Treatment-resistant Depression
Conditions
Keywords
Treatment-resistant Depression, Esketamine, Oral Antidepressant
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.
Interventions
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 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 will self-administer esketamine intranasally (56 mg or 84 mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years) once weekly then individualized to either once weekly or once every other week based on the severity of depressive symptoms. Transferred-entry responder participants from ESKETINTRD3005 \>= 65 years old will start at a dose of 28 mg in Week 5.
Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).
Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. The minimum therapeutic dose is 10 mg/day. Participants \>= 65 years of age will be titrated up to 20 mg/day, but can lower the dose to 10 mg/day for tolerability.
Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline will be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.
Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release will be titrated for participants \< 65 years of age up to a dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day. For participants \>= 65, it can be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 75 mg/day.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 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. |
| Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders | 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 | 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. |
| Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score | 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: One Card Learning Test (OCL) Score | 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: One Back Test (ONB) Score | 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: Groton Maze Learning Test (GMLT) Score | 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: Total Recall | 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 | 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: Number of Words Recalled | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a HSI. HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health). |
| 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) | EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a Health Status Index (HSI). HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health). EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state. |
| 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) | EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). |
| 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) | EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a HSI. HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health). |
| 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) | SDS was a participant-reported outcome measure and was a 5 item questionnaire used for assessment of functional impairment 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 to 10 rating scale. The score for the first three items are summed to create a total score of 0 to 30 where a higher score indicates greater impairment and a negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | Response is defined as greater than or equal to (\>=) 50 % reduction from baseline in the MADRS total score. MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using last observation carried forward (LOCF) method, last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | Remission is defined as MADRS total score less than or equal to (\<=) 12. MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | Remission is defined as PHQ-9 total score \<= 4. PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The scores are summed for a total score ranging from 0-27. A higher score indicates greater severity of depression. severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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]) | The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = Not at all, 1 = Mild, 2 = Moderate, 3 = 'Severe and 4 = Extreme). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition. |
| 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]) | The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = Not at all, 1 = Mild, 2 = Moderate, 3 = 'Severe and 4 = Extreme). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition. |
| 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) | Percentage of participants with treatment-emergent acute hypertension (Systolic Blood Pressure \>=180 millimeters of mercury \[mm Hg\] or Diastolic Blood Pressure \>= 110 mm Hg) during IND and OP/MA Phases were evaluated. |
| 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) | Response is defined as \>= 50 % reduction from baseline (IND phase) in PHQ-9 total score. PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The scores are summed for a total score ranging from 0-27. A higher score indicates greater severity of depression. Severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | MADRS measure depression severity, detects changes due to AD treatment. It evaluates 10 items: apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. A higher score indicates greater severity of depression. Severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. A higher score indicates greater severity of depression. severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | CGI-S measures severity of participant's illness that include knowledge of participant's history, psychosocial circumstances, symptoms, behavior, impact of symptoms on participant's ability to function. CGI-S evaluates severity of psychopathology on a scale range from 0 - 7, where 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as Endpoint. |
| 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) | The CGI-S measures the severity of the participant's illness that include knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 0 to 7, where 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | GAD-7 is brief, validated 7-item self-reported assessment of overall anxiety. Participant's responded to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield total score ranges from 0 to 21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of GAD-7 is categorized as: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Missing data was imputed using LOCF method, last post baseline observation during the phase was carried forward as Endpoint. |
| 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) | GAD-7 is brief and validated 7-item self-reported assessment of overall anxiety. Participants respond to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score ranges from 0 to 21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | SDS was a 5 item questionnaire used for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, (3) family life/home responsibilities using a 0 to 10 rating scale. Score for the first three items are summed to create a total score of 0 to 30, higher score indicates greater impairment and a negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint. |
| 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) | EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a Health Status Index (HSI). HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health). EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state. |
| 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) | EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Finland, France, Germany, Lithuania, Malaysia, Mexico, Poland, South Africa, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
In this study participants from study ESKETINTRD3005 (NCT02422186) were enrolled (transferred entry \[TE\]). ESKETINTRD3005 is referred as TRD3005 in the draft.
