Depressive Disorder, Major
Conditions
Keywords
Major Depressive Disorder, MDD, SAGE-217
Brief summary
The primary purpose of this study is to evaluate the efficacy of SAGE-217 plus an ADT in the treatment of major depressive disorder (MDD) compared to placebo plus an ADT.
Detailed description
This study was previously posted by Sage Therapeutics. In November 2023, sponsorship of the trial was transferred to Biogen.
Interventions
DRUGSAGE-217
Oral capsules
DRUGMatching Placebo
Oral capsules
DRUGSertraline
Oral tablets
DRUGEscitalopram
Oral tablets
DRUGCitalopram
Oral tablets
DRUGDuloxetine
Oral capsules
DRUGDesvenlafaxine
Oral tablets
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of MDD as diagnosed by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Clinical Trials Version (SCID-5-CT), with symptoms that have been present for at least a 4-week period * 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score of ≥24 at Screening and Day 1 * Participant in good physical health and has no clinically significant findings, as determined by the investigator, on physical examination, 12-lead electrocardiogram (ECG), or clinical laboratory tests * Participant is willing, able, and eligible to take at least 1 of the 5 ADTs specified in the protocol (an eligible ADT is an ADT that has not been taken during the current depressive episode and for which the participant has no contraindications; further, a participant is not eligible for citalopram if escitalopram has been taken during the current depressive episode, and vice versa)
Exclusion criteria
* Has attempted suicide associated with the current episode of MDD * Participant had onset of the current depressive episode during pregnancy or 4 weeks postpartum, or the participant has presented for screening during the 6-month postpartum period * Participant has treatment-resistant depression * History of bipolar disorder, schizophrenia, and/or schizoaffective disorder * Known allergy to SAGE-217, allopregnanolone, or related compounds * Has taken antidepressants within 30 days prior to Day 1, and/or has taken fluoxetine within 60 days prior to Day 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the HAMD-17 Total Score at Day 3 | Baseline, Day 3 | The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. Least Squares (LS) mean was estimated using mixed effects model for repeated measures (MMRM) analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HAMD-17 Remission at Day 15 and Day 42 | Days 15 and 42 | HAM-D remission was defined as having a HAM-D total score of ≤7. The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. Percentages were rounded off to the first decimal point. |
| Change From Baseline in CGI-S Score at Day 15 | Baseline and Day 15 | The CGI-S uses a 7-point Likert scale to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. Considering total clinical experience, the investigator rated the participant on severity of mental illness at the time of rating as: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = extremely ill. A higher score indicated extreme illness. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. |
| Percentage of Participants With CGI-I Response, at Day 3 and Day 15 | Days 3 and 15 | CGI-I response was defined as having a CGI-I score of very much improved or much improved. The CGI-I employs a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to IP. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. By definition, all CGI-I assessments are evaluated against baseline conditions. Higher scores indicated worse condition. Percentages were rounded off to the first decimal point. |
| Change From Baseline in MADRS Total Score at Day 15 | Baseline and Day 15 | The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores. Each item yields a score of 0 (no symptoms) to 6 (symptoms of maximum severity). The total MADRS score (sum of all individual items) ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicated more severe depression. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. |
| Percentage of Participants With MADRS Response at Day 15 | Day 15 | MADRS response was defined as having a 50% or greater reduction from baseline in MADRS total score. The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores. Each item yields a score of 0 (no symptoms) to 6 (symptoms of maximum severity). The total MADRS score (sum of all individual items) ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicated more severe depression. Percentages were rounded off to the first decimal point. |
| Percentage of Participants With MADRS Remission at Day 15 | Day 15 | MADRS remission was defined as having a MADRS total score of ≤10. The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores. Each item yields a score of 0 (no symptoms) to 6 (symptoms of maximum severity). The total MADRS score (sum of all individual items) ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicated more severe depression. Percentages were rounded off to the first decimal point. |
| Change From Baseline in HAM-A Total Score at Day 15 | Baseline, Day 15 | Each of the 14 items in the HAM-A was defined by a series of symptoms, and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints). The HAM-A total score was calculated as sum of the 14 individual item scores, each rated on a five point scale ranging from 0 (not present) to 4 (very severe). The total score (sum of all individual items) range from 0 to 56, where \<17 indicated mild severity, 18 to 24 indicated mild to moderate severity, and 25 to 30 indicated moderate to severe severity. Higher scores indicated more severe disease. Negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. |
| Percentage of Participants With HAMD-17 Response at Day 15 and Day 42 | At Days 15 and 42 | HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. Percentages were rounded off to the first decimal point. |
