A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 19, 2021

Detailed Description

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.

Interventions

  • Drug: Esketamine 28 mg
    • Esketamine will be self-administered at a dose of 28 mg as nasal spray.
  • Drug: Esketamine 56 mg
    • Esketamine will be self-administered at a dose of 56 mg as nasal spray.
  • Drug: Esketamine 84 mg
    • Esketamine will be self-administered at a dose of 84 mg (maximum uptitrated dose) as nasal spray.
  • Drug: Quetiapine XR 50 mg
    • Quetiapine XR will be administered at an initial dose of 50 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.
  • Drug: Quetiapine XR 100 mg
    • Quetiapine XR will be administered at a dose of 100 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.
  • Drug: Quetiapine XR 150 mg
    • Quetiapine XR will be administered at a dose of 150 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.
  • Drug: SSRI/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 SmPC (or local equivalent, if applicable).

Arms, Groups and Cohorts

  • Experimental: 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).
  • Active Comparator: 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.

Clinical Trial Outcome Measures

Primary Measures

  • Percentage of Participants with Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS)
    • Time Frame: Week 8
    • Percentage of participants with remission as assessed by the MADRS (total score of <= 10) will be reported.

Secondary Measures

  • Percentage of Participants with Remission at Week 8 Without Relapse Until Week 32
    • Time Frame: Up to Week 32
    • Percentage of participants with remission as assessed by MADRS (total score of <= 10) without relapse until the end Week 32 will be reported. A relapse is defined by any of following: (a) Worsening of depressive symptoms as indicated by MADRS total score >=22 confirmed by 1 additional assessment of MADRS total score >=22 within the next 5 to 15 days. The date of the second MADRS assessment will be used for the date of relapse; (b) Any psychiatric hospitalization for: worsening of depression, suicide prevention or due to a suicide attempt for any of these events, the start date of hospitalization will be used for the date of relapse; (c) Suicide attempt, completed suicide, or any other clinically relevant event determined per the investigator’s clinical judgment to be indicative of a relapse of depressive illness, but for which the participant was not hospitalized. The onset of the event will be used for the date of relapse.
  • Change from Baseline in Clinician-rated MADRS Scale Score
    • Time Frame: Baseline up to Week 32
    • The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to anti depressants (AD) treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or 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, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
  • Change from Baseline in Clinical Global Impression – Severity (CGI-S) Scale Score
    • Time Frame: Baseline up to Week 32
    • The CGI-S measures illness severity and is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (among the most severely ill participants).
  • Clinical Global Impression – Change (CGI-C) Scale Score
    • Time Frame: Baseline up to Week 32
    • The CGI-C rating scale is a global assessment that measures the clinician’s impression illness change. CGI-C scores range from 1 (very much improved) through to 7 (very much worse) as compared to baseline.
  • Change from Baseline in Patient Health Questionnaire (PHQ) 9-item Total Score
    • Time Frame: Baseline up to Week 32
    • The PHQ-9 is a validated 9-item, PRO measure to assess depressive symptoms. The scale scores each of the 9-symptom domains of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition major depressive disorder (DSM-5 MDD) criteria. Each item is 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 are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms.
  • Change from Baseline in Sheehan Disability Scale (SDS) Total Score
    • Time Frame: Baseline up to Week 32
    • The SDS, a patient-reported outcome (PRO) measure, is a 5-item questionnaire that has been widely used and accepted for assessment of functional impairment and associated disability. The first 3 items cover (1) work/school, (2) social life, and (3) family life/home responsibilities using a rating scale from 0 to 10. The SDS also has 1 item assessing days lost from school or work and 1 item assessing days of underproductivity. The score for the first 3 items are summed to create a total score of 0 to 30, where higher score indicates greater impairment.
  • Change from Baseline in Health-Related Quality of life Status as Assessed by 36-item Short-Form Health Survey (SF-36) Domain Scores
    • Time Frame: Baseline up to Week 32
    • The SF-36 is a validated 36-item questionnaire which measures quality of life across 8 domains, which are both physically and emotionally based. The 8 domains that the SF-36 measures are as follows: physical functioning; role limitations due to physical health; role limitations due to emotional problems; energy/fatigue; emotional wellbeing; social functioning; pain; general health. A single item is also included that identifies perceived change in health, making the SF 36 a useful indicator for change in quality of life over time and treatment. For each of the 8 domains that the SF-36 measures, an aggregate score is produced. The scores range from 0 (lowest or worst possible level of functioning) to 100 (highest or best possible level of functioning).
  • Change from Baseline in Quality of Life in Depression Scale (QLDS) Total Score
    • Time Frame: Baseline up to Week 32
    • The QLDS is a disease specific PRO designed to assess health related quality of life in patients with Major Depressive Disorder. The instrument has a recall period of “at the moment”, contains 34-items with “yes”/”no” response options. The total score is computed as sum of the items with range from 0 (good quality of life) to 34 (very poor quality of life).
  • Change from Baseline in European Quality of Life (EuroQol) Group, 5 Dimension, 5-Level (EQ-5D-5L)
    • Time Frame: Baseline up to Week 32
    • The EQ-5D-5L is standardized instrument for use as measure of health outcome, primarily designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ-VAS. EQ-5D-5L descriptive system comprises the following 5 dimensions: Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (1 indicating no problem, 2 indicating slight problems, 3 indicating moderate problems, 4 indicating severe problems, 5 indicating extreme problems). Participant selects an answer for each of 5 dimensions considering the response that best matches his or her health “today”. The responses to the 5 dimensions are used to compute a single score ranging from zero (0.0- worst health state) to 1 (1.0- better health state) representing the general health status of the individual.
  • Change from Baseline in Work Productivity and Activity Impairment (WPAI): Depression Questionnaire
    • Time Frame: Baseline up to Week 32
    • The WPAI: Depression questionnaire is a validated short instrument that assesses impairment in work and other regular activities over the past 7 days. The WPAI questionnaire assesses 4 separate measures: absenteeism (ie, the proportion of work time missed due to MDD), presenteeism (that is, the degree of impairment while working due to MDD), work productivity loss (ie, overall work impairment due to MDD/absenteeism plus presenteeism), and activity impairment (that is, the degree of impairment of regular, nonwork activity due to MDD). The WPAI outcomes are expressed as impairment percentages, with higher values indicating greater impairment and less productivity, that is, worse outcomes.
  • Number of Participants with Intervention-Emergent Adverse Events
    • Time Frame: Up to 32 Weeks
    • Intervention-emergent adverse events (AEs) are AEs occurring or worsening in severity after the start of study intervention. An AE is any untoward medical occurrence attributed to study drug in a participant who received study drug.
  • Suicidal ideation and behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score
    • Time Frame: Up to 32 Weeks
    • Suicidal ideation or behavior will be measured using C-SSRS score. C-SSRS is a clinician rated assessment of suicidal behavior and/ or intent. Scale consists of 28 items in 4 sections: suicide behavior, actual attempts, suicidal ideation, and intensity of ideation. Suicidal ideation consists of 5 yes/no 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, active suicidal ideation with specific plan and intent. Worsening of suicidal ideation will be an increase in severity of suicidal ideation from baseline.

Participating in This Clinical Trial

Inclusion Criteria

  • 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 Exclusion Criteria:

  • 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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 74 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Janssen-Cilag International NV
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Janssen-Cilag International NV Clinical Trials, Study Director, Janssen-Cilag International NV
  • Overall Contact(s)
    • Study Contact, 844-434-4210, JNJ.CT@sylogent.com

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