Evaluate SAGE-547 in Female Participants With Severe Postpartum Depression

Study Overview
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Brief Summary
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This is an open-label proof-of-concept study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of SAGE-547 Injection in adult female participants diagnosed with severe postpartum depression (PPD).

Official Title
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An Open-Label Proof-of-Concept Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-547 Injection in the Treatment of Adult Female Patients With Severe Postpartum Depression

Conditions
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Postpartum Depression

Intervention / Treatment
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* Drug: SAGE-547


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult females, 18-45 years old who experienced a major depressive episode in the postpartum period beginning within the first 4 weeks following delivery Participant has ceased lactating, or if still lactating has already fully and permanently weaned their infant; if still actively breastfeeding, participant must agree to cease giving breast milk to their infant prior to study entry Exclusion Criteria: Recent history or active clinically significant manifestations of metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, or eyes, ears, or nose and throat (EENT) disorders Active psychosis Medical history of seizures

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAGE-547<br>Participants received SAGE-547 intravenous injection over 60 hours (including 12-hour titration infusion of 21.5 micrograms per kilogram per hour [mcg/kg/hr] [4 hrs], 43 mcg/kg/hr [4 hrs] and 64.5 mcg/kg/hr [4 hrs] on Day 1, followed by 13 to 48 hrs [36 hrs] maintenance infusion of 86 mcg/kg/hr from Day 1 to 3, followed by a 12-hr taper infusion of 64.5 mcg/kg/hr [49 - 52 hrs], 43 mcg/kg/hr [53 - 56 hrs] and 21.5 mcg/kg/hr [57 - 60 hrs] on Day 3). | Drug: SAGE-547<br>* Intravenous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | AEs were any untoward medical occurrences in a participant who received study treatment without regard to possibility of causal relationship. TEAEs were defined as AEs with onset after the start of SAGE-547 infusion, or any worsening of a pre-existing medical condition or AEs with onset after the start of SAGE-547 infusion and until 7 days after the end of infusion (Day 11). TESAEs were defined as AEs with onset after the start of SAGE-547 infusion, or any worsening of a pre-existing medical condition or AEs with onset after the start of SAGE-547 infusion and until 30 days after the end of infusion (Day 34). | TEAEs: Up to Day 11, TESAEs: Up to Day 34 | 
| Change From Baseline in Clinical Laboratory Measures: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) | Clinical laboratory evaluation included: Chemistry (ALT, AST, GGT) expressed in terms of units per liter (U/L). The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measures: Carbon Dioxide (CO2), Sodium, Potassium and Chloride | Clinical laboratory evaluation included: Chemistry (carbon dioxide [CO2], sodium, potassium and chloride) expressed in terms of millimoles/liter (mmol/L). The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measures: Glucose, Total Bilirubin, Calcium, Blood Urea Nitrogen (BUN) and Creatinine | Clinical laboratory evaluation included: Chemistry (glucose, total bilirubin, calcium, blood urea nitrogen [BUN] and creatinine) expressed in terms of milligrams/deciliter (mg/dL). The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measures: Albumin, Total Protein and Hemoglobin | Clinical laboratory evaluation included: Chemistry (albumin, total protein), Hematology and Coagulation (hemoglobin) expressed in terms of g/dL. The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measure: Hematocrit | Clinical laboratory evaluation included: Hematocrit expressed in terms of