Adolescents: 12 to <18 years
Must meet DSM-5 diagnostic criteria for MDD, without psychotic features, based upon clinical assessment and confirmed by the MINI-KID
Must have a CGI-SS-R score of “Markedly” or greater (ie, ≥4) at both screening and baseline (predose) visits.
In the physician’s opinion, acute psychiatric hospitalization is clinically warranted due to subject’s acute suicidality.
Must have a CDRS-R total score ≥58 at baseline (predose). 6. As part of SoC treatment, the participant must agree to:
be hospitalized voluntarily (non-compulsory hospitalization) for a recommended period of 5 days (4 nights) from Day 1, Randomization Day (may be shorter or longer if clinically warranted in the investigator’s opinion).
take 1 of the following prescribed SoC SSRI antidepressants, in any approved oral formulation and available in the participating country/territory: fluoxetine, escitalopram, or sertraline at least during the DB treatment phase.
Must be medically stable based on physical examination, medical history, vital signs, and 12-lead ECG performed at screening. If there are abnormalities, the participant may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the participant's source documents and initialed by the investigator. Note: Participants recovering from a recent suicide attempt may be eligible provided they are medically stable.
Must be medically stable based on clinical laboratory tests performed by the local laboratory at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant. This determination must be recorded in the participant’s source documents and initialed by the investigator.
During the DB treatment phase and for at least 6 weeks after the last dose of study intervention, sexual abstinence (avoiding heterosexual intercourse) is strongly recommended. However, heterosexually active participants of child-bearing potential must practice a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly). If oral contraceptives are used, a barrier method of contraception must also be used. Note: if the childbearing potential changes after the start of the study (eg, a premenarchal participant experiences menarche) or the risk of pregnancy changes (eg, a participant who can become pregnant and who was not heterosexually active becomes active), the investigator should reassess the need for contraception. As an approach to prevent pregnancy, the reliability of sexual abstinence or the use of effective contraception needs to be evaluated in relation to the duration of the study, and the preferred and usual lifestyle of the participant. Evaluation of the reliability of abstinence/use of effective contraception should be documented in source notes. Contraceptive use by participants should be consistent with local regulations regarding the use of contraceptive methods in adolescents and should be discussed in detail confidentially with the potential adolescent participant by the study investigator. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study medication.
During the DB phase (from Day 1 through day of last dose of study intervention) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study intervention, a participant who is capable of producing sperm and is heterosexually active:
must practice a highly effective method of contraception with partner of childbearing potential. See Appendix 4 on Contraceptive and Barrier Guidance for details.
must use a condom if participant’s partner is pregnant
must agree not to donate gametes (ie, sperm) or freeze for future use for the purposes of assisted reproduction.
Participants of childbearing potential must have a negative highly sensitive (eg, beta-human chorionic gonadotropin) urine pregnancy test at screening.
Participants must agree not to be pregnant, breastfeeding, planning to become pregnant, or donate gametes (ie, eggs) or freeze for future use for the purposes of assisted reproduction while enrolled in this study or within 3 months after the last dose of study intervention.
The parent(s)/LAR (as defined in Section 2, Introduction) and the participant, must provide informed consent/assent, as described in Section 10.2.3, Informed Consent and Assent Process.
Participant must be comfortable with self-administration of oral and intranasal medication and able to follow instructions provided.
Participant must be willing and able to adhere to the lifestyle restrictions specified in Section 5.3 of this protocol.
A parent(s)/LAR must be available to help the study-site personnel ensure follow-up; ensure the participants are accompanied to the study site on each outpatient assessment day according to the SoA; consistently be available to provide information on the participant.
Participant has a current DSM-5 diagnosis of bipolar (or related disorders), intellectual disability, autism spectrum disorder, conduct disorder, oppositional defiant disorder.
Participant currently meets DSM-5 criteria for borderline personality disorder.
Participant has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD with psychosis.
