A Study to Evaluate Efficacy and Safety of SAGE-547 in Participants With Severe Postpartum Depression (547-PPD-202B)

Study Overview
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Brief Summary
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The purpose of this study was to determine if SAGE-547 Injection infused intravenously at up to 90 micrograms per kilogram per hour (μg/kg/h) for 60 hours reduces depressive symptoms in participants with severe postpartum depression (PPD) compared to placebo injection as assessed by the change from baseline in Hamilton Rating Scale for Depression (HAM-D) total score.

Official Title
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A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of SAGE-547 Injection in the Treatment of Adult Female Subjects With Severe Postpartum Depression and Adult Female Subjects With Moderate Postpartum Depression

Conditions
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Postpartum Depression

Intervention / Treatment
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* Drug: Placebo
* Drug: SAGE-547 60 μg/kg/h
* Drug: SAGE-547 90 μg/kg/h


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participants must have ceased lactating at screening; or if still lactating or actively breastfeeding at screening, agreed to temporarily cease giving breastmilk to their infant(s) from just prior to receiving study drug through nine days (Day 12) after the end of the infusion Participants had a major depressive episode that began no earlier than the third trimester and no later than the first 4 weeks following delivery, as diagnosed by Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) Participant had a HAM-D total score of ≥26 at screening and Day 1 (prior to dosing) Participant was ≤6 months postpartum at screening Participant was amenable to IV therapy Key Exclusion Criteria: Active psychosis Attempted suicide associated with index case of postpartum depression Medical history of bipolar disorders, schizophrenia, and/or schizoaffective disorder. Note: Other protocol-defined inclusion/exclusion criteria applied.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

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: Placebo<br>Participants received infusion rates equivalent to either the 60 micrograms per kilogram per hour (μg/kg/h) or 90 μg/kg/h group. | Drug: Placebo<br>* Intravenous infusion of matching placebo for either SAGE-547 60 μg/kg/h or 90 μg/kg/h.<br>|
| Experimental: SAGE-547 60 μg/kg/h<br>Participants received a 4-hour titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 56 hours), followed by a taper to 30 μg/kg/h (56 to 60 hours). | Drug: SAGE-547 60 μg/kg/h<br>* Intravenous infusion of SAGE-547.<br>|
| Experimental: SAGE-547 90 μg/kg/h<br>Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours). | Drug: SAGE-547 90 μg/kg/h<br>* Intravenous infusion of SAGE-547.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at 60 Hours in the 17-Item Hamilton Rating Scale for Depression (HAM-D) Total Score | The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 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. The Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression. | Baseline, Hour 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HAM-D Total Score at Day 30 | The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 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. The Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression. | Baseline, Day 30 | 
| Change From Baseline in HAM-D Total Score | The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 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. The Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression. | Baseline, Hours 2, 4, 8, 12, 24, 36, 48, 72, and Days 7, 14, and 21 | 
| Percentage of Participants With HAM-D Response | The HAM-D response is defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 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. The Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression. | Hour 60, Days 7 and 30 | 
| Percentage of Participants With HAM-D Remission | The HAM-D remission is defined as having a HAM-D total score of ≤7. The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 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. The Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression. | Hour 60, Days 7 and 30 | 
| Change From Baseline in HAM-D Bech 6 Subscale | The HAM-D Bech 6 subscale score is calculated as the sum of the following six items: Item # 1 (depressed mood), Item # 2 (feelings of guilt), Item # 7 (work and activities), Item # 8 (retardation), Item # 10 (anxiety psychic), and Item # 13 (general somatic symptoms). Each item is scored in a range of 0 to 2 or 0 to 4, with higher scores indicating a greater degree of depression. The scores were transformed to a 100-point scale with a higher score indicating a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression. | Baseline, Hour 60, Days 7 and 30 | 
| Change From Baseline in HAM-D Individual Item Scores | 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, 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. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression. | Baseline, Hour 2, Hour 4, Hour 8, Hour 12, Hour 24, Hour 36, Hour 48, Hour 60, Hour 72 and Days 7, 14, 21 and 30 | 
| Change From Baseline at Key Time Points in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D, to be more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms of treatment. Each item yielded a score of 0 to 6. The MADRS total score was calculated as the sum of the 10 individual item scores, which ranged from 0 to 60. Higher MADRS scores indicates more severe depression. A negative change from baseline indicates less severe depression. A positive change from baseline indicates more severe depression. | Baseline, Hour 60, Days 7 and 30 | 
| Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response | The CGI-I item 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 include: 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. The CGI-I was only rated at post-treatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions. CGI-I response was defined as having a score of 1 (very much improved) or 2 (much improved). | Hour 60, Days 7 and 30 | 
| Change From Baseline in the Generalized Anxiety Disorder 7-Item Scale (GAD-7) Total Score | The GAD-7 is a participant-rated, generalized anxiety symptom severity scale. Scoring for GAD-7 generalized anxiety is calculated by assigning scores of 0 = not at all sure, 1 = several days, 2 = over half the days, and 3 = nearly every day to the response categories. The GAD-7 total score for the seven items ranges from 0 to 21, where a score of 0 to 4 = minimal anxiety, 5 to 9 = mild anxiety, 10 to 14 = moderate anxiety, and 15 to 21 = severe anxiety. The GAD-7 total score was calculated as the sum of the seven individual item scores. A negative change from baseline indicates less anxiety. A positive change from baseline indicates more anxiety. | Baseline, Hour 60, Days 7, 14, 21 and 30 | 
| Percentage of Participants With Treatment-Emergent Adverse Events | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent AE (TEAE) is defined as an AE with onset on or after the start of study drug infusion, or any worsening of a pre-existing medical condition/AE with onset on or after the start of study drug infusion. | Up to approximately 37 days. | 
| Time to Change in Antidepressant Medication | The time to first start or increase in the dose and time to first stop or decrease in the dose of any antidepressant medication. | Up to approximately 37 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SAGE-547, Severe Postpartum Depression