A Study to Evaluate SAGE-217 in Participants With Bipolar I/II Disorder With a Current Major Depressive Episode

Study Overview
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Brief Summary
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This is an open-label study evaluating the safety, tolerability, pharmacokinetics, and efficacy of SAGE-217 in the treatment of participants with bipolar I/II disorder with a current major depressive episode.

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 2-Part Study (Open-label Followed by Double-blind, Randomized, Placebo-controlled, Parallel Group) of the Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in the Treatment of Subjects With Bipolar I/II Disorder With a Current Major Depressive Episode

Conditions
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Bipolar Disorder II, Bipolar Disorder I, Major Depressive Episode

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: 1. Participant had a documented history of hypomanic or manic episode and a diagnosis of bipolar I or bipolar II disorder with a current major depressive episode. Exclusion Criteria: Participant had a history of suicide attempt. Participant had current suicidal ideation with plans. Participant had a history of rapid cycling bipolar 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A (Open-label): SAGE-217<br>Participants self-administered SAGE-217, 30 milligrams (mg), oral capsule, once daily (QD), in the evening, from Day 1 to Day 14. | Drug: SAGE-217<br>* SAGE-217 capsule<br>|
| Experimental: Part B (Double-blind): SAGE-217<br>Participants were to receive SAGE-217, 30 mg, oral capsule, QD, in the evening, from Day 1 to Day 14 in Part B of the study. However, as per the Sponsor's decision, the Part B of the study was not conducted. | Drug: SAGE-217<br>* SAGE-217 capsule<br>|
| Placebo Comparator: Part B (Double-blind): Placebo<br>Participants were to receive SAGE-217 matching placebo capsule, orally, QD, in the evening, from Day 1 to Day 14 in Part B of the study. However, as per the Sponsor's decision, the Part B of the study was not conducted. | Drug: Placebo<br>* SAGE-217 matching placebo capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With at Least One 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 (including an abnormal laboratory finding), 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 adverse event with onset after the start of study through Day 42/early termination. | From first dose of study drug up to Day 42 | 
| Part A: Number of Participants With TEAEs, Graded by Severity | 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 (including an abnormal laboratory finding), 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 adverse event with onset after the start of study through Day 42/early termination. Severity was assessed according to the following scale: mild (awareness of sign or symptom, but easily tolerated); moderate (discomfort sufficient to cause interference with normal activities); severe (incapacitating, with inability to perform normal activities). | From first dose of study drug up to Day 42 | 
| Part A: Percentages of Participants With Response to Suicidal Ideation and Suicidal Behavior Based on the Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidality was monitored using the C-SSRS. This scale consists of a baseline evaluation that assesses the lifetime experience of the participant with suicidal ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last study visit. The C-SSRS includes 'yes' or 'no' responses for assessment of suicidal ideation (wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods, active suicidal ideation with some intent, active suicidal ideation with specific plan) and behavior (preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt (non-fatal), completed suicide). Percentage of participants with response 'yes' are reported for both suicidal ideation and behavior. | Baseline, Post-baseline (any time up to Day 42) | 
| Part A: Change From Baseline in the Young Mania Rating Scale (YMRS) Total Score | Manic symptoms were assessed during the study using the YMRS. The clinician-administered scale is based on 11 items of core symptoms of mania. Four of the items (irritability, speech, thought content, and disruptive/aggressive behavior) were graded on a scale of 0 to 8 (choices given as even numbers), with the remaining 7 items graded on a scale of 0 to 4. Scoring between the points given (whole or half points) is possible. The YMRS total score ranges from 0 (no symptoms) to 60 (extreme severity of symptoms). A higher total score indicates a greater degree of mania. A negative change indicates better state of health. | Baseline, Days 3, 8, 12, 15, 21, 28, 35, and 42, Last value on treatment (up to Day 14), Last value on study (up to Day 42) | 
| Part B: Change From Baseline in the 17-Item Hamilton Depression Rating Scale (HAM-D) Total Score | The 17-item HAM-D was used to rate the severity of depression in participants who were identified as experiencing a major depressive episode (MDE). 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. Items scored in a range of 0 to 4 include: agitation, depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), anxiety (psychic and somatic), hypochondriasis. The HAM-D total score was calculated as the sum of the 17 individual item scores, with a range of 0 (not at all depressed) to 52 (severely depressed). Higher scores indicated more depression. A negative change from baseline indicates improvement. | Baseline up to Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Change From Baseline in the 17-Item HAM-D Total Score at Day 15 | The 17-item HAM-D was used to rate the severity of depression in participants who were identified as experiencing an MDE. 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. Items scored in a range of 0 to 4 include: agitation, depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), anxiety (psychic and somatic), hypochondriasis. The HAM-D total score was calculated as the sum of the 17 individual item scores, with a range of 0 (not at all depressed) to 52 (severely depressed). Higher scores indicated more depression. A negative change from baseline indicates improvement. | Baseline, Day 15 | 
| Part A: Percentage of Participants With HAM-D Response at Day 15 | HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D total score was calculated as the sum of the 17 individual item scores. The 17-item HAM-D comprises individual ratings related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. The HAM-D total score was calculated as the sum of the 17 individual item scores, with a range of 0 (not at all depressed) to 52 (severely depressed). Higher scores indicated more depression. | Day 15 | 
| Part A: Percentage of Participants With HAM-D Remission at Day 15 | HAM-D remission was defined as having a HAM-D total score of ≤7. The HAM-D total score was calculated as the sum of the 17 individual item scores. The 17-item HAM-D comprises individual ratings related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. The HAM-D total score was calculated as the sum of the 17 individual item scores, with a range of 0 (not at all depressed) to 52 (severely depressed). Higher scores indicated more depression. | Day 15 | 
