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  1. Development & Approval Process (Drugs)

Drug Trials Snapshots: ZULRESSO

Drug Trials Snapshots: ZULRESSO

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the ZULRESSO Package Insert for complete information.

ZULRESSO (brexanolone)
zul reh’ soe
Sage Therapeutics, Inc.
Approval date:March 19, 2019


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

ZULRESSO is a drug used to treat adult women with postpartum depression (an episode of major depression starting in the third trimester of pregnancy or within 4 weeks after delivery).

How is this drug used?

ZULRESSO is given as an intravenous infusion (injected into a vein) by a healthcare provider. The intravenous infusion takes about 60 hours (2 ½ days) to complete.

The dose depends on the patient’s weight.

What are the benefits of this drug?

In two trials, patients with moderate or severe postpartum depression who were given ZULRESSO, achieved more improvement of depressive symptoms than patients given placebo.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes efficacy results for the evaluated patients in the clinical trials. The primary endpoint was the mean change from baseline in the HAM-D total score at the end of the infusion (Hour 60).

Table 2. Results for the Primary Endpoint – HAM-D Total Score (Trials 1 and 2)

Trial Number

Treatment Group
 (# ITT subject)

Primary Endpoint: Change from Baseline in HAM-D Score at Hour 60

 

 

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Difference (95% CI)
Unadjusted p-value

1

ZULRESSO target dosage
90 mcg/kg/h (n=41) *
Placebo (n=43)

28.4 (2.5)

28.6 (2.5)

-17.7 (1.2)

-14.0 (1.1)

-3.7 (-6.9, -0.5)
P=0.0252

ZULRESSO target dosage
60 mcg/kg/h (n=38) *
Placebo (n=43)

29.0 (2.7)

28.6 (2.5)

-19.5 (1.2)

-14.0 (1.1)

-5.5 (-8.8, -2.2)
P=0.0013

2

ZULRESSO target dosage
90 mcg/kg/h (n=51) *
Placebo (n=53)

22.6 (1.6)

22.7 (1.6)

-14.6 (0.8)

-12.1 (0.8)

-2.5 (-4.5, -0.5)
P=0.0160

HAM-D: Hamilton depression rating scale; ITT: intention to treat; SD: standard deviation; LS: least squares; SE: standard error;

CI: confidence interval; *: statistically significant after multiplicity adjustments

ZULRESSO Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

  • Sex: All patients in the trial were women.
  • Race: ZULRESSO worked similarly in White and Black or African American patients. The number of patients in other races was limited; therefore, differences in how well ZULRESSO worked in other races could not be determined.
  • Age:ZULRESSO worked similarly in patients less than and older than 27 years of age. All patients were less than 65 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The tables below summarize efficacy results by race based on the mean change from baseline in the HAM-D total score at the end of the infusion (Hour 60).

Table 3. Least Squares Mean Difference between ZULRESSO and Placebo with 95% CI for Change-from-Baseline at Hour 60 in HAM-D Total Score: Trial 1

Subgroup

 

 

N

LS Mean Difference
(Zulresso - placebo)

LCLa

UCLb

Race

 White

60 mcg

25

-6.5

-10.2

-2.8

90 mcg

29

-2.9

-6.5

0.7

 Black or African American

60 mcg

12

-4.5

-10.7

1.6

90 mcg

8

-6.3

-13.1

0.6

      Other

60 mcg

1

13.6

-2.8

29.9

90 mcg

4

-4.8

-17.9

8.3

Age Group

     < 27 years

60 mcg

17

-2.5

-7.8

2.9

 

90 mcg

20

-1.5

-6.6

3.6

    > 27 years

60 mcg

21

-8.3

-12.4

-4.2

90 mcg

21

-5.9

-10.0

-1.8

a Upper Control Limit

b Lower Control Limit

FDA Review

Table 4. Least Squares Mean Difference between ZULRESSO (90 mcg) and Placebo with 95% CI for Change-from-Baseline at Hour 60 in HAM-D Total Score: Trial 2

Subgroup

 

 

N

LS Mean Difference
(Zulresso - placebo)

LCLa

UCLb

Overall

 

104

-2.5

-4.5

-0.5

Race

 White

62

-1.8

-4.6

0.9

 Black or African American

41

-2.7

-6.7

1.4

Age Group

      < 27 years

46

-1.9

-5.4

1.5

       > 27 years

58

-1.9

-5.0

1.1

a Upper Control Limit

b Lower Control Limit

FDA Review

What are the possible side effects?