percentage. The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measures: Platelet Count, White Blood Cells (WBC), Absolute Lymphocytes, Absolute Neutrophils, Absolute Basophils, Absolute Eosinophils, Absolute Monocytes | Clinical laboratory evaluation included: Platelet count, white blood cells (WBC), absolute lymphocytes, absolute neutrophils, absolute basophils, absolute eosinophils, absolute monocytes expressed in terms of 10^9 cells/L. The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measure: Red Blood Cells (RBC) | Clinical laboratory evaluation included: RBC expressed in terms of 10^12 cells/L. The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measure: Mean Corpuscular Volume (MCV) | Clinical laboratory evaluation included: MCV expressed in terms of femtoliters (fL). The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measure: Mean Corpuscular Hemoglobin (MCH) | Clinical laboratory evaluation included: MCH expressed in terms of picogram (pg). The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measure: Prothrombin Time/International Normalized Ratio (PT/INR) | Clinical laboratory evaluation included: PT/INR expressed in terms of seconds. The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measure: Potential of Hydrogen (pH) | Clinical laboratory evaluation included: Urinalysis (pH). The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Clinical Laboratory Measure: Specific Gravity | Clinical laboratory evaluation included: Urinalysis (specific gravity) expressed in terms of ratio. The data was collected at time-points on Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs). | Baseline, Days 2 (at 24 hrs), 3 (at 48 hrs) and 4 (at 84 hrs) | 
| Change From Baseline in Vital Sign: Blood Pressure | Vital sign parameters included supine systolic blood pressure (SBP), supine diastolic blood pressure (DBP), standing systolic blood pressure and standing diastolic blood pressure expressed in terms of millimeters of mercury (mmHg). The data was collected at time-points on Day 1 (12 hrs), Day 2 (at 24 and 36 hrs), on Day 3 (at 48 and 60 hrs), and Day 4 (at 72 and 84 hrs). | Baseline, Day 1 (12 hrs), Day 2 (at 24 and 36 hrs), on Day 3 (at 48 and 60 hrs), and Day 4 (at 72 and 84 hrs) | 
| Change From Baseline in Vital Sign: Heart Rate | Vital sign parameter included heart rate expressed in terms of beats per minute (bpm). The data was collected at time-points on Day 1 (12 hrs), Day 2 (at 24 and 36 hrs), on Day 3 (at 48 and 60 hrs), and Day 4 (at 72 and 84 hrs). | Baseline, Day 1 (12 hrs) Day 2 (at 24 and 36 hrs), on Day 3 (at 48 and 60 hrs), and Day 4 (at 72 and 84 hrs) | 
| Change From Baseline in Vital Sign: Body Temperature | Vital sign parameter included temperature expressed in terms of degree Celsius. The data was collected at time-points on Day 1 (12 hrs), Day 2 (at 24 and 36 hrs), on Day 3 (at 48 and 60 hrs), and Day 4 (at 72 and 84 hrs). | Baseline, Day 1 (12 hrs) Day 2 (at 24 and 36 hrs), on Day 3 (at 48 and 60 hrs), and Day 4 (at 72 and 84 hrs) | 
| Change From Baseline in Vital Sign: Respiratory Rate | Vital sign parameter included respiratory rate expressed in terms of breaths per minute. The data was collected at time-points on Day 1 (12 hrs), Day 2 (at 24 and 36 hrs), on Day 3 (at 48 and 60 hrs), and Day 4 (at 72 and 84 hrs). | Baseline, Day 1 (12 hrs) Day 2 (at 24 and 36 hrs), on Day 3 (at 48 and 60 hrs), and Day 4 (at 72 and 84 hrs) | 
| Change From Baseline in Electrocardiogram (ECG) Parameters: QT Interval, PR Interval, QTc Interval, and QRS Duration | ECGs parameters included QT interval, PR interval, QTc interval, QRS duration expressed in terms of milliseconds (msec). | Baseline, Day 4 (at 84 hrs) | 
| Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate | ECGs parameter included heart rate expressed in terms of beats per minute (bpm). | Baseline, Day 4 (at 84 hrs) | 