Pre-assignment details
Total 802 participants were enrolled (direct-entry \[DE\]=691 + TE from study ESKETINTRD3005 =111). Among 111 TE participants, 88 participants (non-responders from ESKETINTRD3005) joined induction (IND) phase and 23 participants (responders from ESKETINTRD3005) did not join IND phase and directly entered in optimization/maintenance (OP/MA) phase.
Participants by arm
| Arm | Count |
|---|---|
| Intranasal Esketamine + Oral Antidepressant Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (\<65 years) and 28, 56 or 84 mg (\>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release \[XR\]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator's clinical judgement. | 802 |
| Total | 802 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow-up Phase (4 Week) | Adverse Event | 3 |
| Follow-up Phase (4 Week) | Lost to Follow-up | 5 |
| Follow-up Phase (4 Week) | Other | 1 |
| Follow-up Phase (4 Week) | PI Decision | 12 |
| Follow-up Phase (4 Week) | Withdrawal by Subject | 10 |
| Induction Phase (4 Weeks) | Adverse Event | 52 |
| Induction Phase (4 Weeks) | Did Not Met Criteria for OP/MA Phase | 84 |
| Induction Phase (4 Weeks) | Lack of Efficacy | 21 |
| Induction Phase (4 Weeks) | Lost to Follow-up | 5 |
| Induction Phase (4 Weeks) | Non-Compliance with Study Drug | 1 |
| Induction Phase (4 Weeks) | Other | 13 |
| Induction Phase (4 Weeks) | Protocol Violation | 1 |
| Induction Phase (4 Weeks) | Withdrawal by Subject | 22 |
| Optimization/Maintenance (48 Weeks) | Adverse Event | 25 |
| Optimization/Maintenance (48 Weeks) | Death | 2 |
| Optimization/Maintenance (48 Weeks) | Lack of Efficacy | 25 |
| Optimization/Maintenance (48 Weeks) | Lost to Follow-up | 10 |
| Optimization/Maintenance (48 Weeks) | Missed Assessment or Treatment Sessions | 3 |
| Optimization/Maintenance (48 Weeks) | Non-Compliance with Study Drug | 1 |
| Optimization/Maintenance (48 Weeks) | Other | 21 |
| Optimization/Maintenance (48 Weeks) | Pregnancy | 2 |
| Optimization/Maintenance (48 Weeks) | Protocol Violation | 3 |
| Optimization/Maintenance (48 Weeks) | Study Terminated by Sponsor | 331 |
| Optimization/Maintenance (48 Weeks) | Withdrawal by Subject | 30 |
Baseline characteristics
| Characteristic | Intranasal Esketamine + Oral Antidepressant |
|---|---|
| Age, Continuous | 52.2 years STANDARD_DEVIATION 13.69 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 149 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 640 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 81 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants |
| Race (NIH/OMB) More than one race | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants |
| Race (NIH/OMB) White | 686 Participants |
| Region of Enrollment ARGENTINA | 106 Participants |
| Region of Enrollment AUSTRALIA | 23 Participants |
| Region of Enrollment AUSTRIA | 16 Participants |
| Region of Enrollment BELGIUM | 5 Participants |
| Region of Enrollment BRAZIL | 52 Participants |
| Region of Enrollment BULGARIA | 94 Participants |
| Region of Enrollment FINLAND | 2 Participants |
| Region of Enrollment FRANCE | 4 Participants |
| Region of Enrollment GERMANY | 13 Participants |
| Region of Enrollment ITALY | 7 Participants |
| Region of Enrollment MALAYSIA | 19 Participants |
| Region of Enrollment MEXICO | 10 Participants |
| Region of Enrollment POLAND | 6 Participants |
| Region of Enrollment SOUTH AFRICA | 64 Participants |
| Region of Enrollment SOUTH KOREA | 26 Participants |
| Region of Enrollment SPAIN | 42 Participants |
| Region of Enrollment SWEDEN | 90 Participants |
| Region of Enrollment TAIWAN | 33 Participants |
| Region of Enrollment TURKEY | 31 Participants |
| Region of Enrollment UNITED KINGDOM | 12 Participants |
| Region of Enrollment UNITED STATES | 147 Participants |
| Sex: Female, Male Female | 502 Participants |
| Sex: Female, Male Male | 300 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 779 | 2 / 603 | 0 / 357 |
| other Total, other adverse events | 587 / 779 | 454 / 603 | 24 / 357 |
| serious Total, serious adverse events | 17 / 779 | 38 / 603 | 8 / 357 |
Outcome results
Primary
Change From Baseline in Cognitive Test Battery: Detection Test (DET) Score
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.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of Optimization/Maintenance [OP/MA] Phase)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Cognitive Test Battery: Detection Test (DET) Score | -0.0028 log10 msec | Standard Deviation 0.12744 |
Primary
Change From Baseline in Cognitive Test Battery: Groton Maze Learning Test (GMLT) Score
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.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Cognitive Test Battery: Groton Maze Learning Test (GMLT) Score | 6.9 Number of Errors | Standard Deviation 25.36 |
Primary
Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score
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.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score | -0.0083 log10 msec | Standard Deviation 0.09656 |
Primary
Change From Baseline in Cognitive Test Battery: One Back Test (ONB) Score