ZULRESSO may cause serious side effects such as excess sleepiness and sudden loss of consciousness (unable to respond). Because of this risk ZULRESSO is available only through a restricted program called ZULRESSO REMS.

The most common side effects in the trials were sleepiness, dry mouth, loss of consciousness, and hot flashes.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions in patients with moderate to severe postpartum depression in the clinical trials.

Table 5. Table Adverse Reactions in Placebo-Controlled Studies of ZULRESSO in Patients with PPD Reported in ≥ 2% of ZULRESSO-Treated Patients and Greater than Placebo-Treated Patients

System Organ Class

Adverse Event

Placebo
(n=107)

ZULRESSO
60 mcg/kg/hour
(n=38)

ZULRESSO
90 mcg/kg/hour
(recommended dosage)
(n=102)

Cardiac Disorders

Tachycardia

 -

 -

3%

Gastrointestinal Disorders

Diarrhea

1%

3%

2%

Dry mouth

1%

11%

3%

Dyspepsia

-

-

2%

Oropharyngeal pain

-

3%

2%

Nervous System Disorders

Dizziness, presyncope, vertigo

7%

13%

12%

Loss of consciousness

-

5%

3%

Sedation, somnolence

6%

21%

13%

Vascular Disorders

Flushing, hot flush

-

5%

2%

ZULRESSO Prescribing Information

Were there any differences in side effects among sex, race and age?

  • Sex: All patients were women.
  • Race:The occurrence of side effects was similar in White and Black or African American patients. The number of patients in other races was limited; therefore, differences in the occurrence of side effects among other races could not be determined.
  • Age: The occurrence of side effects was similar in patients less than and older than 27 years of age. All patients were less than 65 years of age.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The tables below summarize the occurrence of the most common adverse reactions by race and age group in the safety population. Presented are African American women and White women only because the number of patients in other races was limited.

Table 6. Adverse Events Greater than 2% and Twice the Rate of Placebo by Treatment Group and by Race in Trials 1, 2, and 3.

Table 6: Adverse Events Greater than 2%...
FDA Review

*AA= African American/Black

FDA Review

Table 7. Adverse Events Greater than 2% and Twice the Rate of Placebo by Treatment Group; Breakdown by Median Age of Participants in Trials 1, 2, and 3.

Table 7 Adverse Events Greater than 2% and Twice the Rate...

FDA Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved ZULRESSO based on evidence from three clinical trials (Trial 1/NCT02942004, Trial 3/NCT02614541, Trial 2/ NCT02942017) of 247 women with moderate or severe postpartum depression. The trials were conducted in the United States.

The population that provided data for side effects of ZULRESSO (safety population) is presented below.

Figure 1 summarizes how many women were in the clinical trials used to evaluate safety.

Figure 1. Baseline Demographics by Sex

 

Figure 1: Baseline Demographics by Sex

FDA Review

Figure 2 summarizes the percentage of patients by race in the clinical trials used to evaluate safety.

Figure 2. Baseline Demographics by Race

Figure 2 Baseline Demographics by Race

*Other includes Asian, American Indian or Alsaka Native, and Native Hawaiian or Other Pacific Islander

FDA Review

Table 1. Demographics of Safety Trials by Race

Race

Number of Patients

Percentage of Patients

White

151

61%

Black or African American

89

36%

Asian

1

Less than 1%

American Indian or Alaska Native

1

Less than 1%

Native Hawaiian or Other Pacific Islander

1

Less than 1%

Other

4

2%

FDA Review

Figure 3 summarizes the percentage of patients by age group in the clinical trials used to evaluate safety.

Figure 3. Baseline Demographics by Age

Figure 3 Baseline Demographics by Age

FDA Review

Who participated in the trials?

The table below summarizes demographics of the patients in the combined clinical trials (safety population).

