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Regular Research Article| Volume 28, ISSUE 4, P383-400, April 2020

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials

Open AccessPublished:October 01, 2019DOI:https://doi.org/10.1016/j.jagp.2019.09.009

      Highlights

      • These two randomized controlled trials addressed the question, is brexpiprazole efficacious, safe, and well tolerated for the treatment of agitation in Alzheimer's dementia (AAD)?
      • In Study 1, brexpiprazole 2 mg/day (fixed dose) was superior to placebo in terms of improvement of agitated behaviors (measured using the Cohen-Mansfield Agitation Inventory), with good tolerability. In Study 2, brexpiprazole 0.5–2 mg/day (flexible dose) was numerically superior to placebo (a non-statistically significant difference); the subgroup that was titrated to brexpiprazole 2 mg/day achieved nominal superiority compared with similarly titrated placebo patients.
      • These studies provide evidence that brexpiprazole 2 mg/day has the potential to be an efficacious, safe, and well-tolerated treatment for AAD, a clinical condition with a high burden and no FDA-approved treatments.

      Abstract

      Objective

      To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD).

      Design

      Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258).

      Setting

      Study 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries.

      Participants

      Patients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted.

      Intervention

      Study 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5–2 mg/day or placebo (1:1) for 12 weeks.

      Measurements

      Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29–203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression – Severity of illness (CGI-S) as related to agitation. Safety was also assessed.

      Results

      In Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, −3.77; confidence limits, –7.38, –0.17; t(316) = –2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; −3.40, 3.86; t(314) = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5–2 mg/day did not achieve statistical superiority over placebo (–2.34; –5.49, 0.82; t(230) = −1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (−5.06; −8.99, −1.13; t(144) = −2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (−0.16; −0.39, 0.06; t(337) = −1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5–2 mg/day in Study 2 (−0.31; −0.55, −0.06; t(222) = −2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5–2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity.

      Conclusions

      Brexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.

      Key Words

      INTRODUCTION

      The global prevalence of dementia, most commonly due to Alzheimer disease (AD), is 50 million at present and is projected to almost double in the next 20 years.
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      Clinical trials of new treatments for patients with agitation in Alzheimer's dementia (AAD) require both a definition of AAD and scales to measure agitation. A consensus definition of agitation, for use in clinical and research applications, was developed by the Agitation Definition Workgroup of the International Psychogeriatric Association (IPA).
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      The workgroup defined agitation in cognitive disorders as: A) occurring in patients with a cognitive impairment or dementia syndrome; B) exhibiting behavior consistent with emotional distress: excessive motor activity (e.g., pacing, rocking, or gesturing), verbal aggression (e.g., yelling, excessive loudness, or using profanity), and/or physical aggression (e.g., grabbing, shoving, or pushing); C) causing excess disability with regard to interpersonal relationships, social functioning, or activities of daily living; and D) not solely being attributable to another disorder (psychiatric, medical, or substance-related).
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      With regard to scales, the Cohen-Mansfield Agitation Inventory (CMAI) is a clinically validated agitation rating scale that measures the frequency of 29 agitated behavior items, encompassing physically and verbally aggressive behavior (e.g., hitting or cursing), physically nonaggressive behavior (e.g., pacing or restlessness), and verbally agitated behavior (e.g., complaining or constant requests for attention).
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      Originally developed for use in nursing home residents, the CMAI has since been expanded for use in community-dwelling patients with AD.
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      The CMAI correlates with other neuropsychiatric symptom scales, has high internal consistency, adequate inter-rater reliability with regard to physical aggression and verbal agitation,
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      and is consistent with the IPA consensus definition of agitation in cognitive disorders.
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      The prevalence of AAD is high (up to 86% in care homes, depending on the definition of agitation), and increases with disease severity.
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      The frequent occurrence of AAD combined with its serious consequences for patients and caregivers make it a key target for treatment. Currently, there are no US Food and Drug Administration (FDA)-approved treatments for AAD; risperidone is indicated for the short-term treatment of persistent aggression in AD in some countries outside the United States.
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      Consequently, clinicians resort to off-label use of medications in an attempt to control symptoms, including antipsychotics, anticonvulsants, cannabinoids, sedative-hypnotics, anxiolytics, and antidepressants.
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      There is an unmet need for efficacious and well-tolerated treatment options that are approved by the FDA to reduce the burden associated with AAD and to improve the quality of life for patients and their caregivers.
      • Antonsdottir IM
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      Advancements in the treatment of agitation in Alzheimer's disease.
      Brexpiprazole is a serotonin-dopamine activity modulator that acts as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors, and as an antagonist at serotonin 5-HT2A and noradrenaline α1B2C receptors, all at pharmacologically relevant potency.
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      Brexpiprazole is efficacious and well tolerated in adults as a treatment for schizophrenia, and as adjunctive treatment to antidepressants for the treatment of major depressive disorder.
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      Brexpiprazole has a low propensity for activating and sedating side effects.
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      Serotonin, dopamine, and noradrenaline neurotransmitter systems are implicated in behavioral symptoms of dementia, including agitation,
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      and thus it is hypothesized that brexpiprazole may provide a benefit in the management of such patients. The objective of the two Phase 3 studies reported here was to assess the efficacy, safety, and tolerability of brexpiprazole in patients with AAD, using the CMAI as the primary efficacy measure.

