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 | 21.1 |
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 assess the safety and tolerability of esketamine nasal spray in subjects with TRD, with special attention to the following: •Potential long term effects on cognitive function •Treatment-emergent adverse events (TEAEs), including TEAEs of special interest •Post dose effects on heart rate, blood pressure, respiratory rate and blood oxygen saturation •Potential effects on suicidal ideation/behavior |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess long-term efficacy, including effects on: •Depressive symptoms (clinician and self-reported), •Overall severity of depressive illness, •Functioning and associated disability, •Health related quality of life and health status
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Criterion modified per Amendment 1 1.1 Based on the prior study the subject is entering 54135419TRD3008 from: a. From ESKETINTRD3001 or ESKETINTRD3002 study: i. Subject has completed the induction phase and the 2-week follow up phase visit; or ii. Subject completed the induction phase and was a responder and study ESKETINTRD3003 is terminated. b. From ESKETINTRD3003 study: i. Subject relapsed during the maintenance phase; or ii. Subject was in the induction phase of the ESKETINTRD3003 study when the study was terminated and, after completion of the induction phase, was determined to be a responder; or iii. Subject was in the optimization or maintenance phases at the time the study was terminated; or iv. At Week 16 of Optimization, the subject was not eligible to proceed to the Maintenance phase and sponsor has approved subject's entry into 54135419TRD3008; or v. Subject was in the induction phase and after completion of induction phase was determined to not meet response criteria, and sponsor has approved subject's entry into 54135419TRD3008. c. From ESKETINTRD3004 study: i. Subject completed ESKETINTRD3004 study optimization/maintenance phase; or ii. Subject was in the induction phase of the ESKETINTRD3004 study when the study was terminated and, after completion of the induction phase, was determined to be a responder; or iii. Subject was in the optimization/maintenance phase at the time the study was terminated; or response, and sponsor has approved subject's entry into 54135419TRD3008. d. From ESKETINTRD3005 study: Subject was in the induction phase of the ESKETINTRD3005 study at the time enrollment into the ESKETINTRD3004 study was closed and, after completion of the induction phase, was determined to be a responder or did not meet the criteria for response. e. From ESKETINTRD3006 study (US Study sites only): i. Subject completed the induction phase and was a responder; or ii. Subject completed the induction phase and did not meet the response criteria and sponsor has approved subject's entry into 54135419TRD3008. 2. Subject must be medically stable on the basis of physical examination, vital signs (including blood pressure), pulse oximetry, and 12-lead ECG performed predose on the day of the first intranasal treatment session. 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 subject's source documents and initialed by the investigator. 3. Criterion modified per Amendment 1 3.1 Subject must be medically stable according to the investigator's judgment and knowledge of the subject's medical stability in the parent study. This determination must be documented. . 4. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. A woman must be either: a. Not of childbearing potential defined as: -postmenopausal -permanently sterile b. Of childbearing potential and practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly). Examples of highly effective contraceptives include -user-independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormonereleasing system (IUS); vasectomized partner; sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.) -user-dependent methods: combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. Additional Inclusion Criteria can be found in Protocol Section 4.1
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E.4 | Principal exclusion criteria |
1. The evaluation of the benefit versus risk of continued esketamine nasal spray treatment is not favorable for the participant in the opinion of the investigator 2. Since the last study visit in the participant's prior study, participant has suicidal ideation with intent to act per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (CSSRS) [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) in the suicidal ideation module of the C-SSRS] or suicidal behavior per the investigator's clinical judgment or based on the C-SSRS (corresponding to any score higher than 0 in the suicidal behavior module of the C-SSRS) 3. Subject has a neurodegenerative disorder (eg, Alzheimer's disease, vascular dementia, Parkinson's disease), or evidence of mild cognitive impairment (MCI). 4. Participant has positive test result(s) for drugs of abuse (including barbiturates, methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) predose on the day of the first intranasal treatment session 5. Participant 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 6. Participant has taken any prohibited therapies that would not permit administration of the first intranasal treatment session
Additional Exclusion Criteria can be found in Protocol section 4.2 |
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E.5 End points |
E.5.1 | Primary end point(s) |
1.) Number of Participants With Treatment Emergent Adverse Events (TEAEs) 2.) Change From Baseline in Systolic and Diastolic Blood Pressure 3.) Change From Baseline in Heart Rate 4.) Change From Baseline in Blood Oxygen Saturation 5.) Change From Baseline in Modified Observer's Assessment of Alertness/Sedation (MOAAS) Scale Score 6.) Change from Baseline in Electrocardiogram (ECG) intervals 7.) Change From Baseline in Computerized Cognitive Battery Domain Score and Hopkins Verbal Learning Test-Revised (HVLT-R) Score 8.) Change From Baseline in Columbia-Suicide Severity Rating Scale (CSSRS) Score 9.) Changes From Baseline Over Time in Clinical Laboratory Tests 10.) Time to Discharge Readiness Using the Clinical Global Assessment of Discharge Readiness (CGADR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.) Up to End of Study (approximately 5 years 3 months)
2./3./4./6.) Baseline of each dosing session (predose) up to the last post-dose measurement from the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months)
5.) 1 hour post-dose from the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months)
7./8./9./10.) From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) |
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E.5.2 | Secondary end point(s) |
1.) Change From Baseline in Participant-Reported Depressive Symptoms Using the Patient Health Questionnaire - 9 (PHQ-9) Total Score 2.) Change From Baseline in Clinical Global Impression-Severity (CGI-S) score 3.) Change From Baseline in Participant-Reported Functioning and Associated Disability as Assessed by the Sheehan Disability Scale (SDS) Total Score 4.) Change From Baseline in Participant-Reported Health-related Quality of Life and Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) 5.) Change From Baseline in Participant- Reported Health Related Quality of Life Using the Quality of Life in Depression Scale (QLDS) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1./2./3./4./5.) From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) |
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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 | 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 | No |
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 | No |
E.8.1.1 | Randomised | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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 |
Australia |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Malaysia |
Mexico |
Poland |
Romania |
South Africa |
Spain |
Sweden |
Taiwan |
Turkey |
United Kingdom |
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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The end of the study will occur based on the subject's individual efficacy and tolerability to esketamine nasal spray, and/or until esketamine is approved in the respective country and accessible through the local healthcare system funding or until end of December 2022, whichever is earlier. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 19 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 19 |