| Number of Participants With Physical Examination Findings | Physical examinations included body weight, height, body mass index (BMI) and assessment of body systems (e.g., head, eyes, ears, nose, throat, lungs, abdomen, and extremities) as well as cognitive and mental health examinations (components of the neurological and psychiatric examinations, respectively). | At Day 4 | 
| Number of Participants With Concomitant Medication Usage | Concomitant medications are other prescription medications, over the counter (OTC) drugs or dietary supplements that a study participant takes in addition to the drug under investigation. | Baseline up to Day 11 | 
| Number of Participants With Suicidal Ideation and Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) | C-SSRS 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 and behavior as well as numeric ratings for severity of ideation, (with score range from 1 to 5, higher score indicates more severity). The data was collected at time-points: Pre-infusion (Day 1 prior to dosing), Post-infusion (any time after the start of infusion on Day 1 up to 84 hrs). | Pre-infusion (Day 1 prior to dosing), Post-infusion (any time after the start of infusion on Day 1 up to 84 hrs) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of SAGE-547 |  | Predose (0 hrs), and 0.5, 1, 2, 3, 4, 6, 12, 24, 36, 40, 44, 48, 60, and 72 hrs post-dose | 
| Time to Maximum Plasma Concentration (Tmax) of SAGE-547 | Tmax is defined as the time at which Cmax of SAGE-547 occurred. | Predose (0 hrs), and 0.5, 1, 2, 3, 4, 6, 12, 24, 36, 40, 44, 48, 60, and 72 hrs post-dose | 
| Area Under the Concentration-Time Curve From Start of the Infusion Until the Time of the Last Sample (AUCall) of SAGE-547 | AUCall is defined as the area under the plasma SAGE-547 concentration time curves from the start of the infusion until the time the last sample was taken 72 hours later. | Predose (0 hrs), and 0.5, 1, 2, 3, 4, 6, 12, 24, 36, 40, 44, 48, 60, and 72 hrs post-dose | 
| Area Under the Concentration-Time Curve From Time Zero to 60 Hours (AUC0-60) of SAGE-547 | AUC0-60 is defined as the area under the plasma SAGE-547 concentration time curve during the intravenous infusion. | Predose (0 hrs), and 0.5, 1, 2, 3, 4, 6, 12, 24, 36, 40, 44, 48, and 60 hrs post-dose | 
| Area Under the Concentration-Time Curve in 24 Hours (AUC24) of SAGE-547 | AUC24 is defined as the area under the plasma SAGE-547 concentration-time curve in a 24-hour period during the maintenance dose. | Predose (0 hrs), and 0.5, 1, 2, 3, 4, 6, 12, and 24 hrs post-dose | 
| Average Drug Concentration in the Plasma at Steady State During a Dosing Interval (Cavg) of SAGE-547 | Cavg is defined as the plasma concentration of SAGE-547 at steady-state (average plasma concentration during the maintenance dose period; nominally 12 to 48 hrs). | From 12 to 48 hrs (36 hr of maintenance dose period) | 
| Plasma Clearance (CL) of SAGE-547 | Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. | Predose (0 hrs), and 0.5, 1, 2, 3, 4, 6, 12, 24, 36, 40, 44, 48, 60, and 72 hrs post-dose | 
| Change From Baseline in Hamilton Rating Scale for Depression-17 (HAM-D-17) Total Score | The HAM-D-17 was used to rate the severity of depression in participants who were already diagnosed as depressed. The HAM-D-17 is comprised of 17 individual items: 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, where 0 indicated none/absent and higher scores indicated greater depression. The Total Score can range from 0 (least depression) to 52 (greater depression), and 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 1 (12 hrs), Day 2 (at 24 and 36 hrs), Day 3 (at 48 and 60 hrs), and Day 4 (at 84 hrs) | 
| Clinical Global Impression-Improvement (CGI-I) Score | The CGI-I response was defined as having a score of 1 (very much improved) or 2 (much improved). CGI-I assessment employs a 7-point Likert scale to measure the improvement in the participant's condition. 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. | Day 1 (12 hrs), Day 2 (at 24 and 36 hrs), on Day 3 (at 48 and 60 hrs), and Day 4 (at 84 hrs) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postpartum depression