E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment-resistant Major Depression |
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E.1.1.1 | Medical condition in easily understood language |
Depression is a mental disorder characterized by low mood and/or loss of interest or pleasure in nearly all activities. |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10057840 |
E.1.2 | Term | Major depression |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the efficacy of switching adult subjects with TRD from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms, as assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (pre-randomization) to the end of the 4-week double-blind induction phase. |
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E.2.2 | Secondary objectives of the trial |
The key secondary objectives are to assess the effect of intranasal esketamine plus a newly initiated oral antidepressant (AD) compared with a newly initiated oral AD plus intranasal placebo on the following parameters in adult subjects with TRD:
- Depressive symptoms (subject-reported)
- Onset of clinical response by Day 2
- Functioning and associated disability
Other Secondary Objectives
To assess the effect of intranasal esketamine plus a newly initiated oral AD compared with a newly initiated oral AD plus intranasal placebo on additional parameters in adult subjects with TRD (see protocol for details)
To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral AD compared with a newly initiated oral AD plus intranasal placebo in adult subjects with TRD (see protocol for details)
To assess the pharmacokinetics (PK) of intranasal esketamine in adult subjects with TRD receiving intranasal esketamine plus a newly-initiated oral AD |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- At the time of signing the informed consent form (ICF), participant must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than [>]18) to 64 years of age, inclusive
- At the start of the screening/prospective observational phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single-episode MDD, the duration must be greater than or equal to [>=] 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (MINI)
- At the start of the screening/prospective observational phase, participant must have an Inventory of Depressive Symptomatology - Clinician rated (IDS-C30) total score of greater than or equal to (>=) 34
- At the start of the screening/prospective observational phase, subject must have had non-response (≤25% improvement) to ≥1 but ≤5 (if current episode is >2 years, upper limit is applicable to only the last 2 years) oral antidepressant treatments in the current episode of depression, assessed using the MGH-ATRQ and confirmed by documented records (eg, medical/pharmacy/prescription records or a letter from a treating physician, etc.). In addition, the subject is taking a different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose.
-Subject must be taking one of the oral antidepressant treatment with nonresponse that is documented on the MGH-ATRQ (i.e. this oral antidepressant treatment must have been taken for at least 6 weeks at the minimum therapeutic dose with a lack of clinically meaningful improvement) at the start of the screening/prospective observational phase
- The participant's current major depressive episode, depression
symptom severity (Week 1 MADRS total score >=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Site Independent Qualification Assessment
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E.4 | Principal exclusion criteria |
- Participants who have previously demonstrated nonresponse of
depressive symptoms to esketamine or ketamine in the current major depressive episode, to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (ie, duloxetine, escitalopram, sertraline, and venlafaxine extended release [XR]) in the current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT
- Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression
- Participant has a current or prior DSM-5 diagnosis of a psychotic
disorder or MDD with psychosis, bipolar or related disorders (confirmed by the MINI), comorbid obsessive compulsive disorder, intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
- 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/prospective observational phase, per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS)
- Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at End of Double-blind Induction Phase |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline and End of Doubleblind Induction Phase (Week 4) |
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E.5.2 | Secondary end point(s) |
1)Onset of Clinical Response That Continued Through the End of the 4-Week Double-blind Induction Phase
2)Change From Baseline in Subject-reported Functioning and Associated Disability as assessed by the Sheehan Disability Scale (SDS)Total Score at End of Double-blind Induction Phase
3)Change from Baseline in Subject-reported Depressive Symptoms
Using the Patient Health Questionnaire-9 (PHQ-9)Total Score at End of Double-blind Induction Phase
4)Proportion of responders (>=50% reduction from baseline in MADRS total score)
5)Proportion of subjects in remission (MADRS <=12)
6)Change from baseline (Day 1 prior to randomization) to the end of the 4-week double-blind induction phase in:
-Severity of depressive illness, using the CGI-S
-Anxiety symptoms, as measured by the GAD-7
-Health-related quality of life and health status, as assessed by the EQ-5D-5L |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Day 2 through the End of Double-Blind Induction Phase (Week 4)
2) Baseline and End of Double-blind Induction Phase (Week 4)
3) Baseline and End of Double-blind Induction Phase (Week 4)
4) End of Double-blind Induction Phase (Week 4)
5) Baseline and End of Double-blind Induction Phase (Week 4)
6) Baseline and End of Double-blind Induction Phase (Week 4) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Brazil |
Czech Republic |
Germany |
Poland |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 5 |