A Study to Evaluate the Efficacy of SAGE-217 in the Treatment of Adult Participants With Major Depressive Disorder

Study Overview
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Brief Summary
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This study is a phase 3, multicenter, double-blind, randomized, placebo-controlled study evaluating the efficacy of SAGE-217 in the treatment of adult participants with major depressive disorder (MDD).

Detailed Description
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This study was previously posted by Sage Therapeutics. In November 2023, sponsorship of the trial was transferred to Biogen.

Official Title
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A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Evaluating the Efficacy of SAGE-217 in the Treatment of Adult Subjects With Major Depressive Disorder

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: SAGE-217
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant had a diagnosis of MDD with symptoms that had been present for at least a 4-week period. Participant had a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≥32 and a 17-item Hamilton Rating Scale for Depression (HAM-D) total score ≥22 at screening and Day 1 (prior to dosing). Exclusion Criteria: Participant had active psychosis. Participant had attempted suicide associated with the current episode of MDD. Participant had a medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: SAGE-217 Matched Placebo<br>Participants self-administered SAGE-217 matched placebo capsules, orally, once daily in the evening with food for 14 days. | Drug: Placebo<br>* SAGE-217 matched placebo hard gelatin capsules.<br>|
| Experimental: SAGE-217 20 mg<br>Participants self-administered SAGE-217 20 milligrams (mg) capsules, orally, once daily in the evening with food for 14 days. | Drug: SAGE-217<br>* SAGE-217 hard gelatin capsules.<br>|
| Experimental: SAGE-217 30 mg<br>Participants self-administered SAGE-217 30 mg capsules, orally, once daily in the evening with food for 14 days. | Drug: SAGE-217<br>* SAGE-217 hard gelatin capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the 17-item HAM-D Total Score at Day 15 | The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. The HAM-D total score comprises a sum of the 17 individual item scores. 8 items scored in a range of 0 to 2 include: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following 9 items are scored in a range of 0 to 4: Agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Total HAM-D score can range from 0 to 52, and higher scores indicate severe depression. A negative change from baseline indicates less depression. | Baseline (BL), Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score at Day 15 | The CGI-S uses a 7-point Likert scale to rate the severity of the participant's illness relative to the clinician's past experience with participants who had the same diagnosis. Considering total clinical experience, a participant was assessed 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 indicates extreme illness/more severity. A negative change from baseline indicates less severe illness. | Baseline, Day 15 | 
| Change From Baseline in the 17-item HAM-D Total Score | The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. The HAM-D total score comprises a sum of the 17 individual item scores. 8 items scored in a range of 0 to 2 include: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following 9 items are scored in a range of 0 to 4: Agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Total HAM-D score can range from 0 to 52, and higher scores indicate severe depression. A negative change from baseline indicates less depression. | Baseline, Days 3, 8, 42, and 182 | 
| Number of Participants Achieving HAM-D Response | HAM-D response is defined as a ≥50% reduction in HAM-D score from baseline. The HAM-D total score comprises a sum of the 17 individual item scores. 8 items scored in a range of 0 to 2 include: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following 9 items are scored in a range of 0 to 4: Agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Total HAM-D score can range from 0 to 52, and higher scores indicate severe depression. | Days 15, 42, and 182 | 
| Number of Participants Achieving HAM-D Remission | HAM-D remission is defined as HAM-D total score ≤7. The HAM-D total score comprises a sum of the 17 individual item scores. 8 items scored in a range of 0 to 2 include: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following 9 items are scored in a range of 0 to 4: Agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Total HAM-D score can range from 0 to 52, and higher scores indicate severe depression. | Days 15, 42, and 182 | 
| Number of Participants Achieving Clinical Global Impression - Improvement (CGI-I) Response at Day 15 | CGI-I response is defined as 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 drug treatment. Response choices included: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. | Day 15 | 
| Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Total Score at Day 15 | The 14-item HAM-A is used to rate the severity of symptoms of anxiety. Each of the 14 items is defined by a series of symptoms and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not present) to 4 (very severe) to each item. Total HAM-A score is calculated as the sum of the 14 individual item scores with a total score range of 0 to 56, where the score of <17 indicates mild severity, 18 to 24 indicates mild to moderate severity, and 25 to 30 indicates moderate to severe severity. A negative change from baseline indicates less severe symptoms. | Baseline, Day 15 | 
| Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (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. Each item is rated on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). Total MADRS score, calculated as the sum of the 10 individual items, ranges from 0 to 60 with a higher score indicating more depression. A negative change from baseline indicates less severe symptoms. | Baseline, Day 15 | 
| Change From Baseline in HAM-D Core Subscale Score | The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. HAM-D subscale scores are calculated as the sum of the items comprising each subscale. The core subscale score is the sum of the following symptom scores, scored in a range of 0 to 4: Depressed mood, feelings of guilt, suicide, work and activities, and retardation. Total HAM-D core subscale scores were transformed to a scale of 0 to 100. Higher scores indicate more severe depression. A negative change from baseline indicates less depression. | Baseline, Days 15, and 42 | 
| Change From Baseline in HAM-D Anxiety Subscale Score | The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. HAM-D subscale scores are calculated as the sum of the items comprising each subscale. The anxiety subscale score is the sum of the following symptom scores: Anxiety (psychic and somatic) [scored in a range of 0 to 4], somatic symptoms (gastrointestinal and general) [scored in a range of 0 to 2], hypochondriasis [scored in a range of 0 to 4], and loss of weight [scored in a range of 0 to 2]. Total HAM-D anxiety subscale scores were transformed to a scale of 0 to 100. Higher scores indicate more severe depression/anxiety. A negative change from baseline indicates less depression. | Baseline, Days 15, and 42 | 
| Change From Baseline in HAM-D Bech-6 Subscale Score | The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. HAM-D subscale scores are calculated as the sum of the items comprising each subscale. The Bech-6 subscale score is the sum of the following symptom scores, scored in a range of 0 to 4: Depressed mood, feelings of guilt, work and activities, retardation, anxiety psychic, and somatic symptoms general. Total HAM-D Bech-6 subscale scores were transformed to a scale of 0 to 100. Higher scores indicate more severe depression. A negative change from baseline indicates less depression. | Baseline, Days 15, and 42 | 
| Change From Baseline in HAM-D Maier Subscale Score | The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. HAM-D subscale scores are calculated as the sum of the items comprising each subscale. The Maier subscale score is the sum of the following symptom scores, scored in a range of 0 to 4: Depressed mood, feelings of guilt, work and activities, retardation, agitation, and anxiety psychic. Total HAM-D Maier subscale scores were transformed to a scale of 0 to 100. Higher scores indicate more severe depression. A negative change from baseline indicates less depression. | Baseline, Days 15, and 42 | 
| Change From Baseline in HAM-D Individual Item Scores | The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. The HAM-D comprises individual ratings of the following symptoms scored in a range of 0 to 2: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight (according to participant), and insight. The following symptoms are scored in a range of 0 to 4: Agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. For each symptom, higher scores indicate more severe depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression. | Baseline, Days 15, and 42 | 
| Change From Baseline in Insomnia Severity Index (ISI) Total Score | The ISI is a validated questionnaire designed to assess the nature, severity, and impact of insomnia. The ISI uses a 5-point Likert scale to measure various aspects of insomnia severity (0=none, 1=mild, 2=moderate; 3=severe; 4=very severe), satisfaction with current sleep pattern (0=very satisfied, 1=satisfied, 2=moderately satisfied, 3=dissatisfied, 4=very dissatisfied), and various aspects of the impact of insomnia on daily functioning (0=not at all, 1=a little, 2=somewhat, 3=much, 4=very much). The ISI total score is calculated as the sum of the 7 individual item scores and the possible total score range is from 0 to 28, categorized as follows: 0 to 7=no clinically significant insomnia, 8 to 14=subthreshold insomnia, 15 to 21=clinical insomnia (moderate severity), and 22 to 28=clinical insomnia (severe). Higher scores indicate more severity. A negative change from baseline indicates less severe insomnia. | Baseline, Days 15, and 42 | 
