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We provide a closer look at the result of a randomised, placebo-controlled, active-reference (quetiapine XR), flexible-dose, 6-week study of brexpiprazole in schizophrenia, which did not meet its primary endpoint – change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. We also investigate potential expectancy bias from the well-known side-effect profile of the active reference that could have affected the study outcome.
Pre-specified sensitivity analyses of the primary end point were performed using analysis of covariance (ANCOVA) last observation carried forward (LOCF) and observed cases (OC). Post hoc analyses of change from baseline in PANSS total score were performed using the mixed model for repeated measures approach with treatment groups split by having typical adverse events with potential for functional unblinding, for example, somnolence, increase in weight, dizziness, dry mouth and sedation.
Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at week 6: LOCF, ANCOVA: −4.3 [95% CI (−8.0, −0.5), p = 0.0254]. OC, ANCOVA: −3.9 [95% CI (−7.3, −0.5), p = 0.0260]. Patients treated with brexpiprazole experiencing typical adverse events with potential for functional unblinding before or at Week 2 had a least square (LS) mean PANSS change of −29.5 (improvement), with a difference in change from baseline to Week 6 in PANSS total score between brexpiprazole and placebo of −13.5 [95% CI (−23.1, −4.0), p = 0.0057], and those who did not had an LS mean change of −18.9 and a difference between brexpiprazole and placebo of −2.9 [95% CI (−7.2, 1.4), p = 0.1809].
Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at Week 6. A post hoc analysis suggested a potential confounding of efficacy rating towards symptom improvement in patients who experience known side effects of quetiapine XR.
Effective treatments for patients with high levels of negative symptoms of schizophrenia are lacking. Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all with subnanomolar potency. Long-term treatment with brexpiprazole demonstrated broad efficacy across all five Marder factor groupings, including positive, negative, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. This post-hoc analysis of long-term effects of brexpiprazole in patients with clinically relevant levels of negative symptoms of schizophrenia is based on data from two similarly designed short-term, placebo-controlled studies (Vector; NCT01396421 or Beacon; NCT01393613) for the brexpiprazole-treated patients who continued into an open-label extension study (Zenith; NCT01397786).
In the short-term studies, patients with acute schizophrenia were randomly assigned to fixed once-daily doses of brexpiprazole 0.25mg (Vector), 1mg (Beacon), 2mg , 4mg or placebo for 6weeks. The long-term study was an open-label, 52-week (amended to 26weeks), safety extension study with flexible-dose (1–4mg/day) brexpiprazole. The post-hoc analyses were performed on brexpiprazole-treated patients from the short-term studies who continued into the long-term study, and who had clinically relevant negative symptoms, defined as PANSS Factor Score for Negative Symptoms (PANSS-FSNS; N1, N2, N3, N4, G7, G16) of ≥24, and score of ≥4 on at least two of three core negative symptom PANSS items at randomization in the parent study. The outcome of the analysis included change from baseline to up to 58weeks in PANSS-FSNS, PANSS Total, and PSP. Safety was also assessed.
A total of 187 patients with clinically relevant levels of negative symptoms in the parent study rolled-over into the open-label extension study and were available for analysis. Eighty-three of these patients remained in the studies for 58weeks. Due to the study amendment, not all patients had the opportunity of complete 52weeks of open-label treatment. Baseline PANSS Total score was 104.4, while baseline PANSS-FSNS was 27.6 and baseline PSP Total score was 41.3. Mean change (SD) from baseline in PANSS-FSNS was –10.9 (5.0), and –44.2 (17.5) for PANSS Total score at Week 58. Change from baseline (SD) to Week 58 for PSP Total score was 24.8 (12.9) with improvement in all domains (socially useful activities, personal and social relationship, self-care, and disturbing and aggressive behaviors). The TEAEs reported ≥5% were schizophrenia (18.9%), insomnia (8.6%), weight increased (5.9%) and akathisia (5.9%).
This post-hoc analysis suggests that brexpiprazole has long-term effectiveness on negative symptoms and functioning in patients with schizophrenia and clinically relevant levels of negative symptoms.
Funding Acknowledgements: The study was funded by Otsuka Pharmaceutical Development & Commercialization Inc. and H. Lundbeck A/S
To compare the tolerability and efficacy of different antipsychotic cross-titration schedules, using data from a brexpiprazole study (Equator; NCT01668797).
Patients with schizophrenia were cross-titrated from other antipsychotics to brexpiprazole monotherapy in a 1–4 week open-label conversion phase, then entered a single-blind brexpiprazole treatment phase. Patients were stratified into four “conversion groups,” according to the amount of time spent in the conversion phase. Discontinuation rates, treatment-emergent adverse events (TEAEs), and efficacy (Positive and Negative Syndrome Scale [PANSS]) were compared between conversion groups.
Of the 404 patients treated with brexpiprazole, the majority (72.0%) spent 22–33 days in the conversion phase. Discontinuation rates due to lack of efficacy or adverse events were low in all conversion groups. Of the 292 patients who successfully switched and completed 8 weeks of brexpiprazole treatment, most were converted to brexpiprazole over 22–33 days (80.1%), and fewer were converted over 1–7 days (2.4%), 8–14 days (6.5%), or 15–21 days (11.0%). The incidence of TEAEs over 8 weeks was lower among those converted over 22–33 days (44.4%) than in other conversion groups (62.5–84.2%), although low patient numbers with shorter conversion times limit the generalizability of this finding. Each conversion group showed comparable improvement in PANSS total score from baseline.
The majority of patients were cross-titrated to brexpiprazole over a period of 22–33 days, by investigators’ choice. Additional data on shorter conversions may help clinicians to choose a switching paradigm that best meets their patients’ needs.
To evaluate brexpiprazole adjunctive to antidepressant therapies (ADTs) as maintenance treatment in patients with major depressive disorder with inadequate response to ADT, utilising a novel study design.
The study comprised an 8-week prospective treatment period with open-label ADT with double-blind placebo treatment and a 24-week randomised treatment period. Investigators and patients were blinded to treatment periods, randomisation criteria, and timing of randomisation. Patients with early response to open-label ADT were withdrawn at Week 6. Patients fulfilling criteria for inadequate response were randomised to ADT+brexpiprazole 1–3 mg/day, or ADT+placebo. The primary endpoint was full remission: Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤10 and ≥50% decrease from randomisation (i.e. baseline) in MADRS total score for at least 8 consecutive weeks.
The primary efficacy analysis failed to show a statistically significant difference between the proportions of patients on ADT+brexpiprazole (21.4%) and ADT+placebo (24.9%) achieving full remission; odds ratio: 0.83; p=0.2641. The secondary endpoint of change from baseline to Week 6 in MADRS total score showed no difference between ADT+brexpiprazole and ADT+placebo (−0.4; p=0.3259). The most frequent treatment-emergent adverse event (TEAE) in patients receiving ADT+brexpiprazole was weight increased (9.5% vs. 5.0% in ADT+placebo). The incidence of TEAEs leading to withdrawal in the randomised treatment period was 6.3% in the ADT+brexpiprazole group and 3.4% in the ADT+placebo group.
Adjunctive brexpiprazole did not differentiate from ADT+placebo on the primary endpoint of full remission. A number of design elements in this previously untried study design may have contributed to the study result. Brexpiprazole was well tolerated.
Symptoms of anxiety are prevalent in Major Depressive Disorder (MDD) and are associated with greater illness severity, suicidality, impaired functioning and poor response to antidepressant treatment (ADT). In MDD, anxiety symptoms can be assessed as ‘anxious distress’ (new DSM-5 specifier) or ‘anxious depression’ (score ≥7 on the HAM-D anxiety/somatization factor). Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors – all at similar potency. Brexpiprazole is approved in the US for treatment ofschizophrenia, and as adjunctive treatment in MDD. The objective of this post-hoc analysis was to assess the efficacy of brexpiprazole as adjunct to ADT in patients with MDDand anxiety symptoms, using these two definitions of anxiety.