| Part A: 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. It includes questions on the following symptoms: apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts. Each item was scored in a range of 0 (no symptoms) to 6 (symptoms of maximum severity). The MADRS total score was calculated as the sum of the ten individual item scores and ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicate more severe depression. A negative change indicates improvement. | Baseline, Day 15 | 
| Part A: Change From Baseline in Response to the Clinical Global Impression - Severity (CGI-S) 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 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 negative change from baseline indicates improvement (higher absolute number indicating more illness). | Baseline, Day 15 | 
| Part A: Percentage of Participants With Response to Clinical Global Impression - Improvement (CGI-I) at Day 15 | The CGI-I employs a 7-point Likert scale to measure the overall improvement in the participant's condition posttreatment. 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. Higher number indicating more illness. The CGI-I is only rated at posttreatment assessments. CGI-I response were defined as having a CGI-I score very much improved or much improved. | Day 15 | 
| Part A: Insomnia Severity Index (ISI) at Day 15 | 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 = neutral, 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). ISI total score ranges from 0 to 28, where a total score of 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). A lower value indicates better outcome. | Day 15 | 
| Part B: Change From Baseline in the Total HAM-D Score at Day 15 | The 17-item HAM-D was used to rate the severity of depression in participants who were identified as experiencing an MDE. 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. Items scored in a range of 0 to 4 include: agitation, depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), anxiety (psychic and somatic), hypochondriasis. The HAM-D total score was calculated as the sum of the 17 individual item scores, with a total score of 0 (not at all depressed) to 52 (severely depressed). Higher scores indicated more depression. A negative change from baseline indicates improvement. | Baseline, Day 15 | 
| Part B: Percentage of Participants With HAM-D Response at Day 15 | HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D total score was calculated as the sum of the 17 individual item scores. The 17-item HAM-D comprises individual ratings related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. The HAM-D total score was calculated as the sum of the 17 individual item scores, with a range of 0 (not at all depressed) to 52 (severely depressed). Higher scores indicated more depression. | Day 15 | 
| Part B: Percentage of Participants With HAM-D Remission at Day 15 | HAM-D remission was defined as having a HAM-D total score of ≤7. The HAM-D total score was calculated as the sum of the 17 individual item scores. The 17-item HAM-D comprises individual ratings related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. The HAM-D total score was calculated as the sum of the 17 individual item scores, with a range of 0 (not at all depressed) to 52 (severely depressed). Higher scores indicated more depression. | Day 15 | 
| Part B: Change From Baseline in the 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. It includes questions on the following symptoms: apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts. Each item was scored in a range of 0 (no symptoms) to 6 (symptoms of maximum severity). The MADRS total score was calculated as the sum of the ten individual item scores and ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicate more severe depression. A negative change indicates improvement. | Baseline, Day 15 | 
| Part B: Change From Baseline in Response to the Clinical Global Impression - Severity (CGI-S) 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 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 negative change from baseline indicates improvement (higher absolute number indicating more illness). | Baseline, Day 15 | 
| Part B: Number of Participants With Response to Clinical Global Impression - Improvement (CGI-I) at Day 15 | The CGI-I employs a 7-point Likert scale to measure the overall improvement in the participant's condition posttreatment. 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. Higher number indicating more illness. The CGI-I is only rated at posttreatment assessments. CGI-I response were defined as having a CGI-I score very much improved or much improved. | Day 15 | 
| Part B: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 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 (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. A TEAE is defined as an adverse event with onset after the start of study through Day 42/early termination. | From first dose of study drug up to Day 42 | 
| Part B: Number of Participants With TEAEs, Graded by Severity | 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 (including an abnormal laboratory finding), 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 adverse event with onset after the start of study through Day 42/early termination. Severity was assessed according to the following scale: mild (awareness of sign or symptom, but easily tolerated); moderate (discomfort sufficient to cause interference with normal activities); severe (incapacitating, with inability to perform normal activities). | From first dose of study drug up to Day 42 | 
| Part B: Percentages of Participants With Change From Baseline in Suicidal Ideation and Suicidal Behavior Based on the Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidality was monitored using the C-SSRS. This scale consists of a baseline evaluation that assesses the lifetime experience of the participant with suicidal ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last study visit. The C-SSRS includes 'yes' or 'no' responses for assessment of suicidal ideation (wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods, active suicidal ideation with some intent, active suicidal ideation with specific plan) and behavior (preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt (non-fatal), completed suicide). Percentage of participants with response 'yes' were to be reported for both suicidal ideation and behavior. | Baseline up to Day 42 | 
| Part B: Change From Baseline in the Young Mania Rating Scale (YMRS) Total Score | Manic symptoms were assessed during the study using the YMRS. The clinician-administered scale is based on 11 items of core symptoms of mania. Four of the items (irritability, speech, thought content, and disruptive/aggressive behavior) were graded on a scale of 0 to 8 (choices given as even numbers), with the remaining 7 items graded on a scale of 0 to 4. Scoring between the points given (whole or half points) is possible. The YMRS total score ranges from 0 (no symptoms) to 60 (extreme severity of symptoms). A higher total score indicates a greater degree of mania. A negative change indicates better state of health. | Baseline up to Day 42 | 
| Part B: Insomnia Severity Index (ISI) at Day 15 | 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 = neutral, 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). ISI total score ranges from 0 to 28, where a total score of 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). A lower value indicates better outcome. | Day 15 |