A Study to Evaluate the Efficacy of Sage-217 in the Treatment of Adult Participants With Major Depressive Disorder (MDD)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study to evaluate the efficacy of SAGE-217 in the treatment of participants with MDD.

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

Official Title
-----------------
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
-----------------
Depressive Disorder, Major

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant with diagnosis of MDD as diagnosed by Structured Clinical Interview for Diagnostic and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Clinical Trial Version [SCID-5-CT], with symptoms that have been present for at least a 4-week period. Participant has a Hamilton Rating Scale for Depression (HAM-D) total score ≥24 at screening and Day 1 (prior to dosing). Participants taking antidepressants must have been taking these medications at the same dose for at least 60 days prior to Day 1. Participants who have stopped taking antidepressants within 60 days must have stopped for longer than 5 half-lives of the antidepressant prior to Day 1. Participants receiving psychotherapy must have been receiving therapy on a regular schedule for at least 60 days prior to Day 1. Participant is willing to delay start of other antidepressant or antianxiety medications and any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics and sleep aids, until after completion of the Day 42 visit. Exclusion Criteria: Participant is currently at significant risk of suicide, as judged by the Investigator, or has attempted suicide associated with the current episode of MDD. Participant has 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 a body mass index (BMI) ≤18 or ≥45 kg/m^2 at Screening, which is subject to a broader evaluation of medical comorbidities. Participant has treatment-resistant depression, defined as persistent depressive symptoms despite treatment with adequate doses of antidepressants within the current major depressive episode (excluding antipsychotics) from two different classes for at least 4 weeks of treatment. Participant has a medical history of seizures, bipolar disorder, schizophrenia, and/or schizoaffective disorder. Participant has a history of mild, moderate, or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to screening. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, regularly or as-needed, at Day -28.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days. | Drug: Placebo<br>* SAGE-217 matched-placebo oral capsules.<br>|
| Experimental: SAGE-217 50 mg<br>Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator. | Drug: SAGE-217<br>* SAGE-217 oral capsules.<br>|

What is the study measuring?
-----------------
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 scale is used to assess the severity of depression. It is comprised of individual ratings related to the 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 a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. The total HAM-D score is the sum of individual items, ranging from 0 to 52; where a higher score indicates more depression. A negative change indicates improvement. A mixed Model for Repeated Measures (MMRM)was used for the analysis. | Baseline, Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the CGI-S Score at Day 15 | The CGI-S is 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. A participant is assessed on severity of mental illness at the time of rating as 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7= among the most extremely ill participants. A negative change from baseline indicates improvement. MMRM was used for the analysis. A negative change from baseline indicates improvement. MMRM was used for the analysis. | Baseline, Day 15 | 
| Change From Baseline in the HAM-D Total Score at Days 3, 8 and 42 | The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to the 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 a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. The total HAM-D score is the sum of individual items, ranging from 0 to 52; where a higher score indicates more depression. A negative change from baseline indicates improvement. MMRM was used for the analysis. | Baseline, Days 3, 8, and 42 | 
| Percentage of Participants Achieving HAM-D Response | The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to the 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 a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. The total HAM-D score is the sum of individual items, ranging from 0 to 52; where a higher score indicates more depression. HAM-D response is defined as having a greater than or equal to (≥) 50% reduction in HAM-D score from baseline. Generalized Estimating Equation (GEE) method was used for the analysis. | Days 15 and 42 | 
| Percentage of Participants Achieving HAM-D Remission | The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to the 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 a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. The total HAM-D score is the sum of individual items, ranging from 0 to 52; where a higher score indicates more depression. HAM-D remission is defined as HAM-D total score less than or equal to (≤) 7. GEE model was used for the analysis. | Days 15 and 42 | 
| Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response at Day 15 | CGI-I response is defined as having a CGI-I score of very much improved (score of 1) or much improved (score of 2). The CGI-I employs a 7-point Likert scale to measure the overall improvement in the participant's condition posttreatment. Response choices include 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. GEE model was used for the analysis. | Day 15 | 
| 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 and each item yields a score of 0 to 6. The overall MADRS score ranges from 0 to 60 where higher MADRS scores indicate more severe depression. A negative change indicates improvement. MMRM was used analysis. | Baseline, Day 15 | 
| Change From Baseline in HAM-A Total Score at Day 15 | The 14-item HAM-A is comprised of a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). The HAM-A total score was calculated as the sum of the 14 individual item scores. The scoring for HAM-A is calculated by assigning scores of 0 (not present) to 4 (very severe) to each item, with a total HAM-A score range of 0 to 56, where <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 improvement. MMRM was used for the analysis. | Baseline, Day 15 | 
| Time to First HAM-D Response | 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 a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. Total HAM-D score is sum of individual items, ranging from 0 to 52; where higher score indicates more depression. Time to first HAM-D response is defined as time from first administration of the study drug to first time when ≥50% reduction in HAM-D score from baseline is achieved. | Up to Day 57 | 
| Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 | Participant's health was assessed using PRO health related quality of life (HRQOL) SF-36 V2. SF-36v2 covers 8 health dimensions, including 4 physical health status domains (physical functioning, role participation with physical health problems [role-physical], bodily pain, and general health) and 4 mental health status domains (vitality, social functioning, role participation with emotional health problems [role-emotional], and mental health). Physical Component Summary and the Mental Component Summary are derived from the 8 domains. Each domain is scored by summing the individual items, scores varying between 0 and 100. Both the domain scores and the component summary scores are norm-based. A higher score indicates a better state of health. Positive change indicates improvement. MMRM was used for the analysis. | Baseline, Days 8, 15, 28 and 42 | 
| Change From Baseline in PRO Measures of Depressive Symptoms, as Assessed by the 9-item Patient Health Questionnaire (PHQ-9) Total Score at Days 8, 15, 28 and 42 | The PHQ-9 is a participant-rated depressive symptom severity scale where scoring is based on responses to specific questions. The score was calculated as the sum of the 9 individual item scores. The PHQ-9 total score ranges from 0 to 27 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 with a higher score indicating more depression. A negative change indicates improvements. MMRM was used for analysis. | Baseline, Days 8, 15, 28 and 42 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Depression, Depressive disorder, SAGE-217