E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Major Depressive Disorder with Imminent Risk of Suicide |
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E.1.1.1 | Medical condition in easily understood language |
Depression with Risk of Suicide |
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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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042458 |
E.1.2 | Term | Suicidal ideation |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012397 |
E.1.2 | Term | Depression suicidal |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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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 | 10065604 |
E.1.2 | Term | Suicidal behaviour |
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 is to evaluate the efficacy of intranasal esketamine 84 mg compared with intranasal placebo in addition to comprehensive standard of care in reducing the symptoms of MDD, including suicidal ideation, in subjects who are assessed to be at imminent risk for suicide, as measured by the change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 24 hours post first dose. |
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E.2.2 | Secondary objectives of the trial |
The key secondary objective is to assess the efficacy of intranasal esketamine compared with intranasal placebo in reducing severity of suicidality as measured by the clinical global impression of severity of suicidality revised version (CGI-SS-R) at 24 hours post first dose. Other secondary objectives are listed in Protocol Section 2.1.1. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject must be a man or woman, 18 to 64 years of age, inclusive.
2. Subject must meet Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) diagnostic criteria for MDD, without psychotic features, based upon clinical assessment and confirmed by the MINI.
3. Subjects must have current suicidal ideation with intent, confirmed by a “Yes” response to Question B3 [Think (even momentarily) about harming or of hurting or of injuring yourself: with at least some intent or awareness that you might die as a result; or think about suicide (ie, about killing yourself)?] AND Question B10 [Intend to act on thoughts of killing yourself?] obtained from the MINI. Note: the response to B3 must refer to the present, whereas the response to B10 may reflect the past 24 hours. If the screening period is longer than 24 hours, assessment of B3 and B10 of MINI must be repeated prior to randomization to confirm eligibility.
4. In the physician’s opinion, acute psychiatric hospitalization is clinically warranted due to subject’s imminent risk of suicide.
5. Subject has a MADRS total score of >28 predose on Day 1.
6. Criterion modified per Amendment RS-1 Group 1
6.1. As part of standard of care treatment, subject agrees to be hospitalized voluntarily for a recommended period of 14 days after randomization (may be shorter or longer if clinically warranted in the investigator’s opinion) and take prescribed non-investigational antidepressant therapy(ies) for at least the duration of the double-blind treatment phase (Day 25).
7. Subject is comfortable with self-administration of intranasal medication and able to follow instructions provided.
8. Subject must be medically stable on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening. If there are abnormalities, the subject may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the subject's source documents and initialed by the investigator.
9. Subject must be medically stable on the basis of 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 subject 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 subject's source documents and initialed by the investigator.
10. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subject participating in clinical studies.
Before randomization, a woman must be either:
a. Not of childbearing potential defined as:
-postmenopausal (>45 years of age with amenorrhea for at least 12 months), permanently sterilized (eg, bilateral tubal occlusion/ligation procedures, hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy
b. Of childbearing potential and
-practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly)
-agrees to use a highly effective method throughout the study and for at least 6 weeks after the last dose of study drug.
11. A woman of childbearing potential must have a negative urine pregnancy test at screening.
12. During the study (ie, from Day 1 of the double-blind phase) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study drug, a man who is sexually active with a woman of childbearing potential
-must be practicing a highly effective method of contraception with his female partner
-must use a condom if his partner is pregnant.
-must agree not to donate sperm.
Note: If the childbearing potential changes after start of the study, a female partner of a male study subject must begin a highly effective method of birth control.
13. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
14. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study.
Note: Subjects with acute alcohol intoxication should not be screened (but can be screened once sober).
15. Each subject must sign a separate informed consent form if he or she agrees to provide an optional DNA sample for research (where local regulations permit). Refusal to give consent for the optional DNA research sample does not exclude a subject from participation in the study.
Additional information on inclusion criteria is found in Protocol Section 4.1 |
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E.4 | Principal exclusion criteria |
1. Subject has a current DSM-5 diagnosis of bipolar (or related disorders), antisocial personality disorder, or obsessive compulsive disorder.
2. Subject currently meets DSM-5 criteria for borderline personality disorder.
-Subjects not meeting full DSM-5 criteria for borderline personality disorder but exhibiting recurrent suicidal gestures, threats, or self-mutilating behaviors should also be excluded.