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.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Cognitive Test Battery: One Back Test (ONB) Score | 0.0177 log10 msec | Standard Deviation 0.10026 |
Primary
Change From Baseline in Cognitive Test Battery: One Card Learning Test (OCL) Score
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.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Cognitive Test Battery: One Card Learning Test (OCL) Score | 0.0502 Arcsine ([sqrt] of proportion of [CR]) | Standard Deviation 0.13149 |
Primary
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Delayed Recall
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.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Delayed Recall | 0.8 Number correct | Standard Deviation 2.31 |
Primary
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Number of Words Recalled
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.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Number of Words Recalled | 0.3 Number of words recalled | Standard Deviation 2.83 |
Primary
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Recognition Discrimination Index
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.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Recognition Discrimination Index | 0.5 Number of words | Standard Deviation 3.16 |
Primary
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Total Recall
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.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Total Recall | 2.8 Number correct | Standard Deviation 4.74 |
Primary
Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders
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).
Time frame: Up to End of Follow up Phase (Week 56)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders | Cystitis | 0.6 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders | Urinary tract infections | 8.1 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders | Renal and urinary disorders | 10.5 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders | Renal and urinary tract symptoms | 17.0 Percentage of participants |
Primary
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
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.
Time frame: Up to End of Follow up Phase (Week 56)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 90.1 Percentage of participants |
Secondary
Change From Baseline in Sheehan Disability Scale (SDS) Total Score During IND Phase
SDS was a 5 item questionnaire used for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, (3) family life/home responsibilities using a 0 to 10 rating scale. Score for the first three items are summed to create a total score of 0 to 30, higher score indicates greater impairment and a negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND Phase)
Population: Full (IND) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Sheehan Disability Scale (SDS) Total Score During IND Phase | -9.3 Units on a Scale | Standard Deviation 7.86 |
Secondary
Change From Baseline in Sheehan Disability Scale Total Score During OP/MA Phase
SDS was a participant-reported outcome measure and was a 5 item questionnaire used for assessment of functional impairment 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 to 10 rating scale. The score for the first three items are summed to create a total score of 0 to 30 where a higher score indicates greater impairment and a negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Population: The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline in Sheehan Disability Scale Total Score During OP/MA Phase | -1.6 Units on a Scale | Standard Deviation 8.25 |
Secondary
Change From Baseline to Endpoint in CGI-S Scale Score During OP/MA Phase
The CGI-S measures the severity of the participant's illness that include knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 0 to 7, where 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Population: The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in CGI-S Scale Score During OP/MA Phase | 0.0 Units on a Scale |
Secondary
Change From Baseline to Endpoint in Clinical Global Impression of Severity (CGI-S) Scale Score During IND Phase
CGI-S measures severity of participant's illness that include knowledge of participant's history, psychosocial circumstances, symptoms, behavior, impact of symptoms on participant's ability to function. CGI-S evaluates severity of psychopathology on a scale range from 0 - 7, where 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as Endpoint.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Population: Full (IND) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral AD in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in Clinical Global Impression of Severity (CGI-S) Scale Score During IND Phase | -2.0 Units on a Scale |
Secondary
Change From Baseline to Endpoint in EQ-5D-5L Scale Score During IND Phase: Health Status Index
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a HSI. HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health).
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (direct-entry, transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in EQ-5D-5L Scale Score During IND Phase: Health Status Index | 0.190 Units on a Scale | Standard Deviation 0.2138 |
Secondary
Change From Baseline to Endpoint in EQ-5D-5L Scale Score During OP/MA Phase: Health Status Index
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a HSI. HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health).
Time frame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Population: The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in OP/MA phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in EQ-5D-5L Scale Score During OP/MA Phase: Health Status Index | -0.009 Units on a Scale | Standard Deviation 0.1411 |
Secondary
Change From Baseline to Endpoint in EQ-5D-5L Score During IND Phase: EQ-VAS
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine).
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (direct-entry, transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in EQ-5D-5L Score During IND Phase: EQ-VAS | 17.0 Units on a Scale | Standard Deviation 21.69 |
Secondary
Change From Baseline to Endpoint in EQ-5D-5L Score During OP/MA Phase: EQ-VAS
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine).
Time frame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Population: The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in OP/MA phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in EQ-5D-5L Score During OP/MA Phase: EQ-VAS | 1.6 Units on a Scale | Standard Deviation 18.51 |
Secondary
Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During IND Phase: Sum Score
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a Health Status Index (HSI). HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health). EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (direct-entry, transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During IND Phase: Sum Score | -15.3 Units on a Scale | Standard Deviation 16.26 |
Secondary
Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During OP/MA Phase: Sum Score
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a Health Status Index (HSI). HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health). EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state.
Time frame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Population: The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in OP/MA phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During OP/MA Phase: Sum Score | -0.7 Units on a Scale | Standard Deviation 13.19 |
Secondary
Change From Baseline to Endpoint in GAD-7 Total Score During OP/MA Phase
GAD-7 is brief and validated 7-item self-reported assessment of overall anxiety. Participants respond to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score ranges from 0 to 21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Population: Full (OP/MA) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in GAD-7 Total Score During OP/MA Phase | 0.2 Units on a Scale | Standard Deviation 4.23 |
Secondary
Change From Baseline to Endpoint in Generalized Anxiety Disorder (GAD-7) Total Score During IND Phase
GAD-7 is brief, validated 7-item self-reported assessment of overall anxiety. Participant's responded to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield total score ranges from 0 to 21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of GAD-7 is categorized as: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Missing data was imputed using LOCF method, last post baseline observation during the phase was carried forward as Endpoint.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in Generalized Anxiety Disorder (GAD-7) Total Score During IND Phase | -5.9 Units on a Scale | Standard Deviation 5.85 |
Secondary
Change From Baseline to Endpoint in MADRS Total Score During Optimization/Maintenance (OP/MA) Phase
MADRS measure depression severity, detects changes due to AD treatment. It evaluates 10 items: apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Population: Full (OP/MA) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral AD in the OP/MA phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in MADRS Total Score During Optimization/Maintenance (OP/MA) Phase | 0.3 Units on a Scale | Standard Deviation 8.12 |
Secondary
Change From Baseline to Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score During Induction (IND) Phase
MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using last observation carried forward (LOCF) method, last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral AD in open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score During Induction (IND) Phase | -16.4 Units on a Scale | Standard Deviation 8.76 |
Secondary
Change From Baseline to Endpoint in Patient Health Questionnaire - 9 (PHQ-9) Total Score During IND Phase
PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. A higher score indicates greater severity of depression. Severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Population: Full (IND) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in Patient Health Questionnaire - 9 (PHQ-9) Total Score During IND Phase | -8.9 Unit on a Scale | Standard Deviation 6.67 |
Secondary
Change From Baseline to Endpoint in PHQ-9 Total Score During OP/MA Phase
PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. A higher score indicates greater severity of depression. severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Population: Full (OP/MA) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Change From Baseline to Endpoint in PHQ-9 Total Score During OP/MA Phase | -0.2 Units on a Scale | Standard Deviation 5.65 |
Secondary
Percentage of Participants With an Increase Score From Predose at Any Time in CADSS Total Score During OP/MA Phase
The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = Not at all, 1 = Mild, 2 = Moderate, 3 = 'Severe and 4 = Extreme). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition.
