Post Partum Depression
Conditions
Brief summary
This is a multi-center study evaluating the safety, tolerability, and pharmacokinetics of brexanolone in the treatment of adolescent female participants with postpartum depression (PPD).
Interventions
DRUGBrexanolone
Administered as IV infusion.
Sponsors
Supernus Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Participant has 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 Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Axis I Disorders (SCID-5). 2. Participant is ≤6 months postpartum at screening. Key
Exclusion criteria
1. Active psychosis 2. Attempted suicide during current episode of PPD 3. Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder. Note: Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug up to end of follow-up period (up to Day 30) | An adverse event (AE) is 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 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC From Time Zero to Infinity (AUCinf) | Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion) | — |
| Maximum (Peak) Plasma Concentration (Cmax) | Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion) | — |
| Time at Maximum (Peak) Plasma Concentration (Tmax) | Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion) | — |
| Steady-State Drug Concentration in the Plasma During Constant-Rate Infusion (Css) | Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion) | Given that brexanolone is infused to steady-state plasma concentrations, the model-predicted steady-state drug concentration in the plasma during constant-rate infusion value also represents the predicted maximum plasma concentration at the highest infused dose (90 ug/kg/h). |
| Area Under the Concentration-Time Curve (AUC) From Time Zero to 60 Hours (AUC0-60) | Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion) | — |
| Half-Life of First Elimination Phase of Brexanolone (Thalf) | Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion) | Half-life is the time required for half of the drug to be eliminated from the serum. |
| Clearance of Brexanolone (CL/F) | Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion) | Clearance is defined as the volume of plasma from which a substance is completely removed per unit time. |
| Steady-State of Volume of Distribution (Vss) | Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
| Average Drug Concentration in Plasma at Steady State During a Dosing Interval (Cavg) | Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion) | Cavg was evaluated as the time-weighted average plasma concentrations of brexanolone over the interval. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 8 investigating sites in the United States, from 07 September 2018 to 08 January 2021.
Pre-assignment details
As per Protocol Versions 1 through 3, the study was initiated as a double-blind, placebo-controlled study, in which participants received brexanolone or brexanolone-matching placebo in a blinded manner. As per Protocol Version 4, the study was transitioned to an open-label study, where all participants received brexanolone.
Participants by arm
| Arm | Count |
|---|---|
| Double-Blind Phase: Placebo Participants received a 60-hour single continuous IV infusion of brexanolone-matching placebo, at 30 mcg/kg/hour (0 to 4 hours), at 60 mcg/kg/hour (4 to 24 hours), at 90 mcg/kg/hour (24 to 52 hours), followed by a taper to 60 mcg/kg/hour (52 to 56 hours), and 30 mcg/kg/hour (56 to 60 hours) during double-blind phase of the study. | 8 |
| Double-Blind Phase: Brexanolone Participants received a 60-hour single continuous IV infusion of brexanolone, at 30 mcg/kg/hour (0 to 4 hours), at 60 mcg/kg/hour (4 to 24 hours), at 90 mcg/kg/hour (24 to 52 hours), followed by a taper to 60 mcg/kg/hour (52 to 56 hours), and 30 mcg/kg/hour (56 to 60 hours) during double-blind phase of the study. | 8 |
| Open-Label Phase: Brexanolone Participants received a 60-hour single continuous IV infusion of brexanolone, at 30 mcg/kg/hour (0 to 4 hours), at 60 mcg/kg/hour (4 to 24 hours), at 90 mcg/kg/hour (24 to 52 hours), followed by a taper to 60 mcg/kg/hour (52 to 56 hours), and 30 mcg/kg/hour (56 to 60 hours) during open-label phase of the study. | 12 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Double-Blind Phase: Placebo | Double-Blind Phase: Brexanolone | Open-Label Phase: Brexanolone | Total |
|---|---|---|---|---|
| Age, Continuous | 16.6 years STANDARD_DEVIATION 0.52 | 16.4 years STANDARD_DEVIATION 0.52 | 16.3 years STANDARD_DEVIATION 0.78 | 16.4 years STANDARD_DEVIATION 0.63 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 6 Participants | 12 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 6 Participants | 10 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 12 Participants | 28 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 12 |
| other Total, other adverse events | 4 / 8 | 3 / 8 | 4 / 12 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 1 / 12 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) is 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 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.
