The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) participants from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.
This is a randomized, double-blind (neither the researchers nor the participants know what treatment the participant is receiving), active-controlled, multicenter study (more than 1 study site) in participants with TRD to assess the efficacy, safety, and tolerability of fixed doses of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. The study will consist of 3 phases: Screening/Prospective Observational Phase (4-7 weeks), Double-blind Induction Phase (4-weeks), Follow-up Phase (24-weeks). Participants who rollover into a long-term maintenance study will not participate in the Follow-up Phase. At the start of the screening/prospective observational phase, the participant must have had documented non-response to at least 1 antidepressant treatment (based on Massachusetts General Hospital - Antidepressant Treatment Response Questionnair \[MGH-ATRQ\]) in the current episode of depression, and participant is taking a different oral antidepressant treatment on the MGH-ATRQ for at least the previous 2 weeks at or above the minimum therapeutic dose. This antidepressant treatment, as well as any other ongoing medications being taken for depression at screening (including adjunctive/ augmentation therapies), will continue from the start of Week 1 through the end of Week 4 of the screening/prospective observational phase. Participants will be randomly assigned to receive Intranasal esketamine (56 milligrams \[mg\]), Intranasal esketamine (84 mg), or Intranasal placebo. In addition, each participant will be assigned to receive 1 of 4 oral antidepressant medications from 2 different classes of antidepressant treatments, a Selective Serotonin Reuptake Inhibitor (SSRI) (escitalopram or sertraline) or a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) (duloxetine or venlafaxine extended release \[XR\]), initiated on Day 1 and continued through the double-blind induction phase. Participants will be primarily evaluated for improvement in depressive symptoms as assessed by change in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 4. Participants' safety will be monitored throughout the study.
Study Type
INTERVENTIONAL
Allocation
Participants will self-administer either 84 mg or 56 mg of esketamine, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase.
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase.
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).
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 of Double- Blind Induction Phase- Mixed- Effects Model Using Repeated Measures (MMRM) Analysis
MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time frame: Baseline up to Day 28 of Double-blind Induction Phase
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using Last Observation Carried Forward (LOCF) method and last post baseline observation during double-blind induction phase was carried forward as "End Point" for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8
A participant was defined as having a clinical response if there was at least 50% improvement (decrease) from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained to Day 28. Participants were allowed one excursion (non-response) on Days 8, 15 or 22, however score must show at least 25% improvement. Participants who did not meet these criteria or discontinued during the study before Day 28 were considered as non-responders and were assigned the value of 0 (that is no). MADRS is clinician-rated scale that consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), for total possible score of 0 to 60. Higher scores represent more severe condition.
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RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
346
Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be titrated up to a dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.
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 200 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 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.
Unnamed facility
Birmingham, Alabama, United States
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Little Rock, Arkansas, United States
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Garden Grove, California, United States
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Orange, California, United States
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San Diego, California, United States
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San Marcos, California, United States
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San Rafael, California, United States
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Bradenton, Florida, United States
Unnamed facility
Miami, Florida, United States
Unnamed facility
Orlando, Florida, United States
...and 80 more locations
Time frame: Day 2 up to Day 28 and Day 8 up to Day 28
Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
The SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. The first 3 items assess disruption of 1) work/school, 2) social life, and 3) family life/home responsibilities using 0 (not at all) to 10 (extremely) rating scale. Score for first 3 items are summed to create total score of 0 (unimpaired) to 30 (highly impaired), where higher score indicates greater impairment.
Time frame: Baseline up to Day 28 of Double-blind Induction phase
Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
The SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. The first 3 items assess disruption of 1) work/school, 2) social life, and 3) family life/home responsibilities using 0 (not at all) to 10 (extremely) rating scale. Score for first 3 items are summed to create total score of 0 (unimpaired) to 30 (highly impaired) where higher score indicates greater impairment. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as "End Point" for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
PHQ-9 is 9-item, self-reported scale assessing 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria. Each item is rated on 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half days, 3 = Nearly every day). The scores are summed for a total score ranging from 0-27. 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.
Time frame: Baseline up to Day 28 of Double-blind Induction phase
Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
PHQ-9 is 9-item, self-reported scale assessing 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria. Each item is rated on 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half days, 3 = Nearly every day). The scores are summed for a total score ranging from 0-27. 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. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as "End Point" for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at Day 28 of Double-blind Induction Phase (Observed Data)
A participant was defined as a responder (yes=1 and no=0) at a given time point if the percent reduction from baseline in MADRS total score is at least 50 percent (%). The percentage of participants who achieved at least 50% reduction from baseline were reported. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time frame: At Day 28 of Double-blind Induction phase
Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)
A participant was defined as a responder (yes=1 and no=0) at a given time point if the percent reduction from baseline in MADRS total score is at least 50 percent (%). The percentage of participants who achieved at least 50% reduction from baseline were reported. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as "End Point" for that phase.
Time frame: At Day 28 (Double-blind Endpoint)
Percentage of Participants in Remission (MADRS<=12) at Day 28 of Double-blind Induction Phase (Observed Data)
Participants who had a MADRS total score of less than or equal to (\<=) 12 were considered as remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time frame: At Day 28 of Double-blind Induction Phase
Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis (LOCF Data)
Participants who had a MADRS total score of less than or equal to (\<=) 12 were considered as remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as "End Point" for that phase.
Time frame: At Day 28 (Double-blind Endpoint)
Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint (Double-blind Induction Phase [Day 28])
CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 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 most extremely ill patients (a decrease in score indicates improvement). Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as "End Point" for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Change From Baseline in Generalized Anxiety Disorder-7 Item (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
GAD-7 is a brief and validated 7-item self-reported assessment of overall anxiety. Participants responded to each item using a 4 point scale with response categories of 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 with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15-21). Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as "End Point" for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Health Status Index
EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). The descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). The responses are used to generate Health Status Index (HSI). HSI range is -0.148 to 0.949, is anchored at 0 (dead) and 1 (full health).
Time frame: Baseline up to End of Double-blind Induction Phase (Day 28)
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): EQ-VAS
EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine).
Time frame: Baseline up to end of Double-blind induction phase (Day 28)
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Sum Score
EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). The descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). The responses are used to generate Health Status Index (HSI). HSI range is -0.148 to 0.949, is anchored at 0 (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 scale of 0 (the worst health you can imagine) to 100 (the 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 up to end of Double-blind Induction phase (Day 28)