Participant has a history of moderate or severe Substance or Alcohol Use Disorder, according to DSM-5 criteria, except nicotine or caffeine, within 6 months before screening. A history (lifetime) of (es) ketamine, phencyclidine, lysergic acid diethylamide, or 3, 4-methylenedioxy-methamphetamine hallucinogen-related use disorder is exclusionary.
Participant has a past history of hypertensive crisis. Participants with conditions in which blood pressure elevation could pose a serious risk (including severe cardiovascular disease, recent cerebral injury, increased intracranial pressure/intracranial mass lesion, intracranial bleeding, or acute stroke, primary developmental or secondary acquired glaucoma or perforating eye injury) are excluded.
Participant has a history or current signs and/or symptoms of liver or renal insufficiency. Participants with moderate to severe hepatic impairment are excluded.
Participant has a current diagnosis of clinically significant cardiac (eg, congenital heart disease, cardiomyopathy, or tachyarrhythmias), vascular, pulmonary, gastrointestinal, endocrine (including uncontrolled hyperthyroidism), neurologic, hematologic, rheumatologic, or metabolic (including severe dehydration/hypovolemia) disease based on investigator judgment.
Participant has a history of seizure disorder (excluding childhood febrile seizures).
Participant has a history of malignancy within 5 years before screening, with the exception of a malignancy that, in the opinion of the investigator and in concurrence with the sponsor's medical monitor, is considered to have minimal risk of recurrence.
Participant has anatomical or medical conditions that may impede delivery or absorption of intranasal study medication, including but not limited to an abnormal or deviated nasal septum with any 1 or more of the following symptoms: blockage of 1 or both nostrils, nasal congestion (especially 1-sided), frequent nosebleeds, and frequent sinus infections (and at times has facial pain, headaches, and postnasal drip with the sinus infection).
Participant has known allergies, hypersensitivity, intolerance or contraindications to midazolam, esketamine or ketamine, or their excipients.
Participant is taking any disallowed therapy(ies). Prestudy and Concomitant Therapy.
Participant has received an investigational drug (including esketamine, ketamine, or investigational vaccines) or used an invasive investigational medical device within 60 days before the first dose of study intervention or is currently enrolled in an investigational study.
Participant has received prior (lifetime) treatment with (es) ketamine (other than for anesthetic purposes)
On Day -1 (screening), a supine or semi-supine SBP and/or DBP ≥ the 95th percentile for sex, age and height is exclusionary. Participants who fall below the 5th or above the 95th percentile for their age, sex, and height should be evaluated using the parameters for the 5th or 95th percentile, respectively. Note that participants whose SBP and/or DBP values are ≥ the 95th percentile for sex, age and height may be reevaluated with a repeated measure once after at least 5 minutes of rest to assess eligibility. See Section 10.7 for pediatric blood pressure tables with percentile ranking by age, sex, and height for determination of hypertensive status.
Participant has a positive urine test result(s) for PCP, cocaine, or amphetamines (inclusive of amphetamine, methamphetamine, and methylenedioxy methamphetamine) at screening.
Participants who have a positive test result at screening due to prescribed psychostimulants (eg, amphetamines) and/or benzodiazepines that are permitted during the study in accordance with Table 3, are eligible for study participation.
In addition, participants who have a positive test for opiates, or barbiturates due to prescribed use may be considered eligible per clinician judgment and in consultation with the sponsor’s medical monitor. Participants known to be using heroin should be excluded from the study.
Participants who have a positive test for opiates, benzodiazepines, or barbiturates taken in a suicide attempt (eg, overdose) may be eligible for study participation per clinician judgment and in consultation with the sponsor’s medical monitor.
Participants who have a positive test due to cannabinoids may be eligible provided they do not meet DSM-5 criteria for a moderate to severe substance abuse disorder.
Participant has a body weight of <40 kg at screening visit.
Participant of childbearing potential who is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study intervention.
Participant has any situation or condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
Participant or parent(s)/LAR is an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.