Time frame: From first dose of study drug up to end of follow-up period (up to Day 30)
Population: The safety set included all participants administered study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Double-Blind Phase: Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 4 Participants |
| Double-Blind Phase: Brexanolone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
| Open-Label Phase: Brexanolone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 5 Participants |
Secondary
Area Under the Concentration-Time Curve (AUC) From Time Zero to 60 Hours (AUC0-60)
Time frame: Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion)
Population: The pharmacokinetic (PK) set included participants in the safety set for whom at least one evaluable post-baseline PK sample with a measurable brexanolone concentration was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Phase: Placebo | Area Under the Concentration-Time Curve (AUC) From Time Zero to 60 Hours (AUC0-60) | 3694.9 hours*nanograms per milliliter(hr*ng/mL) | Standard Deviation 397.9 |
| Double-Blind Phase: Brexanolone | Area Under the Concentration-Time Curve (AUC) From Time Zero to 60 Hours (AUC0-60) | 3516.0 hours*nanograms per milliliter(hr*ng/mL) | Standard Deviation 562.85 |
Secondary
AUC From Time Zero to Infinity (AUCinf)
Time frame: Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion)
Population: The PK set included participants in the safety set for whom at least one evaluable post-baseline PK sample with a measurable brexanolone concentration was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Phase: Placebo | AUC From Time Zero to Infinity (AUCinf) | 4125.9 hr*ng/mL | Standard Deviation 481.84 |
| Double-Blind Phase: Brexanolone | AUC From Time Zero to Infinity (AUCinf) | 3982.2 hr*ng/mL | Standard Deviation 709.7 |
Secondary
Average Drug Concentration in Plasma at Steady State During a Dosing Interval (Cavg)
Cavg was evaluated as the time-weighted average plasma concentrations of brexanolone over the interval.
Time frame: Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion)
Population: The PK set included participants in the safety set for whom at least one evaluable post-baseline PK sample with a measurable brexanolone concentration was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Phase: Placebo | Average Drug Concentration in Plasma at Steady State During a Dosing Interval (Cavg) | 61.59 ng/mL | Standard Deviation 6.639 |
| Double-Blind Phase: Brexanolone | Average Drug Concentration in Plasma at Steady State During a Dosing Interval (Cavg) | 58.60 ng/mL | Standard Deviation 9.386 |
Secondary
Clearance of Brexanolone (CL/F)
Clearance is defined as the volume of plasma from which a substance is completely removed per unit time.
Time frame: Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion)
Population: The PK set included participants in the safety set for whom at least one evaluable post-baseline PK sample with a measurable brexanolone concentration was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Phase: Placebo | Clearance of Brexanolone (CL/F) | 66.86 liters per hour (L/hr) | Standard Deviation 13.858 |
| Double-Blind Phase: Brexanolone | Clearance of Brexanolone (CL/F) | 77.88 liters per hour (L/hr) | Standard Deviation 18.026 |
Secondary
Half-Life of First Elimination Phase of Brexanolone (Thalf)
Half-life is the time required for half of the drug to be eliminated from the serum.
Time frame: Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion)
Population: The PK set included participants in the safety set for whom at least one evaluable post-baseline PK sample with a measurable brexanolone concentration was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Phase: Placebo | Half-Life of First Elimination Phase of Brexanolone (Thalf) | 12.24 hour | Standard Deviation 0.466 |
| Double-Blind Phase: Brexanolone | Half-Life of First Elimination Phase of Brexanolone (Thalf) | 12.55 hour | Standard Deviation 1.096 |
Secondary
Maximum (Peak) Plasma Concentration (Cmax)
Time frame: Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion)
Population: The PK set included participants in the safety set for whom at least one evaluable post-baseline PK sample with a measurable brexanolone concentration was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Phase: Placebo | Maximum (Peak) Plasma Concentration (Cmax) | 85.31 nanograms per milliliter (ng/mL) | Standard Deviation 9.571 |
| Double-Blind Phase: Brexanolone | Maximum (Peak) Plasma Concentration (Cmax) | 81.66 nanograms per milliliter (ng/mL) | Standard Deviation 13.528 |
Secondary
Steady-State Drug Concentration in the Plasma During Constant-Rate Infusion (Css)
Given that brexanolone is infused to steady-state plasma concentrations, the model-predicted steady-state drug concentration in the plasma during constant-rate infusion value also represents the predicted maximum plasma concentration at the highest infused dose (90 ug/kg/h).
Time frame: Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion)
Population: The PK set included participants in the safety set for whom at least one evaluable post-baseline PK sample with a measurable brexanolone concentration was available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind Phase: Placebo | Steady-State Drug Concentration in the Plasma During Constant-Rate Infusion (Css) | 79.4 ng/mL |
| Double-Blind Phase: Brexanolone | Steady-State Drug Concentration in the Plasma During Constant-Rate Infusion (Css) | 79.4 ng/mL |
Secondary
Steady-State of Volume of Distribution (Vss)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion)
Population: The PK set included participants in the safety set for whom at least one evaluable post-baseline PK sample with a measurable brexanolone concentration was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Phase: Placebo | Steady-State of Volume of Distribution (Vss) | 448.1 liters (L) | Standard Deviation 70.34 |
| Double-Blind Phase: Brexanolone | Steady-State of Volume of Distribution (Vss) | 588.5 liters (L) | Standard Deviation 187.53 |
Secondary
Time at Maximum (Peak) Plasma Concentration (Tmax)
Time frame: Day 1: From 0 hour (pre-infusion) and at 4, 8, 12, 24, 30, 36, 48 hours during the infusion; at 60 hours (end of infusion)
Population: The PK set included participants in the safety set for whom at least one evaluable post-baseline PK sample with a measurable brexanolone concentration was available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Double-Blind Phase: Placebo | Time at Maximum (Peak) Plasma Concentration (Tmax) | 52.20 hour (hr) |
| Double-Blind Phase: Brexanolone | Time at Maximum (Peak) Plasma Concentration (Tmax) | 52.30 hour (hr) |