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  1. Development & Approval Process (Drugs)

Drug Trials Snapshots: REXULTI for the treatment of major depressive disorder

Drug Trials Snapshots: REXULTI for the treatment of major depressive disorder

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 REXULTI Prescribing Information for complete information.

REXULTI (brexpiprazole)
(REX-ul-TE)
Otsuka America Pharmaceuticals, Inc.
Approval date: July 10, 2015


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

REXULTI is a drug for the treatment of major depressive disorder (MDD). In a patient who is already taking a medication for depression that is not adequately treating their symptoms, REXULTI can be added on to improve symptoms.

MDD, commonly referred to as depression, is a brain disorder characterized by mood changes and other symptoms that interfere with a person's ability to work, sleep, study, eat and enjoy once-pleasurable activities.

How is this drug used?

REXULTI is a tablet that is taken once a day.

What are the benefits of this drug?

REXULTI improved symptoms of depression.

What are the benefits of this drug?

The table below summarizes the primary efficacy endpoints for both trials. This was based on the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) score after 6 weeks. The population represents Efficacy population which includes all subjects in the Safety population who had at least one post-randomization efficacy evaluation for MADRS Total Score.

Table 2. Summary of Efficacy Results for Trials 1 and 2

Trial Treatment Group N Primary Efficacy Measure: MADRS
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo –subtracted Difference a  (95% CI)
1 REXULTI (2mg/day)+ADT*
Placebo +ADT
175
178
26.9 (5.7)
27.3 (5.6)
-8.4 (0.6)
-5.2 (0.6)
-3.2 (-4.9, -1.5)
     -
2 REXULTI (1mg/day)+ADT
REXULTI (3mg/day)+ADT
Placebo +ADT
211
213
203
26.5 (5.6)
26.5 (5.3)
26.5 (5.2)
7.6 (0.5)
-8.3 (0.5)
-6.3 (0.5)
1.3 (-2.7, 0.13)
- 2.0 (-3.4, -0.5)
     -

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval; ADT: antidepressant
* Dosages statistically significantly superior to placebo.
a Difference (drug minus placebo) in least-squares mean change from baseline.
Source: REXULTI Prescribing Information Section 14, Table 11

 

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

Subgroup analyses were conducted for sex, race, and age.

  • Sex: REXULTI worked similarly in men and women.
  • Race: REXULTI worked similarly in all races studied.
  • Age: REXULTI worked similarly in all age groups studied.

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

The tables below summarize the responses to REXULTI for the populations in pooled trials. The population represents Efficacy population which includes all subjects in the Safety population who had at least one post-randomization efficacy evaluation for MADRS Total Score.

Table 3. Subgroup Analysis of Primary Endpoint, Pivotal Efficacy Trials (pooled data from 2 trials)

Subgroup REXULTI 2 and 3 mg Placebo LSMD
95% CI
(LL,UL)
MADRS Total Score at Baseline
Mean (SD)
Change in MADRS Total Score
LS Mean (SE)
N MADRS Total Score at Baseline
Mean (SD)
Change in MADRS Total Score LS Mean (SE) N
Overall Response/All patients 26.66
(5.48)
-8.29
(0.42)
388 26.86
(5.42)
-5.76
(0.41)
381 -2.53
(-3.63,1.43)
Sex
Male 26.68
(5.10)
-8.41
(0.70)
122 26.89
(5.35)
-5.78
(0.69)
123 -2.63
(-4.56,-0.69)
Female 26.65
(5.65)
-7.87 (0.47) 266 26.85
(5.47)
-5.55
(0.48)
258 -2.32
(-3.64,-1.00)
Age Group
>=17 - <40> 27.10
(5.22)
-8.6 (0.70) 128 26.69
(5.33)
-5.05
(0.74)
108 -3.54
(-5.55,-1.54)
>=40 - <65> 26.45
(5.60)
-7.77
(0.47)
259 26.88
(5.48)
-5.79
(0.47)
270 -1.98
(-3.29,-0.68)
>=65 years 24.00 (0) NA 1 31.33
(1.53)
NA 3 NA
Race
White 26.59
(5.46)
-8.14
(0.42)
339 26.78
(5.37)
-5.80
(0.42)
328 -2.34
(-3.51,-1.17)
Black or African American 26.32
(5.67)
-6.40
(1.18)
37 27.26
(5.96)
-4.36
(1.05)
46 -2.05
(-5.19,1.10)
Asian 30.00 (0) NA 1 27.50
(3.54)
NA 2 NA
American Indian or Alaska Native 33.00
(4.76)
NA 4 28.00 (0) NA 1 NA
Other 27.67
(4.97)
NA 6 27.00
(6.56)
NA 3 NA

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; LSMD: least-squares mean difference; CI: unadjusted confidence interval, NA not analyzed
Source: Company Clinical Trial Data

What are the possible side effects?

The most common side effects were weight gain and an inner sense of restlessness, which patients commonly describe as feeling the need to move.

REXULTI can raise the risk of death in elderly who have lost touch with reality (psychosis) due to confusion and memory loss (dementia).

REXULTI may increase suicidal thoughts or actions in teenagers, or young adults within the first few months of treatment.

What are the possible side effects?

The table below summarizes adverse reactions for the two pooled trials. The population represents Safety population, which includes any patient who received at least one dose of trial drug.

Table 4. Adverse Events during Treatment in the Pooled Trials

  Placebo
(N=411)
REXULTI
1 mg/day
(N=226)
2 mg/day
(N=188)
3 mg/day
(N=229)
All
REXULTI#
(N=643)
Gastrointestinal Disorders
Constipation 1% 3% 2% 1% 2%
General Disorders and Administration Site Conditions
Fatigue 2% 3% 2% 5% 3%
Infections and Infestations
Nasopharyngitis 2% 7% 1% 3% 4%
Investigations
Weight Increased 2% 7% 8% 6% 7%
Blood Cortisol Decreased 1% 4% 0% 3% 2%
Metabolism and Nutrition
Increased Appetite 2% 3% 3% 2% 3%
Nervous System Disorders
Akathisia 2% 4% 7% 14% 9%
Headache 6% 9% 4% 6% 7%
Somnolence 0.5% 4% 4% 6% 5%
Tremor 2% 4% 2% 5% 4%
Dizziness 1% 1% 5% 2% 3%
Psychiatric Disorders
Anxiety 1% 2% 4% 4% 3%
Restlessness 0% 2% 3% 4% 3%

* Adverse reactions that occurred in ≥ 2% of REXULTI-treated patients and at a greater incidence than in placebo-treated patients
# Dose groups included in ALL treatment groups were 1mg, 2mg, and 4 mg
Source: REXULTI Prescribing Information, Section 6 Table 8

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

Subgroup analyses were conducted for sex, race, and age.

  • Sex: The risk of overall side effects appeared to be similar in men and women.
  • Race: The risk of overall side effects appeared to be similar in all races studied.
  • Age: The risk of overall side effects appeared to be similar in all age groups studied.

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

The table below summarizes adverse events in the pooled trials by subgroups. The population represents Safety population, which includes any patient who received at least one dose of trial drug.

Table 5. Subgroup Analysis of Adverse Events during Treatment in the Pooled Trials

Subgroup ALL REXULTI Placebo Relative Risk 95% CI
x (%) Total, n x (%) Total, n LL UL
Any TEAEs* 380 (59) 643 192 (47) 411 1.27 1.12 1.43
Sex
Male 103 (52) 199 54 (42) 129 1.24 0.97 1.58
Female 277 (62) 444 138 (49) 282 1.27 1.11 1.47
Age Group
>=17 - <40> 118 (61) 193 57 (50) 113 1.21 0.98 1.50
>=40-<65> 261 (58) 447 133 (45) 294 1.29 1.11 1.50
>=65 1 (33) 3 2 (50) 4 0.67 0.10 4.35
Race
White 330 (60) 547 160 (45) 353 1.33 1.17 1.52
Black or African
American
40 (53) 75 28 (55) 51 0.97 0.70 1.35
Asian 2 (29) 7 2 (100) 2 0.29 0.09 0.92
American Indian or
Alaska Native
3 (60) 5 1 (100) 1 0.60 0.29 1.23
Other 4 (50) 8 1 (33) 3 1.50 0.26 8.58

*TEAEs=treatment emergent adverse events
Source: Company Clinical Trial Data

WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved REXULTI based on evidence from two clinical trials of 1054 patients with MDD. The trials were conducted in the United States, Canada, and Europe.

The figure below summarizes how many men and women participated in the clinical trials. The population represents the Safety population (1054 patients), which includes any patient who received at least one dose of trial drug.