      METHODS

      Two clinical studies were conducted and are reported here: Study 1 investigated two fixed doses of brexpiprazole (2 mg/day and 1 mg/day), whereas Study 2 investigated flexibly dosed brexpiprazole (0.5–2 mg/day). The studies were registered with ClinicalTrials.gov (Study 1: NCT01862640; Study 2: NCT01922258; https://clinicaltrials.gov/) and EudraCT (Study 1: 2013-000504-41; Study 2: 2013-000503-17; https://eudract.ema.europa.eu/) and were conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guideline and local regulatory requirements. The study protocols were approved by relevant institutional review boards and independent ethics committees. All patients and/or their legal representatives provided written informed consent prior to the start of the respective study. The studies were each monitored under the supervision of an independent data monitoring committee.

      Patients

      In Study 1, patients were enrolled by investigators at 81 sites in 7 countries: Russia (29.1% of randomized patients), the United States (27.9%), Ukraine (14.8%), Serbia (12.2%), Croatia (8.5%), Spain (4.4%), and Germany (3.0%). In Study 2, patients were enrolled by investigators at 62 sites in 9 countries: Ukraine (28.9% of randomized patients), the United States (22.6%), Russia (19.3%), Bulgaria (17.8%), Canada (4.8%), France (3.3%), Slovenia (2.2%), the United Kingdom (0.7%), and Finland (0.4%).
      Eligible patients were male or female, aged 55–90 years, with a diagnosis of probable AD according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria,
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      and a Mini-Mental State Examination (MMSE)
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      “Mini–mental state”. A practical method for grading the cognitive state of patients for the clinician.
      score of 5–22 at screening and baseline. Patients must have had a previous magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain, with findings consistent with a diagnosis of AD; if a previous scan was not available, MRI or CT was performed during screening. Patients were also required to have symptoms of agitation or aggression (confirmed by a score of ≥4 on the Neuropsychiatric Inventory – Nursing Home version [NPI-NH] Agitation/Aggression domain
      • Iverson GL
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      Measuring change in psychiatric symptoms using the Neuropsychiatric Inventory: Nursing Home version.
      ,
      • Cummings JL
      Neuropsychiatric Inventory Nursing Home version (NPI-NH): Comprehensive Assessment of Psychopathology in Patients With Dementia Residing in Nursing Homes.
      ), to require pharmacotherapy for the treatment of agitation in the investigator's judgment after an evaluation for reversible factors (e.g., delirium, pain, infection, and polypharmacy) and trial of nonpharmacologic interventions, and to be able to benefit from pharmacotherapy per the investigator's judgment. The NPI-NH Agitation/Aggression domain was chosen as an entry criterion to identify patients with baseline agitation or aggression while avoiding use of the primary endpoint (CMAI) for this purpose. The NPI-NH was completed by a clinician based on an interview with the patient's caregiver. The Agitation/Aggression domain score was obtained by multiplying the frequency rating, from 1 (rarely) to 4 (very often), by the severity rating, from 1 (mild) to 3 (severe).
      • Cummings JL
      Neuropsychiatric Inventory Nursing Home version (NPI-NH): Comprehensive Assessment of Psychopathology in Patients With Dementia Residing in Nursing Homes.
      A score of ≥4 is considered to be clinically relevant and is often used as an entry criterion for clinical trials in dementia with neuropsychiatric symptoms.
      • Lyketsos CG
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      ,
      • Schneider LS
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      National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology.
      The IPA definition of AAD was not available at the time of study initiation but recruitment criteria are aligned with the target symptoms of the definition. Patients could be living in a care facility (e.g., nursing home, dementia unit, assisted living facility, or any other residential care facility providing long-term care) or in a community-based setting provided the patient was not living alone. Patients must have been residing at their current location for at least 14 days prior to screening and were expected to remain at the same location for the duration of the trial. In either setting, the patient was required to have a caregiver who could spend a minimum of 2 hours/day for 4 days/week with the patient in order to assess changes in the patient's condition. Key exclusion criteria were dementia or memory impairment due to a reason other than AD (including mixed pathologies; the Hachinski Ischemic Scale [Rosen modification]
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      Pathological verification of ischemic score in differentiation of dementias.
      was used to exclude patients with probable vascular dementia), diagnosis of a specified Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) Axis I disorder (including current major depressive disorder [unless on a stable dose of antidepressant medication for 30 days prior to randomization], a history of bipolar disorder, or a history of a psychotic disorder not related to dementia), any other specified comorbidity including a history of stroke, and being likely to require prohibited concomitant therapy during the trial (listed below).