Data were pooled from three randomized, double-blind, placebo-controlled studies with similar designs (Pyxis – NCT01360645; Polaris – NCT01360632; Sirius – NCT02196506). In each study, patients with MDD and an inadequate response to 1–3 ADTs received single-blind ADT for 8 weeks. Patients with inadequate response throughout this prospective phase were randomized to receive either ADT+brexpiprazole (2mg in Pyxis and Sirius; 1mg or 3 mg in Polaris) or ADT+placebo for 6 weeks. Proxies used to categorize patients as having ‘anxious distress’ included a score of ≥2 on the following symptoms at randomization: tension (MADRS item 3 score ≥3); restlessness (IDS item 24 score ≥2); concentration (MADRS item 6 score ≥3); or apprehension (HAM-D item 10 score ≥3). Scores on the items of the HAM-D anxiety/somatization factor at randomization (baseline) were used to identify patients with ‘anxious depression’. Efficacy was assessed as the change in MADRS total score from baseline to Week 6. Statistical analysis used a Mixed Model Repeated Measure approach using pooled brexpiprazole doses.
After 8 weeks of prospective ADT monotherapy, 57.6% (n=797/1,383) of patients met the criteria for anxious distress, and 48.5% (n=671/1,383) for anxious depression. The mean MADRS total score was 29.0 for patients with anxious distress in the adjunctive brexpiprazole (n=462) group and 29.1 in the placebo (n=327) group; while those with anxious depression were 28.9 (brexpiprazole; n=384) and 28.6 (placebo; n=282). Compared to those receiving placebo, patients with both anxious distress and anxious depression who received adjunctive brexpiprazole showed a greater improvement in MADRS total score (LS mean difference -2.38, p=0.0001 and -1.68, p=0.012, respectively). These improvements, compared to placebo, were similar to those in patients who had not met the criteria for anxious distress (-1.40, p=0.023) or anxious depression (-2.17, p<0.001).
Adjunctive brexpiprazole may be efficacious in reducing depressive symptoms both in patients with or without symptoms of anxiety.
The studies were funded by H. Lundbeck A/S and Otsuka Pharmaceutical Development & Commercialization, Inc.
Review efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies.
Patients experiencing a current exacerbation of schizophrenia received brexpiprazole in two fixed-dose (2 and 4 mg), 6-week, placebo-controlled studies, one flexible-dose (2–4 mg), 6-week, placebo-control and active reference study, and one fixed-dose (1–4 mg), 52-week, placebo-controlled maintenance study.
The efficacy of brexpiprazole was demonstrated in the two short-term fixed-dose studies with statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo. In the flexible-dose short-term study, treatment with brexpiprazole resulted in numerically greater improvements in PANSS total score than with placebo that approached statistical significance (p=0.056). A meta-analysis of these short-term studies showed a mean change in PANSS total score of −20.1, reflecting a clinically meaningful reduction in symptoms. In the maintenance study, brexpiprazole had a beneficial effect relative to placebo on time to exacerbation of psychotic symptoms/impending relapse (p<0.0001). For all studies, brexpiprazole demonstrated clinically meaningful treatment effects on the Personal and Social Performance scale. Brexpiprazole had a favourable safety profile, with a relatively low prevalence of activating and sedating side effects. Weight gain in the short-term studies was ~1 kg greater than placebo. No safety concerns were observed with brexpiprazole in laboratory values, electrocardiogram, or vital signs.
Overall, the results indicate brexpiprazole, used either short-term or as part of a long-term maintenance treatment programme, is an efficacious therapy option in adults with schizophrenia and has a favourable safety/tolerability profile.
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