An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression
Overview
- Phase
- Phase 3
- Intervention
- Esketamine (Intranasal Spray)
- Conditions
- Treatment-resistant Depression
- Sponsor
- Janssen Research & Development, LLC
- Enrollment
- 802
- Primary Endpoint
- Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The purpose of this open-label, multicenter study is to assess the long term safety and efficacy of intranasal esketamine plus an oral antidepressant in participants with treatment-resistant depression (TRD).
Detailed Description
This is an open-label (the researchers and participants know the treatment the participant is receiving), multicenter (more than 1 study site), long-term safety and efficacy study of intranasal esketamine plus an oral antidepressant in participants with treatment-resistant depression (TRD). Participants will enter the study either directly (direct-entry participants) or after completing the Double-Blind Induction Phase of ESKETINTRD3005 (transferred-entry participants). The study consists of 4 phases: Screening Phase (4 weeks), Open-Label Induction Phase (4 weeks), Open-Label Optimization/Maintenance phase (48 weeks), and Follow up Phase (4 weeks). Transferred entry non-responders in the ESKETINTRD3005 may enter study at the Open-Label Induction Phase and responders in the ESKETINTRD3005 may enter Optimization/Maintenance phase. In the Open-Label Induction Phase, participants will self-administer flexibly-dosed intranasal esketamine (participants who are less than (\<) 65 years old self-administer 56 mg or 84 mg dose, participants who are greater than or equal to (\>=) 65 years old self-administer 28 mg, 56 mg or 84 mg dose) twice weekly for 4 weeks. The starting dose for all participants \>= 65 years old will be 28 mg. In addition, each direct-entry participants will be assigned to receive 1 of 4 selected oral antidepressant medications (escitalopram or sertraline or duloxetine or venlafaxine extended release \[XR\]), initiated on Day 1 of the open-label induction phase and continued through the duration of the study. Transferred-entry participants will continue their same antidepressant from ESKETINTRD3005 through the duration of this study. Participants who are responders at the end of the Open-Label Induction phase and transferred-entry responder participants (from study ESKETINTRD3005) will enter the Optimization/Maintenance Phase where intranasal esketamine treatment sessions will be reduced from that in the induction phase (twice weekly) to weekly for the first 4 weeks of this phase, and then individualized to either once weekly or once every other week based on the severity of depressive symptoms. Participants' safety and depressive symptoms will be assessed and monitored throughout the study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •A). For Direct-Entry Participants
- •At the time of signing the informed consent form (ICF), participant must be a man or woman ≥18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than \[\>\]18)
- •At the start of the screening phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single-episode MDD, the duration must be greater than or equal to \[\>=\] 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (MINI)
- •At screening, participant must have a MADRS total score of \>=22
- •At the start of the screening phase, participants must have had nonresponse to \>=2 oral antidepressant treatments in the current episode of depression, as assessed using the the MGHATRQ and confirmed by documented records (example medical/pharmacy/prescription records or a letter from treating a physician, etc,) B). For Transferred-entry Participants
- •All participants who completed the double-blind induction phase of ESKETINTRD3005 study, regardless of their response status, will be eligible to participate in this study, if they meet the study specific eligibility criteria
Exclusion Criteria
- •A). For Direct-Entry Participants
- •Participant's depressive symptoms have previously not responded to: Esketamine or ketamine in the current major depressive episode per clinical judgment or All of the 4 oral antidepressant treatment options available in the respective country for the open-label induction phase (that is, duloxetine, escitalopram, sertraline, and venlafaxine XR) in the current major depressive episode (based on Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire \[ MGH-ATRQ\])
- •Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by the MINI), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
- •Participant has homicidal ideation/intent, per the investigator's clinical judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of the screening phase, per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS)
- •Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria
- •Participants who has a Mini Mental State Examination (MMSE) \<25; Has neurodegenerative disorder (example, Alzheimer's disease, vascular dementia, Parkinson's disease), or evidence of mild cognitive impairment (MCI) B). Transferred-Entry Participants
- •Participant has taken any prohibited therapies that would not permit dosing on Day 1
Arms & Interventions
Intranasal Esketamine plus oral antidepressant
Open-Label Induction Phase: Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen (56 mg or 84 mg). Participants greater than or equal to (\>=) 65 will start at a dose of 28 mg on Day 1. Direct-entry participants will initiate a new, open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1; transferred-entry participants will continue the same oral antidepressant from ESKETINTRD3005. Optimization/Maintenance Phase: Participants will self-administer esketamine (56mg or 84mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years) intranasally once per week for 4 weeks; transferred entry responder subjects from ESKETINTRD3005 will start at a dose of 28 mg in the first week. All participants will continue their same oral antidepressant during this phase.