3. Subject has a current clinical diagnosis of autism, dementia, or intellectual disability.
4. Subject has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD with psychotic features.
5. Criterion modified per Amendment RS-1 Group 1
5.1. Subject meets the DSM-5 severity criteria for moderate or severe substance or alcohol use disorder (except for nicotine or caffeine) within the 12 months before screening. A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is exclusionary.
6. Subject has a history or current signs and symptoms of liver or renal insufficiency or of clinically significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic (including current or past history of seizures except uncomplicated childhood febrile seizures with no sequelae), hematologic, rheumatologic, or metabolic disease.
7. Subject has uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg) despite diet, exercise or a stable dose of anti-hypertensive treatment for at least 2 weeks at screening; or any past history of hypertensive crisis.
8. Subject has a positive urine test result(s) for phencyclidine (PCP), cocaine, or amphetamines at screening.
-Subjects who have a positive test due to the appropriate use of prescribed opiates, benzodiazepines, or barbiturates may be eligible for study participation per clinician judgment. In addition, subjects who have a positive test for opiates, benzodiazepines, or barbiturates used without a prescription, may be considered eligible per clinician judgment and in consultation with the sponsor’s medical monitor.
-Subjects who have a positive test due to 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.
9. Subject has a history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered to have minimal risk of recurrence).
10. Subject has any anatomical or medical condition that, per the investigator’s clinical judgment based on assessment, may impede delivery or absorption of intranasal study drug.
11. Subject has known allergies, hypersensitivity, intolerance or contraindications to esketamine or ketamine or its excipients (refer to Investigator's Brochure for esketamine, Summary of Product Characteristics, US prescribing information).
12. Subject has taken any disallowed therapy(ies) as noted in Section 8, Prestudy and Concomitant Therapy, and Attachment 1 of the protocol.
13. Subject has received an investigational drug (including esketamine, ketamine, or investigational vaccines) or used an invasive investigational medical device within 60 days before the planned first dose of study drug or is currently enrolled in an investigational study.
14. Subject is a woman who is pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug.
15. Subject has any situation or condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
16. Subject 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in depressive symptoms, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) total score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1, predose to 24 hours post first dose |
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E.5.2 | Secondary end point(s) |
1) Change from baseline in severity of suicidality, as measured by the clinical global impression of severity of suicidality revised version (CGI-SS-R)
2) Remission rate (MADRS ≤12)
3) Change from baseline of MADRS total score
4) Change from baseline of CGI-SS-R
5) Proportion of subjects achieving resolution of suicidality (CGI-SS-R score of 0 or 1)
6) Change from baseline of clinical global impression of imminent suicide risk (CGI SR-I)
7) Change from baseline of Beck Hopelessness Scale (BHS)
8) Change from baseline of European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L)
9) Change from baseline of Quality of Life in Depression Scale (QLDS)
10) Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores
11) Suicidal Ideation and Behaviors Assessment Tool (SIBAT): Change from baseline in Module 3 My Current Thinking and Module 5 My Risk, Question 3 (patient-reported frequency of suicidal thinking)
12) Pharmacokinetics: Plasma esketamine and noresketamine concentrations will be summarized; plasma concentrations of esketamine (and noresketamine concentrations, if warranted) will be included in a population analysis
13) Safety endpoints will be evaluated throughout the study - Monitoring of treatment emergent adverse events (TEAEs), Clinical laboratory tests, physical examination, nasal examination, 12-lead electrocardiogram (ECG), and vital signs, SIBAT, On dosing days only: MOAA/S, CADSS, and pulse oximetry |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) From day 1, predose to 24 hours post first dose
2, 5, 6) 4 hours and 24 hours post first dose, and through the end of the double-blind treatment phase (Day 25)
3,4) 4 hours post first dose and through the end of the double-blind treatment phase (Day 25)
7, 8, 9, 10, 11) Through the end of the double-blind treatment phase (Day 25)
12, 13) Throughout the study |
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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 | 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 | Yes |
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) | No |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Argentina |
Austria |
Belgium |
Brazil |
Canada |
Czech Republic |
France |
Lithuania |
Poland |
Turkey |
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 | 2 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |