A Long-term Safety Study of Esketamine Nasal Spray in Treatment-resistant Depression

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and tolerability of esketamine nasal spray in participants with treatment-resistant depression (TRD).

Detailed Description
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This is an open-label (the researchers and participants know the treatment the participant is receiving) long-term extension study. The study will consist of 2 open-label Phases: 4-week Induction phase (if applicable) and Open-Label Optimization/Maintenance phase (variable). Participants will enter the study Induction Phase from ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868), ESKETINTRD3005 (NCT02422186) and ESKETINTRD3006 (US sites only). Participants will enter the study Open-Label Optimization/Maintenance phase from ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868) (if appropriate at week 16) or ESKETINTRD3006 (US sites only). In the Open-Label Induction Phase, participants will self-administer flexibly-dosed esketamine nasal spray. During first 4 weeks in Optimization/Maintenance Phase responder participants from the induction phase of study 54135419TRD3008, will continue on the same dose of esketamine nasal spray from the induction phase and have a weekly intranasal treatment session frequency. Participants entering the optimization/maintenance phase from study ESKETINTRD3005 will also have a weekly intranasal treatment session frequency. However, as the ESKETINTRD3005 intranasal study medication is blinded at the time of entry into the current study, the dose of esketamine nasal spray will be administered as outlined in protocol. Participants entering the optimization/maintenance phase from study ESKETINTRD3003 (Direct Entry) or ESKETINTRD3004 who were ongoing in the Optimization, Maintenance, or Optimization/Maintenance phase, respectively, will have the option to have their current intranasal dosing frequency adjusted at the time of entry into 54135419TRD3008 study and should remain on the selected frequency from week 1 to week 4. A one-time dose change will be permitted at study entry. After 4 weeks, esketamine nasal spray treatment sessions will be individualized to either once weekly or once every other week at the fixed 2-week interval (based on clinical global impression - severity [CGI-S] performed at that visit), and every 4 weeks for participants dosed at the 4 week interval. Participants safety will be monitored throughout the study.

Official Title
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An Open-label Long-term Extension Safety Study of Esketamine Nasal Spray in Treatment-resistant Depression

Conditions
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Depressive Disorder, Treatment-Resistant

Intervention / Treatment
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* Drug: Esketamine Nasal Spray


