressive disorder (MDD). The mechanism of action of ketamine is distinct from conventional antidepressants (ADs), which target the monoamines (serotonin, norepinephrine, and/or dopamine). Esketamine, the S-enantiomer of ketamine, is approved and widely used for the induction and maintenance of anesthesia via intramuscular or intravenous (IV) administration. There is a significant unmet need to develop novel AD treatments based on the relevant psychophysiological pathways underlying MDD. The goal of any novel treatment would be the rapid and long-lasting relief of depressive symptoms, especially in participants with treatment-resistant depression (TRD), who lack a sufficient response to the currently available treatment strategies. The study consists of a Screening Phase (up to 14 days), an Acute Phase (8 Weeks), a Maintenance Phase (24 Weeks) and a Safety Follow-up Phase (2 Weeks). Safety assessment includes adverse event, serious adverse events, physical examination, vital signs, electrocardiogram, clinical safety laboratory assessments, suicidal risk monitoring. The total duration of the study is approximately 36 Weeks for all participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 74 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •At screening, each participant must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) or recurrent MDD, without psychotic features, based on clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI)
- •At screening and baseline, each participant must have an Inventory of Depressive Symptomatology - Clinician-rated, 30 item (IDS-C30) total score of greater than or equal to (>=) 34
- •Must be on a current antidepressive treatment that includes an selective serotonin reuptake inhibitor (SSRI)/ serotonin-norepinephrine reuptake inhibitor (SNRI) at screening that resulted in nonresponse (less than 25% improvement of symptoms) after having been given at an adequate dosage (based on antidepressive dosages from SmPC [or local equivalent, if applicable]) for an adequate duration of at least 6 weeks and having been uptitrated to the maximum tolerated dose; however, at screening the participant must show signs of minimal clinical improvement to be eligible for the study. Clinical improvement of a participant on their current AD treatment will be retrospectively evaluated in a qualified psychiatric interview performed by an experienced clinician. At baseline (Day 1) prior to randomization, the investigator will evaluate any changes in the participant's signs/symptoms of depression since the screening assessment and confirm that the inclusion criteria for the current AD treatment are still met (that is nonresponse and minimal clinical improvement)
- •The current antidepressive treatment, was immediately preceded by nonresponse to at least 1 but not more than 5 different, consecutive treatments (all within the current moderate to severe antidepressive episode) with anti-depressants (ADs) taken at an adequate dosage for an adequate duration of at least 6 weeks and must be documented
- •Must have been treated with at least 2 different antidepressive substance classes among the treatments taken at an adequate dosage for an adequate duration of at least 6 weeks resulting in nonresponse in the current moderate to severe depressive episode (including the current treatment with an selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor [SSRI/SNRI])
- •Must be on a single oral SSRI/SNRI on Day 1 prior to randomization
排除标准
- •Received treatment with esketamine or ketamine in the current moderate to severe depressive episode
- •Received treatment with quetiapine extended- or immediate-release in the current moderate to severe depressive episode of a dose higher than 50 milligram per day (mg/day)
- •Had depressive symptoms in the current moderate to severe depressive episode that previously did not respond to an adequate course of treatment with electroconvulsive therapy (ECT), defined as at least 7 treatments with unilateral/bilateral ECT
- •Has no signs of clinical improvement at all or with a significant improvement on their current AD treatment that includes an SSRI/SNRI as determined at screening by an experienced clinician during the qualified psychiatric interview
- •Received vagal nerve stimulation or has received deep brain stimulation in the current episode of depression
- •has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by the Mini International Neuropsychiatric Interview [MINI]), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality disorder, or antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
- •age at onset of first episode of MDD was more than or equal to (>=) 55 years
- •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 screening, 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, or a history of suicidal behavior within the past year prior to screening. Participants reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the acute phase should also be excluded
研究组 & 干预措施
Esketamine Arm
Participants will receive treatment with esketamine nasal spray (28 milligram [mg] [initial dose for elderly participants 65 to 74 years of age and adults of Japanese ancestry; may be used throughout the study in these populations; may be uptitrated in 28 mg increments], 56 mg [initial dose for adult participants aged 18 to 64 years and may be used for all age groups throughout the study], or 84 mg [maximum dose esketamine nasal spray may be uptitrated to]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).