| Change From Baseline in Core Consensus Sleep Diary Parameters: Sleep Onset Latency (sSL), Wake After Sleep Onset (sWASO), and Total Sleep Time (sTST) | The Core Consensus Sleep Diary collected subjective responses to a series of questions related to participant's daily sleep pattern (i.e., time to bed, time to fall asleep, time to final awakening, and a question related to quality of sleep) to derive sleep parameters, including sSL, sTST, and sWASO. The take-home participant sleep diary assessment was administered using an eDiary solution. The eDiary was captured using either a provisioned smartphone device or a bring-your-own-device solution, depending on the participant's preference. sTST is a derived parameter calculated as: Time of final awakening - (time when tried to sleep + time taken to fall asleep)-time of being awake after sleep onset. Negative change from baseline in sSL and sWASO indicates improvement. Positive change from baseline in sTST indicates improvement. | Baseline, Days 15, and 28 | 
| Change From Baseline in Core Consensus Sleep Diary Parameter: Number of Awakenings (sNAW) | The Core Consensus Sleep Diary was used to collect subjective sleep parameter of sNAW. sNAW was calculated from the onset of persistent sleep until lights on. An awakening is defined as at least 2 consecutive epochs of wake. Individual awakenings were separated by at least 1 epoch of Stage N2 (also fairly light, with sudden increases in brain wave frequency known as sleep spindles), N3 (slow wave or deep sleep) or rapid eye movement (REM) sleep. Lower ratings indicate better sleep quality and more refreshing/restorative quality of sleep. | Baseline, Days 15, and 28 | 
| Change From Baseline in Core Consensus Sleep Diary Parameter: Number of Participants With Subjective Sleep Quality (sSQ) Response | The Core Consensus Sleep Diary collected subjective sleep parameters, including sleep quality (sSQ). The take-home participant sleep diary assessment was administered using an eDiary solution. The eDiary was captured using either a provisioned smartphone device or a bring-your-own-device solution, depending on the participant's preference. sSQ is rated on a 5-point Likert scale ranging from 1 (very poor) to 5 (very good). Higher ratings indicate better sleep quality. sSQ response is defined as having a sSQ score of very good or good. | Baseline, Days 15, and 28 | 
| Change From Baseline in the 36-item Short Form Survey Version 2 (SF-36v2) Physical and Mental Component Summary Scores | Participant's health was assessed using Patient-reported outcome (PRO) health related quality of life (HRQOL), SF-36v2 which is a 36-item measure of health status. It covers eight health dimensions including four physical health status domains (physical functioning, role participation with physical health problems, bodily pain, and general health) and four mental health status domains (vitality, social functioning, role participation with emotional health problems, and mental health). Two summary scores, physical component summary (PCS), and mental component summary (MCS) were produced by taking a weighted linear combination of the eight individual domains. The score range for PCS and MCS is 0 to 100 (100=highest level of functioning). Higher scores indicate a better state of health. A negative change from baseline indicates deteriorating health. | Baseline, Days 15, and 42 | 
| Change From Baseline in the 9-item Patient Health Questionnaire (PHQ-9) Total Score | The PHQ-9 is a participant-rated depressive symptom severity scale to monitor severity over time for newly diagnosed participants or participants in current treatment for depression. Scoring was based on participants' responses to each of the 9 questions, as follows: 0=not at all; 1=several days; 2=more than half the days; and 3=nearly every day. The PHQ-9 total score was calculated as the sum of the 9 individual item scores. The PHQ-9 total score was categorized as follows: 1 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. Higher scores indicate more severe depression. A negative change from baseline indicates reduced depression. | Baseline, Days 15, and 42 | 
| Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE) and Serious TEAE in Treatment and FU Periods | An adverse event (AE) is any untoward medical occurrence in a participant administered with 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 an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. A TEAE is 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. A serious TEAE is defined as a TEAE that at any dose results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or results in a congenital abnormality or birth defect. | Treatment period: Up to Day 14; FU period: Day 15 to 42 | 
| Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE) and Serious TEAE in Extended FU Period | An adverse event (AE) is any untoward medical occurrence in a participant administered with 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 an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. A TEAE is 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. A serious TEAE is defined as a TEAE that at any dose results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or results in a congenital abnormality or birth defect. | Extended FU Period: Day 43 to 182 | 
| Number of Participants With Clinically Significant Abnormalities in Laboratory Measures in Treatment and FU Periods | Laboratory parameters include serum chemistry- Alanine aminotransferase: >3x upper limit of normal (ULN); Alanine aminotransferase or aspartate aminotransferase: >3x ULN; Bilirubin: >1.5x ULN, >2x ULN; Calcium: <2.0 millimoles per liter (mmol/L); Gamma Glutamyl Transferase [units per liter (U/L)]: >3xULN; Potassium: >5.4 mmol/L; Sodium: >150 mmol/L; Hematology- Hematocrit : Male <0.385 liter/liter (L/L) and Female <0.345 L/L and Male >0.55 L/L and Female >0.49 L/L; Hemoglobin: Male <115 grams/liter (g/L) and Female <100 g/L; Neutrophils: <1.5 10^9/L. | Treatment period: Up to Day 14; FU period: Day 15 to 42 | 