Participation Criteria
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Eligibility Criteria
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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 the 2-weeks follow up phase visit; or Participants completed the induction phase and was a responder and study ESKETINTRD3003 is terminated.; 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; or (4) or (5) Participants was in the induction phase and after completion of induction phase was determined to not meet response criteria (1) Participant completed ESKETINTRD3004 study (optimization/maintenance 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; (4) Participant was in the induction phase and did not meet criteria for response may be eligible for to be rolled over into 54135419TRD3008. 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 did not meet the criteria for response. e) From ESKETINTRD3006 study (US Study sites only) (1) Participant completed the induction phase and was a 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 according to the investigator's judgment and knowledge of the subject's medical stability in the parent study. This determination must be documented. 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, 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 c) must agree not to donate sperm. Exclusion Criteria: 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 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 barbiturates, 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Esketamine Nasal Spray<br>Open-Label Induction Phase: Participants will self-administer with esketamine nasal spray twice per week for 4 weeks as a flexible dose regimen (56 milligram [mg] or 84 mg for those < 65 years; 28 mg, 56 mg or 84 mg for those >= 65 years). Participants >= 65 years old will start at a dose of 28 mg on Day 1. Optimization/Maintenance Phase: Participants entering from studies ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868), ESKETINTRD3004 (NCT02497287), or ESKETINTRD3006 (US sites only) will self-administer esketamine nasal spray (same dose) once weekly. Participants entering from study ESKETINTRD3005 (NCT02422186) will self-administer esketamine nasal spray (28 mg in week 1; 28 or 56 mg in week 2; and 28, 56 or 84 mg in week 3 and 4) once weekly. After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants can be adjusted based upon efficacy and tolerability. | Drug: Esketamine Nasal Spray<br>* Open-Label Induction Phase: Participants will self-administer with esketamine nasal spray twice per week for 4 weeks as a flexible dose regimen (56 milligram [mg] or 84 mg for those < 65 years; 28 mg, 56 mg or 84 mg for those >= 65 years). Participants >= 65 years old will start at a dose of 28 mg on Day 1. Optimization/Maintenance Phase: Participants entering from studies ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585) or ESKETINTRD3006 (US sites only) will self-administer esketamine nasal spray (same dose) once weekly. Participants entering from study ESKETINTRD3005 (NCT02422186) will self-administer esketamine nasal spray (28 mg in week 1; 28 or 56 mg in week 2; and 28, 56 or 84 mg in week 3 and 4) once weekly. After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants can be adjusted based upon efficacy and tolerability.<br>* Other names: JNJ-54135419;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) |  | Up to End of Study (approximately 5 years 3 months) | 
| Change From Baseline in Systolic and Diastolic Blood Pressure | Change From Baseline (predose) in systolic and diastolic blood pressure will be assessed. | 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) | 
| Change From Baseline in Heart Rate | Change from Baseline (predose) in heart rate will be assessed. | 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) | 
| Change From Baseline in Blood Oxygen Saturation | Change From Baseline in Blood oxygen saturation (predose) will be assessed. | 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) | 
| Change From Baseline in Modified Observer's Assessment of Alertness/Sedation (MOAAS) Scale Score | The MOAA/S will be used to measure treatment-emergent sedation, with correlation to levels of sedation defined by the American Society of Anesthesiologists (ASA) continuum. The MOAA/S scores range from 0=no response to painful stimulus (corresponds to ASA continuum for general anesthesia) to 5=readily responds to name spoken in normal tone (awake; corresponds to ASA continuum for minimal sedation). | 1 hour post-dose from the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change from Baseline in Electrocardiogram (ECG) intervals | Change From Baseline (predose) in Electrocardiogram (ECG) intervals will be assessed. | 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) | 
| Change From Baseline in Computerized Cognitive Battery Domain Score | The Change From Baseline in computerized cognitive battery will provide assessment of multiple cognitive domains, including attention, visual learning memory, and executive function. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score | The HVLT-R is a measure of verbal learning and memory, is a 12-item word list recall test. Scores include learning, delayed recall, and recognition. The HVLT-R is a well-validated and widely used measure of verbal episodic memory. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change From Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) Score | Change from baseline in suicidal ideation or behavior measured using C-SSRS score will be reported. C-SSRS is a clinician rated assessment of suicidal behavior and / or intent. Scale consists of 28 items in 4 sections: suicide behavior, actual attempts, suicidal ideation, and intensity of ideation. Suicidal ideation consists of 5 'yes/no' items: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intention to act, active suicidal ideation with some intent to act without specific plan, active suicidal ideation with specific plan and intent. Only items with yes responses are listed. Worsening of suicidal ideation was an increase in severity of suicidal ideation from baseline. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Changes From Baseline Over Time in Clinical Laboratory Tests |  | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Time to Discharge Readiness Using the Clinical Global Assessment of Discharge Readiness (CGADR) | The CGADR will be used to measure the participant's current clinical status and is the clinician's assessment of the readiness to be discharged from the study site. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Participant-Reported Depressive Symptoms Using the Patient Health Questionnaire - 9 (PHQ-9) Total Score | The PHQ-9 is a 9-item scale used to assess depressive symptoms. The responses for each item are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change From Baseline in Clinical Global Impression-Severity (CGI-S) score | The CGI-S evaluates the severity of psychopathology on a scale of 0 to 7. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change From Baseline in days when participants assess disruption of (1) work/school, (2) social life, leisure activities, and (3) family life/home responsibilities as Assessed by the Sheehan Disability Scale (SDS) Total Score | The SDS, a patient-reported outcome measure, is a 5 item questionnaire which has been widely used and accepted for assessment of functional and associated disability impairment. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items are summed to create a total score of 0-30 where a higher score indicates greater impairment. It also has one item on days lost from school or work and one item on days when underproductive. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change From Baseline in days symptoms caused participants to miss school or work or were unable to carry out normal daily responsibilitieswhen participant lost from school or work as as Assessed by the Sheehan Disability Scale (SDS) | The SDS, a patient-reported outcome measure, is a 5 item questionnaire which has been widely used and accepted for assessment of functional and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items are summed to create a total score of 0-30 where a higher score indicates greater impairment. It also has one item on days lost from school or work and one item on days when underproductive. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change From Baseline in days when participant was underproductive as Assessed by the Sheehan Disability Scale (SDS) | The SDS, a patient-reported outcome measure, is a 5 item questionnaire which has been widely used and accepted for assessment of functional and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items are summed to create a total score of 0-30 where a higher score indicates greater impairment. It also has one item on days lost from school or work and one item on days when underproductive. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change From Baseline in Participant-Reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) ) Valuation Index Score | The EQ-5D questionnaire is a brief, generic health-related quality of life assessment (HRQOL) that can also be used to incorporate participant preferences into health economic evaluations. The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and as overall health using a thermometer visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health). Lower scores indicate worsening. EQ-5D scores include EQ-5D valuation index score (a weighted scoring of the 5 dimension scores with a possible range from 0 to 1) and EQ5D descriptive system scores (five scores reflecting each of the 5 EQ-5D health dimensions ranging from 0 [no limitation] to 4 [incapacity]). | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change From Baseline in Participant-Reported Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Visual Analog Scale (VAS) | EQ-5D visual analog scale (VAS) is a 20 centimeter (cm) vertical VAS with scores ranging from 0 (worst imaginable health) to 100 (perfect health. A higher score indicates an improvement in health in the Health Status Index. The EuroQol-5 is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating full health and 0 representing dead. | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 
| Change From Baseline in Participant- Reported Health Related Quality of Life Using the Quality of Life in Depression Scale (QLDS) | The QLDS is a disease specific PRO designed to assess health related quality of life in patients with Major Depressive Disorder. The instrument has a recall period of at the moment, contains 34-items with yes/no response options and takes approximately 5-10 minutes to complete. The score range is from 0 (good quality of life) to 34 (very poor quality of life). | From the start of Induction Phase to End of Optimization/Maintenance Phase (approximately 5 years 3 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depressive Disorder, Treatment-Resistant, Esketamine, JNJ-54135419