Primary Endpoint
Adding REXULTI® (brexpiprazole) amplified
antidepressant symptom response vs placebo when taken with an antidepressant
Change in MADRS from Baseline at Week 6 in Adult Patients for Adjunctive
Treatment of MDD (Study 1 and Study 2)1
Change in MADRS from Baseline at Week 6 in Adult Patients for Adjunctive
Treatment of MDD (Study 1 and Study 2)1
Change from Baseline in MADRS Total Score by Study Visit (Week) In
Patients with MDD in Adults (Study 1)1
Change from Baseline in MADRS Total Score by Study Visit (Week) In
Patients with MDD in Adults (Study 1)1
It is unknown if the differences observed at time points earlier than Week 6 represent clinically relevant treatment effects.
Mean MÅDRS before prospective treatment (SD): 31.0 (4.7). Mean MÅDRS after prospective treatment (SD): 27.1 (5.7). Mean MÅDRS at randomization (SD): ADT + placebo (n=178), 27.3 (5.6); ADT + REXULTI 2 mg/day (n=175), 26.9 (5.7).2
MDD study design and efficacy summary
REXULTI was studied in two 6-week, double-blind, placebo-controlled, fixed-dose pivotal trials of adult patients meeting DSM-IV-TR criteria for MDD. After a screening phase of 1-4 weeks, patients entered into an 8-week prospective treatment phase with an SSRI or SNRI (+ single-blind placebo). Subsequently, patients having persistent symptoms without substantial improvement throughout the course of treatment and who met inclusion criteria were randomized to receive adjunctive REXULTI or placebo.3,4
Primary endpoint was the mean change from baseline to Week 6 in the MÅDRS total score in the randomization phase.3,4
In the second pivotal trial, at the 3 mg/day maximum dose, the mean change from baseline (SE) at 6 weeks (randomized phase) was -8.3 (0.5) for ADT + REXULTI (n=213) vs -6.3 (0.5) for ADT + placebo (n=203), and the MÅDRS baseline (SD) for ADT + REXULTI and ADT + placebo was 26.5 (5.3) and 26.5 (5.2), respectively.4
Full study design
REXULTI® (brexpiprazole)—full MDD study design
Screening—patients with partial response to antidepressant treatment entered the clinical trial with1,4:
- Partial response to 1 to 3 courses of antidepressant treatment in current episode
- MDD ≥8 weeks’ duration
- HAM-D17 score ≥18
- <50% reduction in symptoms via ATRQ
Study 1 (N=1227), Study 2 (N=2310)
Prospective phase—clinical investigators initiated a different antidepressant treatment (+ single-blind placebo) at optimal dose and duration to confirm persistent partial response1,4,a
SSRIs
Escitalopram
Sertraline
Paroxetine CR
Fluoxetine
10 or 20 mg/day
100, 150, or 200 mg/day
37.5 or 50 mg/day
20 or 40 mg/day
SNRIs
Duloxetine DR
Venlafaxine XR
40 or 60 mg/day
75, 150, or 225 mg/day
Study 1 (N=826), Study 2 (N=1532)1,4
Randomized double-blind phase—patients with confirmed partial response were randomized to add REXULTI or remain on antidepressant treatment alone (+ placebo)1,4
ADT + REXULTI
2 mg/day (n=175)c
ADT + Placebo
(n=178)c
ADT + REXULTI
3 mg/day (n=213)c
ADT + Placebo
(n=203)c
Study 1 (N=826), Study 2 (N=1532)1,4
- Titration—all patients randomized to REXULTI initiated treatment at 0.5 mg/day during Week 1. At Week 2, the REXULTI dose was increased to 1 mg/day and either maintained at 1 mg/day or increased to 2 mg/day or 3 mg/day, based on treatment assignment, from Week 3 onward
- Primary endpoint—change from baseline to Week 6 in MÅDRS in the randomization phase3,4
MÅDRS
clinician-rated
symptoms5:
- Apparent sadness
- Reported sadness
- Lassitude
- Inability to feel
- Inner tension
- Inner tension
- Reduced appetite
- Reduced sleep
- Concentration difficulties
- Pessimistic thoughts
- Suicidal thoughts
- Pessimistic thoughts
- Suicidal thoughts
aInclusion criteria for the randomized phase: <50% reduction in HAM-D17 Total Score and ≥14 HAM-D17 score at Week 8 of the prospective phase; <50% reduction in MÅDRS Total Score and Clinical Global Impression-Improvement Score of ≥3 at each scheduled visit of the prospective phase.3,4
bThe efficacy and safety of REXULTI 1 mg/day were also studied in Study 2 (n=211).
cn values represent efficacy population per final protocol.3,4
ATRQ, Antidepressant Treatment Response Questionnaire; CR, controlled release; DR, delayed release; HAM-D17, 17-Item Hamilton Depression Rating Scale; MÅDRS, Montgomery-Åsberg Depression Rating Scale; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; XR, extended release.