干预措施: Esketamine 28 mg (Drug)
Esketamine Arm
Participants will receive treatment with esketamine nasal spray (28 milligram [mg] [initial dose for elderly participants 65 to 74 years of age and adults of Japanese ancestry; may be used throughout the study in these populations; may be uptitrated in 28 mg increments], 56 mg [initial dose for adult participants aged 18 to 64 years and may be used for all age groups throughout the study], or 84 mg [maximum dose esketamine nasal spray may be uptitrated to]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).
干预措施: Esketamine 56 mg (Drug)
Esketamine Arm
Participants will receive treatment with esketamine nasal spray (28 milligram [mg] [initial dose for elderly participants 65 to 74 years of age and adults of Japanese ancestry; may be used throughout the study in these populations; may be uptitrated in 28 mg increments], 56 mg [initial dose for adult participants aged 18 to 64 years and may be used for all age groups throughout the study], or 84 mg [maximum dose esketamine nasal spray may be uptitrated to]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).
干预措施: Esketamine 84 mg (Drug)
Esketamine Arm
Participants will receive treatment with esketamine nasal spray (28 milligram [mg] [initial dose for elderly participants 65 to 74 years of age and adults of Japanese ancestry; may be used throughout the study in these populations; may be uptitrated in 28 mg increments], 56 mg [initial dose for adult participants aged 18 to 64 years and may be used for all age groups throughout the study], or 84 mg [maximum dose esketamine nasal spray may be uptitrated to]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).
干预措施: SSRI/SNRI (Drug)
Comparator Arm
Participants will continue to take their current SSRI/SNRI augmented with quetiapine extended release (XR) as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable). In adult participants aged 18 to 64 years, the initial dose is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 [lowest effective dose]; a further dose increase to 300 mg/day on Day 5 and onward will be based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose is 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day will be based on individual participant evaluation no earlier than Day 22.
干预措施: Quetiapine XR 50 mg (Drug)
Comparator Arm
Participants will continue to take their current SSRI/SNRI augmented with quetiapine extended release (XR) as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable). In adult participants aged 18 to 64 years, the initial dose is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 [lowest effective dose]; a further dose increase to 300 mg/day on Day 5 and onward will be based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose is 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day will be based on individual participant evaluation no earlier than Day 22.
干预措施: Quetiapine XR 100 mg (Drug)
Comparator Arm
Participants will continue to take their current SSRI/SNRI augmented with quetiapine extended release (XR) as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable). In adult participants aged 18 to 64 years, the initial dose is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 [lowest effective dose]; a further dose increase to 300 mg/day on Day 5 and onward will be based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose is 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day will be based on individual participant evaluation no earlier than Day 22.
干预措施: Quetiapine XR 150 mg (Drug)
Comparator Arm
Participants will continue to take their current SSRI/SNRI augmented with quetiapine extended release (XR) as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable). In adult participants aged 18 to 64 years, the initial dose is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 [lowest effective dose]; a further dose increase to 300 mg/day on Day 5 and onward will be based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose is 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day will be based on individual participant evaluation no earlier than Day 22.
干预措施: SSRI/SNRI (Drug)
结局指标
主要结局
Percentage of Participants With Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) Score at Week 8
时间窗: Week 8
Percentage of participants with remission as assessed by the MADRS at Week 8 was reported. The MADRS is 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), for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. A participant was defined as being in remission if the MADRS total score was less than or equal to (\<=)10 and no treatment or study discontinuation before Week 8.
次要结局
- Percentage of Participants With Both Remission at Week 8 and Relapse-free Until Week 32(Week 32)
- Change From Baseline in Clinician-rated Overall MADRS Score(Baseline, Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32)
- Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF(Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score(Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32)
- Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF(Baseline, LOCF at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32)
- Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF)(Baseline, LOCF at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32)
- Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score(Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF(Baseline, LOCF at Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 32)
- Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score(Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32)
- Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF(Baseline, LOCF at Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score(Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score(Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF(Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index(Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF(Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF(Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score(Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF(Baseline, LOCF at Weeks 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF(Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(Up to Week 35)
- Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score(Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS(Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire(Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32)
- Number of Participants With TEAEs of Special Interest(Up to Week 35)