| Change From Baseline in the HAMD-17 Total Score at Days 15 and 42 | Baseline, Days 15 and 42 | The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. The missing values were imputed for the analysis. |
| Time to First HAMD-17 Response | From first dose of study drug up to first HAMD-17 response (up to approximately 65 days) | HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. Time (in days) from first dose of study drug to time of first HAMD response was reported in this outcome measure. |
| Change From Baseline in Depressive Symptoms at Day 15, as Assessed by PHQ-9 | Baseline and Day 15 | The PHQ-9 is a participant-rated depressive symptom severity scale. The PHQ-9 total score is calculated as the sum of the 9 individual item scores. For individual items, scoring is based on responses to specific questions, as follows: 0 = not at all; 1 = several days; 2 = more than half the days; and 3 = nearly every day. The PHQ-9 possible total score range is 0 to 27, with higher scores reflecting greater depressive symptoms, and is categorized as follows: 0 to 4 = minimal depression, 5 to 9 = mild depression, 10 to 14 = moderate depression, 15 to 19 = moderately severe depression, and 20 to 27 = severe depression. Negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Up to approximately 58 weeks | An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. A TEAE was defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. |
| Percentage of Participants With TEAEs, Graded by Severity | Up to approximately 58 weeks | An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. A TEAE was defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. The severity was graded as mild, moderate and severe. |
| Change From Baseline in the HAMD-17 Total Score Around End of Blinded Treatment | Baseline, End of blinded treatment assessment (i.e., average of Days 12, 15 , and 18) | The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. End of blinded treatment was defined as the average of change from baseline values of Days 12, 15 and 18. LS mean was estimated using MMRM analysis. |
| Change From Baseline in the HAMD-17 Total Score Over the Double-Blind Treatment Period | Baseline through Day 15 | The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. The data reported is summary of data collected and analyzed during double-blind treatment period at Baseline, Day 3, Day 8, Day 12, and Day 15 using equal weights for the scheduled visits. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 53 investigative sites in the United States from 9 November 2020 to 22 December 2021.
Pre-assignment details
A total of 440 participants were enrolled in the study of which 430 participants received at least 1 dose of the assigned treatment. The study consisted of a 28-day Screening period, a 14-day Double-blind Treatment Period, and a 28-day antidepressant therapy (ADT) continuation period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Assigned ADT Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42. | 218 |
| SAGE-217 + Assigned ADT Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42. | 212 |
| Total | 430 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 11 |
| Overall Study | Lost to Follow-up | 7 | 4 |
| Overall Study | Non-compliance with Investigational Product (IP) | 1 | 0 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Deviation | 2 | 0 |
| Overall Study | Randomized but not Dosed | 2 | 8 |
| Overall Study | Withdrawal by Subject | 20 | 16 |
Baseline characteristics
| Characteristic | Placebo + Assigned ADT | Total | SAGE-217 + Assigned ADT |
|---|---|---|---|
| 17-item Hamilton Rating Scale for Depression (HAMD-17) Total Score | 26.6 score on a scale STANDARD_DEVIATION 2.58 | 26.7 score on a scale STANDARD_DEVIATION 2.54 | 26.8 score on a scale STANDARD_DEVIATION 2.51 |
| Age, Continuous | 37.7 years STANDARD_DEVIATION 12.28 | 38.1 years STANDARD_DEVIATION 12.49 | 38.6 years STANDARD_DEVIATION 12.72 |
| Clinical Global Impression - Severity (CGI-S) Score | 4.9 score on a scale STANDARD_DEVIATION 0.57 | 4.9 score on a scale STANDARD_DEVIATION 0.55 | 5.0 score on a scale STANDARD_DEVIATION 0.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 52 Participants | 93 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 166 Participants | 337 Participants | 171 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hamilton Anxiety Rating Scale (HAM-A) Total Score | 20.4 score on a scale STANDARD_DEVIATION 5.8 | 20.1 score on a scale STANDARD_DEVIATION 5.55 | 19.9 score on a scale STANDARD_DEVIATION 5.28 |
| Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | 34.9 score on a scale STANDARD_DEVIATION 4.89 | 35.0 score on a scale STANDARD_DEVIATION 4.8 | 35.2 score on a scale STANDARD_DEVIATION 4.7 |
| Race/Ethnicity, Customized American-Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 12 Participants | 18 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African-American | 31 Participants | 77 Participants | 46 Participants |
| Race/Ethnicity, Customized More than one race | 4 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 6 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 168 Participants | 321 Participants | 153 Participants |
| Sex: Female, Male Female | 140 Participants | 269 Participants | 129 Participants |
| Sex: Female, Male Male | 78 Participants | 161 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 220 | 0 / 220 |
| other Total, other adverse events | 113 / 218 | 123 / 212 |
| serious Total, serious adverse events | 0 / 218 | 2 / 212 |
Outcome results
Primary
Change From Baseline in the HAMD-17 Total Score at Day 3
The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. Least Squares (LS) mean was estimated using mixed effects model for repeated measures (MMRM) analysis.