Figure 1. Baseline Demographics by Sex

Figure 1. Baseline Demographics by Sex REXULTI

Source: Company Clinical Trial Data

The figure and table below summarize how many patients by race participated in the clinical trials. The population represents the Safety population (1054 patients), which includes any patient who received at least one dose of trial drug.

Figure 2. Baseline Demographics by Race

Bar chart summarizing the percentage of patients by race enrolled in the REXULTI clinical trial. In total, 900 White (85%), 126 Black (12%), 9 Asian (1%), 6 American Indian or Alaska Native (1%), 11 identified as Other (1%), and 2 could not be identified (less than 1%).

*=defined as any race not included in other categories
Source: Company Clinical Trial Data

Table 1. Baseline Demographics by Race

Race Number of Patients Percentage of Patients
White 900 85%
African American 126 12%
Asian 9 1%
American Indian or Alaska Native 6 1%
Other* 11 1%
Unknown 2 less than 1%

*= defined as any race not included in other categories
Source: Company Clinical Trial Data

The figure below summarizes how many patients by age participated in the clinical trials. The population represents the Safety population (1054 patients), which includes any patient who received at least one dose of trial drug.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were enrolled in the REXULTI clinical trial.  In total, 1047 were between 18 and 64 years (99%) and 7 were 65 years and older (30%).

Source: Company Clinical Trial Data

Who participated in the trials?

The table below summarizes baseline demographics for the population that participated in the two trials. The population represents Safety population (1054 patients), which includes any patient who received at least one dose of trial drug.

Table 6. Baseline Demographics for the Trials

Demographic Parameters Treatment Groups Placebo
(N=411)
n (%)
Total
(N=1054)
n (%)
REXULTI
1 mg
(N=226)
n (%)
REXULTI
2 mg
(N=188)
n (%)
REXULTI
 3 mg
(N=229)
n (%)
Sex
Male 68 (30) 58 (31) 73 (32) 129 (31) 328 (31)
Female 158 (70) 130 (69) 156 (68) 282 (69) 726 (69)
Age
Mean years (SD) 45.7 (11.6) 44.1 (11.6) 44.6 (11.2) 45.9 (11.2) 45.3 (11.4)
Median (years) 48 44 46 47 46
Min, Max (years) 19, 65 18,65 18, 64 18, 65 18, 65
Age Group
>=17 - <40> 57 (25) 66 (35) 70 (31) 113 (27) 306 (29)
>=40-<65> 168 (74) 120 (64) 159 (69) 294 (72) 741 (70)
>=65 1 (<> 2 (1) 0 4 (1) 7 (1)
Race
White 183 (81) 163 (87) 201 (87) 353 (86) 900 (85)
Black or African American 34 (15) 19 (10) 22 (10) 51 (12) 126 (12)
Asian 6 (3) 1 (<> 0 2 (1) 9 (1)
American Indian or
Alaska Native
1 (<> 1 (1) 3 (1) 1 (<> 6 (1)
Other 2 (1) 3 (2) 3 (1) 3 (1) 11 (1)
Unknown 0 1 (<> 0 1 (<> 2 (<>
Ethnicity
Hispanic or Latino 13 (6) 20 (11) 14 (6) 34 (8) 81 (8)
Not Hispanic or Latino 213 (94) 162 (86) 213 (93) 372 (91) 960 (91)
Unknown 0 (0) 6 (3) 2 (1) 5 (1) 13 (1)
Region
United States 148 (65) 125 (67) 148 (64) 274 (67) 695 (66)
Canada 4 (2) 14 (7) 6 (3) 19 (5) 43 (4)
Europe 74 (33) 49 (26) 75 (33) 118 (28) 316 (30)

Source: Company Clinical Trial Data

How were the trials designed?

There were two trials that evaluated the benefit and side effects of REXULTI. In each trial, patients were randomly assigned to receive either REXULTI or placebo once daily for 6 weeks in addition to the antidepressant medication that they were already taking. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed.

The trials measured overall improvement in the symptoms of depression.

How were the trials designed?

Two randomized, placebo-controlled trials were conducted in adults with MDD (with or without symptoms of anxiety) who had an inadequate response to prior antidepressant therapy. Patients were treated with RELUXI or placebo as an adjunctive treatment to the antidepressant for 6 weeks.

The primary endpoint was the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-related scale used to assess the degree of depressive symptomatology.

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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