E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment-resistant Major Depression |
|
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. |
|
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 | 19.0 |
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 |
|
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 intranasal esketamine 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 |
|
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
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Based on the prior study the participant is entering 54135419TRD3008 from: a) From ESKETINTRD3001 (NCT02417064) or
ESKETINTRD3002 (NCT02418585) study: Participant has completed the induction phase and 6-month follow up phase;
b) From ESKETINTRD3003 (NCT02493868) study: (1) Participant relapsed during the maintenance phase; or (2) Participant 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 (3) Participant was in the optimization or maintenance phases at the time the study was terminated;
c) From ESKETINTRD3004 (NCT02497287) study: (1) Participant completed the
ESKETINTRD3004 study (that is, Week 52 of the optimization/maintenance phase and the follow up phase); or (2) Participant 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 (3) Participant was in the optimization/maintenance phase at the time the study was terminated;
d) From ESKETINTRD3005 (NCT02422186) study: Participant 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 a non-responder.
-Participant must be medically stable on the basis of physical examination, vital signs, pulse oximetry, and 12-lead Electrocardiogram (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 participant's source documents and initialed by the investigator
-Participant must be medically stable on the basis of clinical laboratory tests performed predose on the day of the first intranasal treatment session. 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 or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialed by the investigator
-A woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [b-hCG]) predose on the day of the first intranasal treatment session
-During the study (that is, from the first intranasal treatment session) and for a
minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after
receiving the last dose of intranasal study medication, in addition to the user
independent highly effective method of contraception, a man a) who is sexually active with a woman of childbearing potential must agree to use a doublebarrier method of contraception (example, diaphragm or cervical/vault caps plus condom with spermicidal foam/gel/film/cream/suppository); b) who is sexually active with a woman who is pregnant must use a condom; c) must
agree not to donate sperm. Alternatively female partners of childbearing potential may be practicing a highly effective method of birth control, example, established use of oral, injected, or implanted hormonal methods of
contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); or male partner sterilization. |
|
E.4 | Principal exclusion criteria |
-The evaluation of the benefit versus risk of continued intranasal esketamine treatment is not favorable for the participant in the opinion of the investigator
-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 (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) 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)
-Participant has positive test result(s) for drugs of abuse (including arbiturates,
methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) predose on the day of the first intranasal treatment session
-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
-Participant has taken any prohibited therapies that would not permit
administration of the first intranasal treatment session |
|
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) |
|
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) |
|
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) |
|
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) |
|
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 |
|
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
|
|
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 |