Time frame: Predose, up to 1.5 hours postdose (up to end of OP/MA phase [Week 52])
Population: The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With an Increase Score From Predose at Any Time in CADSS Total Score During OP/MA Phase | 86.1 Percentage of participants |
Secondary
Percentage of Participants With an Increase Score From Predose at Any Time in Clinician-Administered Dissociative States Scale (CADSS) Total Score During IND Phase
The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = Not at all, 1 = Mild, 2 = Moderate, 3 = 'Severe and 4 = Extreme). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition.
Time frame: Predose, up to 1.5 hours postdose (up to end of IND phase [Week 4])
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral AD in open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With an Increase Score From Predose at Any Time in Clinician-Administered Dissociative States Scale (CADSS) Total Score During IND Phase | 92.0 Percentage of participants |
Secondary
Percentage of Participants With Remission as Assessed by MADRS Total Score During IND Phase
Remission is defined as MADRS total score less than or equal to (\<=) 12. MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Days 8, 15, 22 and Endpoint (last post-baseline assessment value during 4 weeks of IND Phase)
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'n' signifies those participants who were evaluable at specific time point for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Remission as Assessed by MADRS Total Score During IND Phase | Day 8 | 7.3 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Remission as Assessed by MADRS Total Score During IND Phase | Day 15 | 15.6 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Remission as Assessed by MADRS Total Score During IND Phase | Day 22 | 27.2 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Remission as Assessed by MADRS Total Score During IND Phase | End point | 47.2 Percentage of participants |
Secondary
Percentage of Participants With Remission as Assessed by PHQ-9 Total Score During IND Phase
Remission is defined as PHQ-9 total score \<= 4. PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The scores are summed for a total score ranging from 0-27. A higher score indicates greater severity of depression. severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Day 15 and Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'n' signifies those participants who were evaluable at specific time point for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Remission as Assessed by PHQ-9 Total Score During IND Phase | Day 15 | 12.7 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Remission as Assessed by PHQ-9 Total Score During IND Phase | Endpoint | 26.9 Percentage of participants |
Secondary
Percentage of Participants With Response as Assessed by MADRS Total Score During IND Phase
Response is defined as greater than or equal to (\>=) 50 % reduction from baseline in the MADRS total score. MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Days 8, 15, 22 and Endpoint (last post-baseline assessment during 4 weeks of IND phase)
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'n' signifies those participants who were evaluable at specific time point for this endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Response as Assessed by MADRS Total Score During IND Phase | Day 8 | 11.6 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Response as Assessed by MADRS Total Score During IND Phase | Day 15 | 25.0 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Response as Assessed by MADRS Total Score During IND Phase | Day 22 | 42.8 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Response as Assessed by MADRS Total Score During IND Phase | End point | 78.4 Percentage of participants |
Secondary
Percentage of Participants With Response as Assessed by PHQ-9 Total Score During IND Phase
Response is defined as \>= 50 % reduction from baseline (IND phase) in PHQ-9 total score. PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The scores are summed for a total score ranging from 0-27. A higher score indicates greater severity of depression. Severity of PHQ-9 categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). The recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the Endpoint.
Time frame: Day 15 and Endpoint (last post-baseline assessment value during 4 Week IND phase)
Population: The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'n' signifies those participants who were evaluable at specific time point for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Response as Assessed by PHQ-9 Total Score During IND Phase | Day 15 | 37.2 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Response as Assessed by PHQ-9 Total Score During IND Phase | End point | 62.0 Percentage of participants |
Secondary
Percentage of Participants With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases
Percentage of participants with treatment-emergent acute hypertension (Systolic Blood Pressure \>=180 millimeters of mercury \[mm Hg\] or Diastolic Blood Pressure \>= 110 mm Hg) during IND and OP/MA Phases were evaluated.
Time frame: Up to End of OP/MA phase (Week 52)
Population: All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases | Systolic BP >=180 | 2.2 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases | Diastolic BP >=110 | 2.4 Percentage of participants |
| Intranasal Esketamine + Oral Antidepressant | Percentage of Participants With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases | Acute hypertension | 4.1 Percentage of participants |