| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment-Resistant Major Depressive Disorder |
|
| E.1.1.1 | Medical condition in easily understood language |
| Major Depressive Disorder |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10081270 |
| E.1.2 | Term | Major depressive disorder |
| E.1.2 | System Organ Class | 100000004873 |
|
| 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 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 (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI), in achieving remission in participants who have treatment-resistant Major Depressive Disorder (MDD) with a current moderate to severe depressive episode. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
1. Assess the efficacy of esketamine nasal spray compared with quetiapine XR, both in combination with a continuing SSRI/SNRI, in the proportion of participants being relapse-free at Week 32 after remission at Week 8
2. Assess the effect of esketamine nasal spray compared with quetiapine XR, both in combination with a continuing SSRI/SNRI, in Clinician-rated overall severity of depressive illness, Early onset of action, Clinician-rated depressive symptoms, Participant-reported depressive symptoms, Participant-reported functional impairment and associated disability, Participant-reported health-related quality of life and health status, Participant-reported work productivity
3. Assess the safety and tolerability of esketamine nasal spray compared with quetiapine XR, both in combination with a continuing SSRI/SNRI
Exploratory:
To assess the potential relationship of biomarkers with response/non-response to study intervention in participants with treatment-resistant MDD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. male or female, 18 years (or older if the minimum legal age of consent in the country in which the study is taking place is >18 years) to 74 years of age, inclusive, at the time of signing the ICF.
2. at screening, each participant must meet DSM-5 diagnostic criteria for single-episode MDD or recurrent MDD, without psychotic features, based on clinical assessment and confirmed by the MINI.
3. at screening and baseline, each participant must have an IDS-C30 total score of ≥34.
4. must be on a current antidepressive treatment that includes an SSRI/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; additional guidance for this interview is provided in Section 8.1.1.1.
5. 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 ADs taken at an adequate dosage for an adequate duration of at least 6 weeks and must be documented (as described in Appendix 3, Regulatory, Ethical, and Study Oversight Considerations: Source Documents) during screening.
6. 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 SSRI/SNRI).
7. must be on a single oral SSRI/SNRI on Day 1 prior to randomization.
Participants who are taking combination ADs and/or augmentation at screening are eligible for the study. All AD treatments, including any augmenting substances, must be stopped prior to randomization on Day 1 according to applicable SmPCs (or local equivalents, if applicable), except the SSRI/SNRI to be continued;
8. must be medically stable based on physical examination, medical history, vital signs (including blood pressure) at screening. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, their clinical significance must be determined by the investigator and recorded in the participant’s source documents.
9. must be comfortable with self-administration of nasal medication and be able to follow the nasal administration instructions provided.
10. must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
11. must sign a separate ICF at baseline (Day 1) visit if he or she agrees to provide optional biomarker and/or genomic (DNA and RNA) samples for research (where local regulations permit). Refusal to give consent for the optional biomarker and/or genomic DNA and RNA research samples does not exclude a participant from participation in the main study.
12. a woman of childbearing potential must have a negative highly sensitive serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) at screening and a negative urine pregnancy test prior to the first dose of study intervention on Day 1.
13. a woman must be
(a). Not of childbearing potential
(b). Of childbearing potential and practicing a highly effective, preferably userindependent method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study intervention and until at least 6 weeks after last dose –the end of relevant systemic exposure.
14. a man who is sexually active with a woman of childbearing potential during the study (ie, from Day 1 prior to first dosing) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study intervention (ie, esketamine nasal spray or quetiapine XR, both in combination with continuing SSRI/SNRI), must fulfill the following criteria:
(a). must be practicing a highly effective method of contraception with his female partner.
(b). must use a condom if his partner is pregnant.
(c). must agree not to donate sperm.
15. willing and able to adhere to the lifestyle restrictions specified in this protocol |
|
| E.4 | Principal exclusion criteria |
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
1. received treatment with esketamine or ketamine in the current moderate to severe depressive episode.
2. received treatment with quetiapine extended- or immediate-release in the current moderate to severe depressive episode of a dose higher than 50 mg/day.
3. 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.
4. 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.
5. received vagal nerve stimulation or has received deep brain stimulation in the current episode of depression.
6. 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), 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, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder.
7. age at onset of first episode of MDD was ≥55 years.
8. 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 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.
9. history of moderate or severe substance use disorder or severe alcohol use disorder according to DSM-5 criteria, except nicotine or caffeine, within 6 months before the start of the screening or current clinical signs.
10. history (lifetime) of ketamine, PCP, lysergic acid diethylamide (LSD), or 3,4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder.
11. has a neurodegenerative disorder (eg, Alzheimer’s disease, vascular dementia, Parkinson’s disease with clinical evidence of cognitive impairment) or evidence of mild cognitive impairment.