Time frame: Baseline, Day 3
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, 9-item Patient Health Questionnaire (PHQ-9) or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or Clinical Global Impression - Improvement (CGI-I) score. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Assigned ADT | Change From Baseline in the HAMD-17 Total Score at Day 3 | -7.0 score on a scale | Standard Error 0.38 |
| SAGE-217 + Assigned ADT | Change From Baseline in the HAMD-17 Total Score at Day 3 | -8.9 score on a scale | Standard Error 0.39 |
p-value: 0.000495% CI: [-3, -0.9]MMRM
Secondary
Change From Baseline in CGI-S Score at Day 15
The CGI-S uses a 7-point Likert scale to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. Considering total clinical experience, the investigator rated the participant on severity of mental illness at the time of rating as: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = extremely ill. A higher score indicated extreme illness. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis.
Time frame: Baseline and Day 15
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Assigned ADT | Change From Baseline in CGI-S Score at Day 15 | -1.7 score on a scale | Standard Error 0.09 |
| SAGE-217 + Assigned ADT | Change From Baseline in CGI-S Score at Day 15 | -1.9 score on a scale | Standard Error 0.09 |
p-value: 0.199395% CI: [-0.4, 0.1]MMRM
Secondary
Change From Baseline in Depressive Symptoms at Day 15, as Assessed by PHQ-9
The PHQ-9 is a participant-rated depressive symptom severity scale. The PHQ-9 total score is calculated as the sum of the 9 individual item scores. For individual items, scoring is based on responses to specific questions, as follows: 0 = not at all; 1 = several days; 2 = more than half the days; and 3 = nearly every day. The PHQ-9 possible total score range is 0 to 27, with higher scores reflecting greater depressive symptoms, and is categorized as follows: 0 to 4 = minimal depression, 5 to 9 = mild depression, 10 to 14 = moderate depression, 15 to 19 = moderately severe depression, and 20 to 27 = severe depression. Negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis.
Time frame: Baseline and Day 15
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Assigned ADT | Change From Baseline in Depressive Symptoms at Day 15, as Assessed by PHQ-9 | -8.7 score on a scale | Standard Error 0.44 |
| SAGE-217 + Assigned ADT | Change From Baseline in Depressive Symptoms at Day 15, as Assessed by PHQ-9 | -8.9 score on a scale | Standard Error 0.44 |
p-value: 0.775895% CI: [-1.4, 1]MMRM
Secondary
Change From Baseline in HAM-A Total Score at Day 15
Each of the 14 items in the HAM-A was defined by a series of symptoms, and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints). The HAM-A total score was calculated as sum of the 14 individual item scores, each rated on a five point scale ranging from 0 (not present) to 4 (very severe). The total score (sum of all individual items) range from 0 to 56, where \<17 indicated mild severity, 18 to 24 indicated mild to moderate severity, and 25 to 30 indicated moderate to severe severity. Higher scores indicated more severe disease. Negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis.
Time frame: Baseline, Day 15
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Assigned ADT | Change From Baseline in HAM-A Total Score at Day 15 | -9.0 score on a scale | Standard Error 0.44 |
| SAGE-217 + Assigned ADT | Change From Baseline in HAM-A Total Score at Day 15 | -9.5 score on a scale | Standard Error 0.44 |
p-value: 0.418895% CI: [-1.7, 0.7]MMRM
Secondary
Change From Baseline in MADRS Total Score at Day 15
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores. Each item yields a score of 0 (no symptoms) to 6 (symptoms of maximum severity). The total MADRS score (sum of all individual items) ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicated more severe depression. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis.