Intervention: Esketamine (Intranasal Spray)
Intranasal Esketamine plus oral antidepressant
Open-Label Induction Phase: Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen (56 mg or 84 mg). Participants greater than or equal to (\>=) 65 will start at a dose of 28 mg on Day 1. Direct-entry participants will initiate a new, open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1; transferred-entry participants will continue the same oral antidepressant from ESKETINTRD3005. Optimization/Maintenance Phase: Participants will self-administer esketamine (56mg or 84mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years) intranasally once per week for 4 weeks; transferred entry responder subjects from ESKETINTRD3005 will start at a dose of 28 mg in the first week. All participants will continue their same oral antidepressant during this phase.
Intervention: Duloxetine (Oral Antidepressant)
Intranasal Esketamine plus oral antidepressant
Open-Label Induction Phase: Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen (56 mg or 84 mg). Participants greater than or equal to (\>=) 65 will start at a dose of 28 mg on Day 1. Direct-entry participants will initiate a new, open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1; transferred-entry participants will continue the same oral antidepressant from ESKETINTRD3005. Optimization/Maintenance Phase: Participants will self-administer esketamine (56mg or 84mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years) intranasally once per week for 4 weeks; transferred entry responder subjects from ESKETINTRD3005 will start at a dose of 28 mg in the first week. All participants will continue their same oral antidepressant during this phase.
Intervention: Escitalopram (Oral Antidepressant)
Intranasal Esketamine plus oral antidepressant
Open-Label Induction Phase: Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen (56 mg or 84 mg). Participants greater than or equal to (\>=) 65 will start at a dose of 28 mg on Day 1. Direct-entry participants will initiate a new, open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1; transferred-entry participants will continue the same oral antidepressant from ESKETINTRD3005. Optimization/Maintenance Phase: Participants will self-administer esketamine (56mg or 84mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years) intranasally once per week for 4 weeks; transferred entry responder subjects from ESKETINTRD3005 will start at a dose of 28 mg in the first week. All participants will continue their same oral antidepressant during this phase.
Intervention: Sertraline (Oral Antidepressant)
Intranasal Esketamine plus oral antidepressant
Open-Label Induction Phase: Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen (56 mg or 84 mg). Participants greater than or equal to (\>=) 65 will start at a dose of 28 mg on Day 1. Direct-entry participants will initiate a new, open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1; transferred-entry participants will continue the same oral antidepressant from ESKETINTRD3005. Optimization/Maintenance Phase: Participants will self-administer esketamine (56mg or 84mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years) intranasally once per week for 4 weeks; transferred entry responder subjects from ESKETINTRD3005 will start at a dose of 28 mg in the first week. All participants will continue their same oral antidepressant during this phase.
Intervention: Venlafaxine Extended Release (XR) (Oral Antidepressant)
Outcomes
Primary Outcomes
Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders
Time Frame: Up to End of Follow up Phase (Week 56)
Percentage of participants with cystitis, urinary tract infections, renal and urinary tract symptoms, renal and urinary disorders were evaluated. Cystitis and urinary tract infections are selected MedDRA preferred terms, "renal and urinary tract symptoms" refers to any preferred term (PT) in the group of selected PTs; and "renal and urinary disorders" refers to a MedDRA System Organ Class (SOC).
Change From Baseline in Cognitive Test Battery: Detection Test (DET) Score
Time Frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of Optimization/Maintenance [OP/MA] Phase)
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. The DET is a measure of psychomotor function and uses a well-validated simple reaction time. In this outcome measure, speed of performance of participants (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Total score ranges from 2 to 3.3 log 10 milliseconds (msec). Lower score indicates better performance. Higher change from baseline indicates better performance.
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time Frame: Up to End of Follow up Phase (Week 56)
An adverse event is any untoward medical occurrence in a clinical study participants who administered a medicinal (investigational or non-investigational) product and does not necessarily have a causal relationship with the treatment. A TEAE defined as an event that was new in onset or increased in severity following treatment initiation.