Table 8. Baseline Demographics for Trials 1, 2, and 3

Characteristic

ZULRESSO
60 mcg/kg/h
(n=38)
n (%)

ZULRESSO
90 mcg/kg/h
(n=102)
n (%)

Placebo
(n=107)
n (%)

Total
(n=247)
n (%)

Sex

     Women

38 (100.0%)

102 (100.0%)

107 (100.0%)

247 (100.0%)

Race

 White

25 (65.8%)

61 (59.8%)

65 (60.7%)

151 (61.1%)

 Black/African

12 (31.6%)

37 (36.3%)

40 (37.4%)

89 (36.0%)

     Asian

0 (0%)

1 (1.0%)

0 (0%)

1 (0.4%)

     American Indian or Alaska Native

0 (0%)

0

1 (0.9%)

1 (0.4%)

     Native Hawaiian or Other Pacific Islander

0 (0%)

1 (1.0%)

0 (0%)

1 (0.4%)

     Other

1 (2.6%)

2 (2.0%)

1 (0.9%)

4 (1.6%)

Age (years)

     Mean (SD)

27.7 (6.5)

27.7 (5.8)

27.8 (5.5)

27.7 (5.9)

     Median Age

27

27

27

27

     Minimum, Maximum

18, 42

19, 42

18, 44

18, 44

Age Group

     < 27 years

17 (44.7)

47 (46.1)

47 (43.9)

111 (44.9)

> 27 years

21 (55.3

55 (53.9)

60 (56.1)

136 (55.1)

     < 65 years

38 (100.0%)

102 (100.0%)

107 (100.0%)

247 (100.0%)

     > 65 years

0 (0%)

0 (0%)

0 (0%)

0 (0%)

Ethnicity

 Hispanic

3 (7.9%)

17 (16.7%)

21 (19.6%)

41 (16.6%)

 Non-Hispanic

35 (92.1%)

85 (83.3%)

86 (80.4%)

206 (83.4%)

Region

     United States

38 (100.0%)

102 (100.0%)

107 (100.0%)

247 (100.0%)

FDA Review

How were the trials designed?

The benefit of ZULRESSO was primarily evaluated in two clinical trials and the side effects in three clinical trials.

All trials enrolled patients 18 to 45 years old with postpartum depression who had an episode of major depression starting in the third trimester of pregnancy or within 4 weeks after delivering a baby. The investigator used the Hamilton Depression Rating Scale (HAM-D) to determine the patient’s level of depression. The HAM-D scores 8 items on a 5-point grading scale (0 = not present to 4 = severe) and 9 items on a 3-point grading scale (0 = not present to 2 = severe).

Trial 1 enrolled patients with severe postpartum depression (a HAM-D score of ≥26) and Trial 2 enrolled patients with moderate postpartum depression (a HAM-D score of 20 to 25). Patients in Trial 1 were randomized to receive a single 60-hour intravenous infusion of one of two doses of ZULRESSO or placebo. Patients in Trial 2 were randomized to receive a single dose of ZULRESSO or placebo through a 60-hour intravenous infusion. In both trials, neither the patients nor the health care providers knew which treatment was being given until after the trial was completed. The benefit of ZULRESSO was assessed in both trials by determining the improvement in depressive symptoms (the difference in HAM-D scores before and after treatment).

In Trial 3, patients with severe postpartum depression were randomized to receive a single dose of ZULRESSO or placebo through a 60-hour intravenous infusion. Neither the patients nor the health care providers knew which treatment was being given until after the trial was completed. Assessment of side effects included data from Trial 3.

How were the trials designed?

ZULRESSO was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult women (18 to 45 years) with postpartum depression (PPD) who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode (DSM-IV) with onset of symptoms in the third trimester or within 4 weeks of delivery.

The benefit of ZULRESSO was assessed in Trials 1 and 2. Safety was assessed using Trials 1, 2, and 3.

Trial 1 included patients with severe PPD (Hamilton Depression Rating Scale [HAM-D score > 26], and Trial 2 included patients with moderate PPD (Hamilton Depression Rating Scale [HAM-D score of 20 to 25]. Patients in Trial 1 were randomized to receive a 60-hour intravenous infusion of ZULRESSO 90 mcg/kg/hr or placebo. Patients in Trial 2 were randomized to receive a 60-hour intravenous infusion of ZULRESSO 90 mcg/kg/hr, ZULRESSO 60 mcg/kg/hr, or placebo. The primary efficacy endpoint was the mean change from baseline in the HAM-D total score at the end of the infusion (Hour 60).

Trial 3 included patients with severe PPD (Hamilton Depression Rating Scale [HAM-D score > 26]. Patients were randomized to receive a 60-hour intravenous infusion of ZULRESSO 90 mcg/kg/hr or placebo. Assessment of side effects included data from Trial 3.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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