Time frame: Baseline and Day 15
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Assigned ADT | Change From Baseline in MADRS Total Score at Day 15 | -15.9 score on a scale | Standard Error 0.75 |
| SAGE-217 + Assigned ADT | Change From Baseline in MADRS Total Score at Day 15 | -17.2 score on a scale | Standard Error 0.76 |
p-value: 0.232295% CI: [-3.4, 0.8]MMRM
Secondary
Change From Baseline in the HAMD-17 Total Score Around End of Blinded Treatment
The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. End of blinded treatment was defined as the average of change from baseline values of Days 12, 15 and 18. LS mean was estimated using MMRM analysis.
Time frame: Baseline, End of blinded treatment assessment (i.e., average of Days 12, 15 , and 18)
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Assigned ADT | Change From Baseline in the HAMD-17 Total Score Around End of Blinded Treatment | -12.7 score on a scale | Standard Error 0.45 |
| SAGE-217 + Assigned ADT | Change From Baseline in the HAMD-17 Total Score Around End of Blinded Treatment | -13.2 score on a scale | Standard Error 0.46 |
p-value: 0.445895% CI: [-1.8, 0.8]MMRM
Secondary
Change From Baseline in the HAMD-17 Total Score at Days 15 and 42
The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. The missing values were imputed for the analysis.
Time frame: Baseline, Days 15 and 42
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + Assigned ADT | Change From Baseline in the HAMD-17 Total Score at Days 15 and 42 | Day 15 | -12.9 score on a scale | Standard Error 0.49 |
| Placebo + Assigned ADT | Change From Baseline in the HAMD-17 Total Score at Days 15 and 42 | Day 42 | -14.9 score on a scale | Standard Error 0.56 |
| SAGE-217 + Assigned ADT | Change From Baseline in the HAMD-17 Total Score at Days 15 and 42 | Day 15 | -13.7 score on a scale | Standard Error 0.5 |
| SAGE-217 + Assigned ADT | Change From Baseline in the HAMD-17 Total Score at Days 15 and 42 | Day 42 | -14.9 score on a scale | Standard Error 0.56 |
Comparison: Day 15p-value: 0.247795% CI: [-2.2, 0.6]MMRM
Comparison: Day 42p-value: 0.924895% CI: [-1.6, 1.5]MMRM
Secondary
Change From Baseline in the HAMD-17 Total Score Over the Double-Blind Treatment Period
The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. The data reported is summary of data collected and analyzed during double-blind treatment period at Baseline, Day 3, Day 8, Day 12, and Day 15 using equal weights for the scheduled visits.
Time frame: Baseline through Day 15
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Assigned ADT | Change From Baseline in the HAMD-17 Total Score Over the Double-Blind Treatment Period | -10.1 score on a scale | Standard Error 0.39 |
| SAGE-217 + Assigned ADT | Change From Baseline in the HAMD-17 Total Score Over the Double-Blind Treatment Period | -11.7 score on a scale | Standard Error 0.4 |
p-value: 0.005495% CI: [-2.7, -0.5]MMRM
Secondary
Percentage of Participants With CGI-I Response, at Day 3 and Day 15
CGI-I response was defined as having a CGI-I score of very much improved or much improved. The CGI-I employs a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to IP. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. By definition, all CGI-I assessments are evaluated against baseline conditions. Higher scores indicated worse condition. Percentages were rounded off to the first decimal point.
Time frame: Days 3 and 15
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Number analyzed is the number of participants with data available for analysis at the specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Assigned ADT | Percentage of Participants With CGI-I Response, at Day 3 and Day 15 | Day 15 | 54.3 percentage of participants |
| Placebo + Assigned ADT | Percentage of Participants With CGI-I Response, at Day 3 and Day 15 | Day 3 | 12.9 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With CGI-I Response, at Day 3 and Day 15 | Day 15 | 56.6 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With CGI-I Response, at Day 3 and Day 15 | Day 3 | 22.9 percentage of participants |
Comparison: Day 3p-value: 0.007995% CI: [1.21, 3.47]Binary Response Model
Comparison: Day 15p-value: 0.658895% CI: [0.74, 1.62]Binary Response Model
Secondary
Percentage of Participants With HAMD-17 Remission at Day 15 and Day 42
HAM-D remission was defined as having a HAM-D total score of ≤7. The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. Percentages were rounded off to the first decimal point.