| Number of Participants With Clinically Significant Abnormalities in Laboratory Measures in Extended FU Period | Laboratory parameters include serum chemistry- Alanine aminotransferase: >3x upper limit of normal (ULN); Alanine aminotransferase or aspartate aminotransferase: >3x ULN; Bilirubin: >1.5x ULN, >2x ULN; Calcium: <2.0 millimoles per liter (mmol/L); Gamma Glutamyl Transferase [units per liter (U/L)]: >3xULN; Potassium: >5.4 mmol/L; Sodium: >150 mmol/L; Hematology- Hematocrit : Male <0.385 liter/liter (L/L) and Female <0.345 L/L and Male >0.55 L/L and Female >0.49 L/L; Hemoglobin: Male <115 grams/liter (g/L) and Female <100 g/L; Neutrophils: <1.5 10^9/L. | Extended FU Period: Day 43 to 182 | 
| Number of Participants With Clinically Significant Vital Sign Abnormalities in Treatment and FU Periods | Vital signs include supine and standing systolic blood pressure (SBP) [millimeters of mercury (mmHg)]: <90, >180, increase and decrease from baseline of >=30; Supine and standing diastolic blood pressure (DBP) (mmHg): Increase and decrease from baseline >=20; Standing heart rate (>120 beats per minute); Orthostatic SBP (>=20); Orthostatic DBP (>=10); Orthostatic hypotension (SBP >=20 and DBP >=10, SBP >=20 or DBP >=10). | Treatment period: Up to Day 14; FU period: Day 15 to 42 | 
| Number of Participants With Clinically Significant Vital Sign Abnormalities in Extended FU Period | Vital signs include supine and standing SBP [mmHg]: <90, >180, increase and decrease from baseline of >=30; Supine and standing DBP (mmHg): Increase and decrease from baseline >=20; Standing heart rate (>120 beats per minute); Orthostatic SBP (>=20); Orthostatic DBP (>=10); Orthostatic hypotension (SBP >=20 and DBP >=10, SBP >=20 or DBP >=10). | Extended FU Period: Day 43 to 182 | 
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities in Treatment and FU Periods | Supine 12-lead ECGs were performed in triplicate and the standard intervals (heart rate, PR, QRS, QT, and corrected QT interval by Fridericia [QTcF]) as well as any rhythm abnormalities were recorded. Criteria for clinically significant ECG abnormalities included QTcF interval (msec)- females: >450 to 480, male: >450 to 470, females: >480 to 500, male: >470 to 500 or >500. | Treatment period: Up to Day 14; FU period: Day 15 to 42 | 
| Number of Participants With Clinically Significant ECG Abnormalities in Extended FU Period | Supine 12-lead ECGs were performed in triplicate and the standard intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities were recorded. Criteria for clinically significant ECG abnormalities included QTcF interval (msec)- females: >450 to 480, male: >450 to 470, females: >480 to 500, male: >470 to 500 or >500. | Extended FU Period: Day 43 to 182 | 
| Number of Participants With Suicidal Ideation or Behavior Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS) in Double-blind Treatment Period at Day 42 | Suicidality was monitored during the study using the C-SSRS scale. The C-SSRS includes 'yes' or 'no' responses for 5 questions for assessment of suicidal ideation and behavior. Any suicidal behavior: When response is yes for any these questions- actual attempt to suicide, engaged in non-suicidal self-injurious behavior, interrupted attempt, aborted attempt, preparatory acts. Any suicidal ideation: When response is yes for any of these questions- wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent to suicide. | Day 42 | 
| Number of Participants With Suicidal Ideation or Behavior Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS) in Extended FU Period at Day 182 | Suicidality was monitored during the study using the C-SSRS scale. The C-SSRS includes 'yes' or 'no' responses for 5 questions for assessment of suicidal ideation and behavior. Any suicidal behavior: When response is yes for any these questions- actual attempt to suicide, engaged in non-suicidal self-injurious behavior, interrupted attempt, aborted attempt, preparatory acts. Any suicidal ideation: When response is yes for any of these questions- wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent to suicide. | Day 182 | 
| Change From Baseline in the 20-item Physician Withdrawal Checklist (PWC-20) Total Score | The PWC-20 was used to monitor for the presence of potential withdrawal symptoms following discontinuation of SAGE-217. The PWC-20 was made up of a list of 20 symptoms (loss of appetite, nausea-vomiting, diarrhea, anxiety-nervousness, irritability, dysphoric mood-depression, insomnia, fatigue-lethargy-lack of energy, poor coordination, restlessness-agitation, diaphoresis, tremor-tremulousness, dizziness-lightheadedness, headaches, muscle aches or stiffness, weakness, increased acuity [sound, smell, touch, pain], paresthesia, difficulty concentrating and remembering, depersonalization-derealization) that were rated on a scale of 0 (not present) to 3 (severe). The PWC-20 total score was derived as the sum of individual item scores, which ranges from 0 (not present) to 60 (severe). Higher scores indicate more severe withdrawal. A negative change from baseline indicates less severe withdrawal. | Baseline, Days 15, 18, and 21 |