This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study
of the efficacy, safety, and pharmacokinetics of SAGE-547 Injection in adult female
participants diagnosed with severe postpartum depression.

A Study to Evaluate SAGE-547 in Participants With Severe Postpartum Depression

Severe Postpartum Depression

Placebo

SAGE-547

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

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. A negative change from baseline indicates less depression.
A positive change from baseline indicates more depression.

The HAM-D response was defined as having a 50 percent (%) 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. A negative change from baseline indicates less
depression. A positive change from baseline indicates more depression.

The HAM-D remission was defined as having a HAM-D total score of less than or equal to
(<=)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. A negative change from baseline indicates less depression.
A positive change from baseline indicates more depression.

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 indicate more severe depression. A
negative change from baseline indicate less severe depression. A positive change from
baseline indicates more severe depression.

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, and by definition, was evaluated
against baseline conditions. CGI-I response was defined as having a CGI-I score of "very
much improved" or "much improved".

The HAM-D Bech 6 subscale score was calculated as the sum of the following six items:
depressed mood, feelings of guilt, work and activities, retardation, psychic anxiety, and
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 scale
of 0 to 100, 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.

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.

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.

An adverse event (AE) was defined as any untoward medical occurrence in a clinical
investigation participant administered a drug; it did 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 TEAE was 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.

Participants received infusion rates of placebo matched to SAGE-547.

Participants received a 4-hour dose titration of 30 micrograms per kilogram per hour
(micrograms/kg/hr) (0 to 4 hours), then 60 micrograms/kg/hr (4 to 24 hours), then 90
micrograms/kg/hr (24 to 52 hours), followed by a taper to 60 micrograms/kg/hr (52 to 56
hours), and 30 micrograms/kg/hr (56 to 60 hours).

This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of
      the efficacy, safety, and pharmacokinetics of SAGE-547 Injection in adult female participants
      diagnosed with severe postpartum depression.

Sage Investigational Site

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. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

The HAM-D response was defined as having a 50 percent (%) 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. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

The HAM-D remission was defined as having a HAM-D total score of less than or equal to (<=)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. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

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 indicate more severe depression. A negative change from baseline indicate less severe depression. A positive change from baseline indicates more severe depression.

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, and by definition, was evaluated against baseline conditions. CGI-I response was defined as having a CGI-I score of "very much improved" or "much improved".

The HAM-D Bech 6 subscale score was calculated as the sum of the following six items: depressed mood, feelings of guilt, work and activities, retardation, psychic anxiety, and 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 scale of 0 to 100, 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.

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.

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.

An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it did 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 TEAE was 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.

Participants received a 4-hour dose titration of 30 micrograms per kilogram per hour (micrograms/kg/hr) (0 to 4 hours), then 60 micrograms/kg/hr (4 to 24 hours), then 90 micrograms/kg/hr (24 to 52 hours), followed by a taper to 60 micrograms/kg/hr (52 to 56 hours), and 30 micrograms/kg/hr (56 to 60 hours).

A Study to Evaluate SAGE-547 in Participants With Severe Postpartum Depression

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