12. is currently suffering from seizures, has a history of epilepsy, Neuroleptic Malignant Syndrome, or Tardive Dyskinesia.
13. has one of the following cardiovascular-related conditions:
•cerebrovascular disease with a history of stroke or transient ischemic attack.
•aneurysmal vascular disease (including intracranial, thoracic, or abdominal aorta, or peripheral arterial vessels).
•history of intracerebral hemorrhage.
•coronary artery disease with myocardial infarction, unstable angina, or revascularization procedure (eg, coronary angioplasty or bypass graft surgery) within 12 months before baseline (Day 1). Participants who have had a revascularization performed >12 months prior to screening and are clinically stable and symptom-free, per investigator’s clinical judgment, can be included.
•uncontrolled brady or tachyarrhythmias that lead to hemodynamic instability.
•hemodynamically significant valvular heart disease such as mitral regurgitation, aortic stenosis, or aortic regurgitation.
•confirmed or suspected cardiomyopathy or myocarditis.
•New York Heart Association Class III-IV heart failure of any etiology.
14. has clinically significant or unstable respiratory conditions, including, but not limited to:
(a). significant pulmonary insufficiency, including chronic obstructive pulmonary disease.
(b). sleep apnea with morbid obesity (body mass index ≥35).
15. uncontrolled hypertension despite diet, exercise, or antihypertensive therapy on Day 1 or any history of hypertensive crisis or ongoing evidence of uncontrolled hypertension defined as a supine SBP >140 mmHg or DBP >90 mmHg.
Potential participants may have their current antihypertensive medication(s) adjusted during the screening phase and be re-evaluated to assess their blood pressure control prior to randomization.
16. history of additional risk factors for torsade des pointes (eg, heart failure, hypokalemia, or family history of long QT syndrome).
Refer the protocol for all the exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Remission at the Week 8 visit, defined as a MADRS total score of ≤10. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Remission at Week 8 visit (ie, MADRS total score of ≤10 at the end of Week 8) and no relapse within the consecutive 24 weeks until the end of the prospective observation period at Week 32 visit.
2. Change from baseline at all visits for the following scale scores:
a. Clinician-rated MADRS:
• Overall severity of depressive illness (total score)
• Early onset of action (change in total score from baseline at Day 8 visit)
• Depressive symptoms (individual items)
b. Clinician-rated overall severity of depressive illness:
• Clinical Global Impression – Severity (CGI-S)
• Clinical Global Impression – Change (CGI-C), is a measure of change, analyzed as a score not as change from baseline
c. Participant-reported depressive symptoms: Patient Health Questionnaire 9-item (PHQ-9)
d. Participant-reported functional impairment and associated disability: Sheehan Disability Scale (SDS)
e. Participant-reported health-related quality of life and health status: 36-item Short-Form Health Survey (SF-36)
f. Participant-reported Quality of Life in Depression Scale (QLDS)
g. Participant-reported European Quality of Life (EuroQoL) Group, 5-Dimension, 5-Level (EQ-5D-5L) questionnaire
h. Participant-reported work productivity: Work Productivity and Activity Impairment (WPAI): Specific Health Problem (SHP) questionnaire
3. Intervention-emergent AEs, including intervention emergent AEs of special interest
4. Suicidal ideation and behavior: Columbia-Suicide Severity Rating Scale (C-SSRS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. W8 followed by every alternate week till W32 and follow-up
2.a. W1 (D1, D8), W2 (D15), W4 (D29), W6 (D43), W8 (D57) and every alternate week till W32 and follow-up
2.b. • CGI-S: Screening, W1 (D1, D8), W2 (D15), W3 (D22), W4 (D29), W8 (D57) and W12, W16, W20, W24, W28, W32 and follow-up
• CGI-C: W1 (D8), W2 (D15), W3 (D22), W4 (D29), W8 (D57), W12, W16, W20, W24, W28, W32 and follow-up
2.c. W1 (D1), W2 (D15), W4 (D29), W6 (D43), W8 (D57) and every alternate week till W32 and follow-up
2.d. to 2.h. W1 (D1), W4 (D29), W8 (D57) and W12, W16, W20, W24, W28, W32 and follow-up
3. Through out the study
4. W1 (D1), W4 (D29), W8 (D57) and W12, W16, W20, W24, W28, W32 and follow-up
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability , Biomarkers evaluations |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 127 |
| 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 |
| Israel |
| Korea, Republic of |
| Malaysia |
| South Africa |
| Taiwan |
| Turkey |
| Austria |
| Belgium |
| Bulgaria |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Sweden |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 9 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 9 |
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