Time frame: Days 15 and 42
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Number analyzed is number of participants with data available for analysis at the specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Assigned ADT | Percentage of Participants With HAMD-17 Remission at Day 15 and Day 42 | Day 15 | 21.8 percentage of participants |
| Placebo + Assigned ADT | Percentage of Participants With HAMD-17 Remission at Day 15 and Day 42 | Day 42 | 39.2 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With HAMD-17 Remission at Day 15 and Day 42 | Day 15 | 29.1 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With HAMD-17 Remission at Day 15 and Day 42 | Day 42 | 37.9 percentage of participants |
Comparison: Day 15p-value: 0.141795% CI: [0.89, 2.24]Binary Response Model
Comparison: Day 42p-value: 0.787295% CI: [0.62, 1.44]Binary Response Model
Secondary
Percentage of Participants With HAMD-17 Response at Day 15 and Day 42
HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. Percentages were rounded off to the first decimal point.
Time frame: At Days 15 and 42
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Number analyzed is the number of participants with data available for analysis at the specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Assigned ADT | Percentage of Participants With HAMD-17 Response at Day 15 and Day 42 | Day 15 | 49.2 percentage of participants |
| Placebo + Assigned ADT | Percentage of Participants With HAMD-17 Response at Day 15 and Day 42 | Day 42 | 65.3 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With HAMD-17 Response at Day 15 and Day 42 | Day 15 | 53.4 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With HAMD-17 Response at Day 15 and Day 42 | Day 42 | 59.9 percentage of participants |
Comparison: Day 15p-value: 0.494695% CI: [0.78, 1.69]Binary Response Model
Comparison: Day 42p-value: 0.357995% CI: [0.55, 1.24]Binary Response Model
Secondary
Percentage of Participants With MADRS Remission at Day 15
MADRS remission was defined as having a MADRS total score of ≤10. The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores. Each item yields a score of 0 (no symptoms) to 6 (symptoms of maximum severity). The total MADRS score (sum of all individual items) ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicated more severe depression. Percentages were rounded off to the first decimal point.
Time frame: Day 15
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Assigned ADT | Percentage of Participants With MADRS Remission at Day 15 | 28.4 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With MADRS Remission at Day 15 | 30.9 percentage of participants |
p-value: 0.705495% CI: [0.7, 1.69]Binary Response Model
Secondary
Percentage of Participants With MADRS Response at Day 15
MADRS response was defined as having a 50% or greater reduction from baseline in MADRS total score. The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores. Each item yields a score of 0 (no symptoms) to 6 (symptoms of maximum severity). The total MADRS score (sum of all individual items) ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicated more severe depression. Percentages were rounded off to the first decimal point.
Time frame: Day 15
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Assigned ADT | Percentage of Participants With MADRS Response at Day 15 | 48.2 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With MADRS Response at Day 15 | 51.6 percentage of participants |
p-value: 0.543995% CI: [0.76, 1.68]Binary Response Model
Secondary
Percentage of Participants With TEAEs, Graded by Severity
An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. A TEAE was defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. The severity was graded as mild, moderate and severe.
Time frame: Up to approximately 58 weeks
Population: Safety Set was defined as all participants who administered blinded IP.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Assigned ADT | Percentage of Participants With TEAEs, Graded by Severity | Mild | 38.1 percentage of participants |
| Placebo + Assigned ADT | Percentage of Participants With TEAEs, Graded by Severity | Moderate | 25.2 percentage of participants |
| Placebo + Assigned ADT | Percentage of Participants With TEAEs, Graded by Severity | Severe | 2.3 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With TEAEs, Graded by Severity | Mild | 35.8 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With TEAEs, Graded by Severity | Moderate | 34.4 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With TEAEs, Graded by Severity | Severe | 3.8 percentage of participants |
Secondary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. A TEAE was defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study.
Time frame: Up to approximately 58 weeks
Population: Safety Set was defined as all participants who administered blinded IP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Assigned ADT | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 65.6 percentage of participants |
| SAGE-217 + Assigned ADT | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 74.1 percentage of participants |
Secondary
Time to First HAMD-17 Response
HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. Time (in days) from first dose of study drug to time of first HAMD response was reported in this outcome measure.
Time frame: From first dose of study drug up to first HAMD-17 response (up to approximately 65 days)
Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Assigned ADT | Time to First HAMD-17 Response | 15 days |
| SAGE-217 + Assigned ADT | Time to First HAMD-17 Response | 13 days |