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

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.
4.1 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; 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 (ie, nonresponse and minimal clinical improvement).
5.1 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.
6.1 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.
14.1 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 74 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

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.
6.1 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.
13.1 has one of the following cardiovascular-related conditions:
(a). cerebrovascular disease with a history of stroke or transient ischemic
attack.
(b). aneurysmal vascular disease (including intracranial, thoracic, or
abdominal aorta, or peripheral arterial vessels).
(c). history of intracerebral hemorrhage.
(d). 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.
(e). uncontrolled brady- or tachyarrhythmias that lead to hemodynamic
instability.
(f). hemodynamically significant valvular heart disease such as mitral
regurgitation, aortic stenosis, or aortic regurgitation.
(g).confirmed or suspected cardiomyopathy or myocarditis
(h). 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).
17. history of, or symptoms and signs suggestive of, liver cirrhosis (eg,
esophageal varices, ascites, and increased prothrombin time) or alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) values >=3 × the
upper limit of normal in routine laboratory test or medical record or at
screening.
18. has a fasting triglyceride concentration >=500 mg/dL at screening.

Refer the protocol for all the exclusion criteria.