The efficacy and safety of REXULTI were also studied in patients randomized to receive 1 mg/day in Study 2 (n=211). Results for the ADT + REXULTI 1 mg group for the primary efficacy parameter were not statistically significant when compared with ADT + placebo.4
ADT, antidepressant treatment; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Text Revision); MÅDRS, Montgomery-Åsberg Depression Rating Scale; SD, standard deviation; SE, standard error; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
Contraindication
In patients with known hypersensitivity to brexpiprazole or any of its components. Reactions have included: rash, facial swelling, urticaria and anaphylaxis.
Additional Analysis
REXULTI® (brexpiprazole) + ADT separated from ADT + placebo as early as Week 1 and continued to Week 63
The weekly time points prior to Week 6 were not powered for statistical comparison and are descriptive only. Primary endpoint was the mean change from baseline to Week 6 in the MÅDRS total score in the randomization phase.
Mean change from baseline in MÅDRS total scorea,b
aBaseline mean MÅDRS scores were 27.3 for ADT + placebo (n=178) and 26.9 for ADT + REXULTI (n=175).
bp values are based on mixed model repeated-measures analysis.
*p=nominal.
ADT, antidepressant treatment; LS, least squares; MÅDRS, Montgomery-Åsberg Depression Rating Scale.
Secondary Endpoint
REXULTI® (brexpiprazole) SDS data from a pooled analysis of three 6-week randomized studies in adult patients with MDD
SDS functioning data for adult patients treated with REXULTI + ADT vs ADT + placebo6
The results require cautious interpretation as the statistical hierarchical testing procedure was terminated after the primary endpoint test.
The key secondary endpoint was change from baseline to Week 6 in SDS mean score across all studies.6
In 2 mg/day or 3 mg/day arms, the mean change in SDS total score from baseline (SE) at Week 6 was -1.43 (0.09) for ADT + REXULTI (N=555) vs -1.03 (0.09) for ADT + placebo (N=564).
Sheehan Disability Scale (SDS):
The SDS measures functional disability on 3 items:
- Work/studies
- Social life
- Family life
Patients use visual scales to rate the extent to which each of the 3 items has been disrupted by their symptoms from 0 to 10.7
ADT, antidepressant treatment; LE, latest estimate; LS, least squares; MDD, major depressive disorder; SD, standard deviation; SDS, Sheehan Disability Scale; SE, standard error.
Post-hoc analysis
REXULTI® (brexpiprazole) + ADT change in MÅDRS total score in adult patients with MDD—with or without symptoms of anxiety
Using pooled data from 3 similarly designed 6-week randomized studies, including both 2 mg and 3 mg doses, changes were evaluated in MÅDRS total score in patients with MDD—with and without symptoms of anxiety.3,4,8,a,b
Effect on MÅDRS total score in patients with MDD, stratified
by the presence or absence of symptoms of anxiety at baseline:
Patients with MDD with symptoms of anxiety
Patients with MDD without symptoms of anxiety
Effect on MÅDRS total score in patients with MDD, stratified by the presence or absence of symptoms of anxiety at baseline:
Patients with MDD with symptoms of anxiety
Patients with MDD without symptoms of anxiety
Study limitations: These analyses did not assess the effect of treatment on symptoms of anxiety. Patients with anxiety symptoms had a higher MÅDRS total score at baseline and the effects of anxiety and illness severity on outcomes were not differentiated. Statistical adjustments were not made for multiple comparisons, potentially inflating the type 1 error rate.
Adding REXULTI reduced mean MÅDRS total score by over 2 points in patients with MDD with or without symptoms of anxiety:
- For patients with symptoms of anxiety, the LS mean change at Week 6 between ADT + REXULTI 2-3 mg/day and ADT + placebo was -2.19 (95% CI: -3.60 to -0.78)8
- For patients without symptoms of anxiety, the LS mean change at Week 6 between ADT + REXULTI 2-3 mg/day and ADT + placebo was -2.34 (95% CI: -3.58 to -1.10)8
aBaseline demographics and clinical characteristics were similar between treatment subgroups; however, patients with symptoms of anxiety were more likely to be female and have a higher MÅDRS total score at baseline compared with patients without symptoms of anxiety.8
bOf the patients that received an ADT plus REXULTI 2 mg, 3 mg, or placebo, 49% had symptoms of anxiety, defined as a score of ≥7 at baseline on the
ADT, antidepressant treatment; CI, confidence interval;
Important Warning and Precaution for Cerebrovascular Adverse Events, Including Stroke
In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease.
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