4 results
P170: Safety and Tolerability of Brexpiprazole for the Treatment of Agitation in Alzheimer’s Dementia: Pooled Results From Three Phase III Trials
- Anja Farovik, Maia Miguelez, Daniel Lee, Mary Slomkowski, Nanco Hefting, Dalei Chen, Klaus Larsen, Eva Kohegyi, Mary Hobart, Alpesh Shah, Alvin Estilo, Moeen Panni, Pedro Such, George T. Grossberg
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- Journal:
- International Psychogeriatrics / Volume 35 / Issue S1 / December 2023
- Published online by Cambridge University Press:
- 02 February 2024, pp. 259-260
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Objective:
Agitation in Alzheimer’s dementia (AAD) is prevalent, distressing, and burdensome. Medications for agitation are commonly prescribed off-label, although use is hindered by safety and tolerability concerns. This pooled analysis evaluates the safety and tolerability of brexpiprazole in patients with AAD.
Methods:Data were pooled from three Phase 3, 12-week, placebo-controlled trials (NCT01862640, NCT01922258, NCT03548584) (overall, and by brexpiprazole dose). The primary objective of each trial was to assess the efficacy of brexpiprazole on agitation. Safety was a secondary objective.
Results:658 patients were randomized to brexpiprazole (0.5–3 mg/day, depending on the trial; n=655 treated), and 389 patients were randomized to placebo (n=388 treated). Mean baseline age was 73.5–74.2 years, and mean time since diagnosis of Alzheimer’s disease was 28.2–35.6 months. The pooled incidence of treatment-emergent adverse events (TEAEs) was 51.1% with brexpiprazole, with no notable differences between doses, and 45.9% with placebo. The incidence of serious TEAEs was 6.4% (brexpiprazole) versus 4.1% (placebo), and the incidence of TEAEs leading to discontinuation was 6.3% versus 3.4%, respectively. TEAEs that occurred in ≥2% of patients receiving brexpiprazole and more than in placebo-treated patients were insomnia (3.7% versus 2.8%), somnolence (3.4% versus 1.8%), nasopharyngitis (2.7% versus 2.6%), and urinary tract infection (2.6% versus 1.5%). Other TEAEs of interest included falls (1.7% versus 2.6%) and sedation (0.3% versus 0.0%). TEAE categories of interest included extrapyramidal symptom (EPS)-related TEAEs (5.3% versus 3.1%), cardiovascular TEAEs (3.7% versus 2.3%), and cerebrovascular TEAEs (0.5% versus 0.3%). The mean change from baseline to last visit in Mini–Mental State Examination score was 0.21 (brexpiprazole) and 0.14 (placebo). Six patients receiving brexpiprazole (0.9%) and one patient receiving placebo (0.3%) died; none of the deaths was considered related to brexpiprazole.
Conclusion:Based on pooled data, brexpiprazole was well tolerated in patients with AAD, and had a clinical safety profile consistent with that of brexpiprazole in other indications. Patients receiving brexpiprazole had a similar incidence of sedation, EPS events, falls, cardiovascular events, and cerebrovascular events compared with placebo, and no worsening of cognition. The incidence of death was low, and no deaths were considered related to study treatment.
P96: Efficacy of Brexpiprazole for the Treatment of Agitation in Alzheimer’s Dementia: Post Hoc Line Item Analysis of the Cohen-Mansfield Agitation Inventory
- Jyoti Aggarwal, Daniel Lee, Mary Slomkowski, Nanco Hefting, Dalei Chen, Klaus Larsen, Denise Chang, Eva Kohegyi, Mary Hobart, Maia Miguelez, Pedro Such
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- Journal:
- International Psychogeriatrics / Volume 35 / Issue S1 / December 2023
- Published online by Cambridge University Press:
- 02 February 2024, pp. 209-210
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Objective:
Agitation is a common neuropsychiatric symptom in Alzheimer’s dementia. The Cohen-Mansfield Agitation Inventory (CMAI) assesses the frequency of 29 agitation behaviors in elderly persons. The frequency of each behavior is rated from 1–7 (1=never, 2=less than once a week, 3=once or twice a week, 4=several times a week, 5=once or twice a day, 6=several times a day, 7=several times an hour), typically reported as a single total score. This post hoc analysis explored the efficacy of brexpiprazole on the frequency of individual agitation behaviors.
Methods:Post hoc analyses were conducted for two 12-week, randomized, double- blind, placebo-controlled, parallel-arm, fixed-dose trials of brexpiprazole in patients with agitation in Alzheimer’s dementia (NCT01862640, NCT03548584). Data are reported using descriptive statistics for brexpiprazole (2 or 3 mg/day) and placebo, for patients who completed 12 weeks of treatment.
Results:In the first fixed-dose trial (brexpiprazole 2 mg/day, n=120; placebo, n=118), baseline behavior frequency was similar between groups (range 1.12 to 4.92). At baseline, the most frequently observed behavior was “general restlessness” (brexpiprazole, 4.92; placebo, 4.82; approximately “once or twice a day”), and the least frequently observed behaviors were “biting” (brexpiprazole, 1.12) and “making physical sexual advances” (placebo, 1.14). At Week 12, the average reduction in mean frequency was -0.73 (brexpiprazole) and -0.60 (placebo), with a greater numerical reduction for 21/29 behaviors with brexpiprazole versus placebo. In the second fixed-dose trial (brexpiprazole 2 or 3 mg/day, n=192; placebo, n=103), baseline behavior frequency was similar between groups (range 1.12 to 5.22), and higher than in the first trial due to study inclusion criteria. At baseline, the most frequently observed behavior was “general restlessness” (brexpiprazole, 5.22; placebo, 5.09; approximately “once or twice a day”), and the least frequently observed behaviors were “making physical sexual advances” (brexpiprazole, 1.13) and “intentional falling” (placebo, 1.12). At Week 12, the average reduction in mean frequency was -0.78 (brexpiprazole) and -0.54 (placebo), with a greater numerical reduction for 26/29 behaviors with brexpiprazole versus placebo.
Conclusion:In this post hoc analysis, brexpiprazole was associated with numerically greater reduction in the frequency of most individual agitation behaviors versus placebo.
14 Long-term Efficacy of Brexpiprazole in Patients with Schizophrenia with Clinically Relevant Levels of Negative Symptoms
- Catherine Weiss, Peter Zhang, Ross A Baker, Mary Hobart, Nanco Hefting, Stine R Meehan
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, p. 180
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Background
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).
MethodsIn 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.
ResultsA 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%).
ConclusionThis 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
A randomised, placebo-controlled 24-week study evaluating adjunctive brexpiprazole in patients with major depressive disorder
- Michael Bauer, Nanco Hefting, Annika Lindsten, Mette Krog Josiassen, Mary Hobart
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- Journal:
- Acta Neuropsychiatrica / Volume 31 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 18 September 2018, pp. 27-35
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Objective
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.
MethodsThe 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.
ResultsThe 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.
ConclusionAdjunctive 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.