Change From Baseline in Cognitive Test Battery: One Back Test (ONB) Score
Time Frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
The ONB is a measure of working memory and scored for speed of correct response (mean of the log10-transformed reaction times for correct responses). Total score ranges from 2 to 3.54 log10 msec. Lower score indicates better performance. Higher change from baseline indicates better performance.
Change From Baseline in Cognitive Test Battery: One Card Learning Test (OCL) Score
Time Frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses (CR). The range for OCL is 0 to 100 percent (%) accuracy; presented as an arcsin transformation, the range is 0 to 1.57. Higher score indicates better performance. Higher change from baseline indicates better performance.
Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score
Time Frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. IDN test is a measure of visual attention (choice reaction time) and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Total score ranges from 2 to 3.3 log 10 msec. Lower score indicates better performance. Higher change from baseline indicates better performance.
Change From Baseline in Cognitive Test Battery: Groton Maze Learning Test (GMLT) Score
Time Frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. GMLT measures executive function; maze/sequencing test, scored for total number of errors. Total score ranges from 0 to 999 number of errors. Lower score indicates better performance. Higher change from baseline indicates better performance.
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Number of Words Recalled
Time Frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
HVLT measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Total Recall
Time Frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Hopkins Verbal Learning Test (HVLT) measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Delayed Recall
Time Frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
HVLT measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Recognition Discrimination Index
Time Frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
HVLT measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.
Secondary Outcomes
- Change From Baseline to Endpoint in PHQ-9 Total Score During OP/MA Phase(Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase))
- Change From Baseline to Endpoint in Clinical Global Impression of Severity (CGI-S) Scale Score During IND Phase(Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase))
- Change From Baseline to Endpoint in CGI-S Scale Score During OP/MA Phase(Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase))
- Change From Baseline to Endpoint in MADRS Total Score During Optimization/Maintenance (OP/MA) Phase(Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase))
- Change From Baseline to Endpoint in GAD-7 Total Score During OP/MA Phase(Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase))
- Change From Baseline to Endpoint in EQ-5D-5L Score During IND Phase: EQ-VAS(Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase))
- Change From Baseline to Endpoint in EQ-5D-5L Scale Score During OP/MA Phase: Health Status Index(Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase))
- Change From Baseline to Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score During Induction (IND) Phase(Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase))
- Change From Baseline to Endpoint in Patient Health Questionnaire - 9 (PHQ-9) Total Score During IND Phase(Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase))
- Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During IND Phase: Sum Score(Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase))
- Change From Baseline to Endpoint in EQ-5D-5L Score During OP/MA Phase: EQ-VAS(Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase))
- Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During OP/MA Phase: Sum Score(Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase))
- Change From Baseline in Sheehan Disability Scale Total Score During OP/MA Phase(Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase))
- Percentage of Participants With Response as Assessed by PHQ-9 Total Score During IND Phase(Day 15 and Endpoint (last post-baseline assessment value during 4 Week IND phase))
- Percentage of Participants With Remission as Assessed by MADRS Total Score During IND Phase(Days 8, 15, 22 and Endpoint (last post-baseline assessment value during 4 weeks of IND Phase))
- Change From Baseline to Endpoint in Generalized Anxiety Disorder (GAD-7) Total Score During IND Phase(Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase))
- Change From Baseline to Endpoint in EQ-5D-5L Scale Score During IND Phase: Health Status Index(Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase))
- Change From Baseline in Sheehan Disability Scale (SDS) Total Score During IND Phase(Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND Phase))
- Percentage of Participants With Response as Assessed by MADRS Total Score During IND Phase(Days 8, 15, 22 and Endpoint (last post-baseline assessment during 4 weeks of IND phase))
- Percentage of Participants With an Increase Score From Predose at Any Time in Clinician-Administered Dissociative States Scale (CADSS) Total Score During IND Phase(Predose, up to 1.5 hours postdose (up to end of IND phase [Week 4]))
- Percentage of Participants With an Increase Score From Predose at Any Time in CADSS Total Score During OP/MA Phase(Predose, up to 1.5 hours postdose (up to end of OP/MA phase [Week 52]))
- Percentage of Participants With Remission as Assessed by PHQ-9 Total Score During IND Phase(Day 15 and Endpoint (last post-baseline assessment value during 4 weeks of IND phase))
- Percentage of Participants With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases(Up to End of OP/MA phase (Week 52))