      Study Design

      These were multicenter, randomized, double-blind, placebo-controlled, parallel-arm studies, designed to compare the efficacy, safety, and tolerability of brexpiprazole with placebo in patients with AAD. The studies each comprised a screening period of up to 42 days, a 12-week double-blind treatment period, and a 30-day post-treatment follow-up period. The purpose of the screening period was to determine eligibility and to wash out prohibited concomitant pharmacotherapy. Prohibited medications included antipsychotics, mood stabilizers, and anticonvulsants. Medications to treat AD (cholinesterase inhibitors, memantine, and other cognitive enhancers) were permitted during the study provided that the dose was stable for 90 days prior to randomization and was not changed for the duration of the study. Similarly, antidepressants were permitted if the dose was stable for 30 days prior to randomization and did not change during the study. Benzodiazepines were allowed during the first 4 weeks of the randomized phase only (limited to 4 days/week with a maximum dose of 2 mg/day of lorazepam or equivalent), provided they were not used in the 12 hours prior to administration of the efficacy and safety scales.
      In Study 1, eligible patients were randomized in a 1:1:1 ratio to fixed doses of brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo, for 12 weeks. The study initially included a fourth treatment arm, brexpiprazole 0.5 mg/day; this was removed by the study sponsor under a protocol amendment on July 7, 2014 (after 20 patients had been randomized to this arm) in response to new information from completed studies in other indications and pharmacokinetic data in elderly participants that indicated this dose was nonefficacious. Doses were titrated over a period of 2–4 weeks (Days 1–3, 0.25 mg/day; Days 4–14, 0.5 mg/day; Days 15–28, 1 mg/day; Day 29 onwards, assigned dose). Patients unable to tolerate their assigned dose (or matching placebo) were discontinued from the trial. In Study 2, eligible patients were randomized in a 1:1 ratio to flexibly dosed brexpiprazole 0.5–2 mg/day or placebo, for 12 weeks. Brexpiprazole was initiated at 0.25 mg/day (Days 1–3), increased to 0.5 mg/day (Days 4–14), and further increased to a target dose of 1 mg/day (Days 15–28; could be decreased back to 0.5 mg/day). An additional dose increase to 2 mg/day could be initiated from Day 29 (Week 4 visit) onwards. After Week 4, stepwise dose decreases and increases could occur at any time (scheduled or unscheduled visits), based on the investigator's clinical evaluation of the patient's response and tolerability. Patients unable to tolerate brexpiprazole 0.5 mg/day (or matching placebo) were discontinued from the trial.
      Brexpiprazole and placebo were taken orally, once daily. Treatments were assigned by an interactive voice/web response system based on a fixed-block, computer-generated randomization code provided by the study sponsor and stratified by study center. Treatment assignments were blinded to patients, investigators, and sponsor personnel, including those involved in data analysis. Brexpiprazole and matching placebo tablets were provided by the sponsor, packaged in numbered, weekly blister cards.

      Assessments

      The primary efficacy measure was CMAI Total score, calculated as the sum of the 29 agitated behavior items, with each item scored from 1 (never) to 7 (a few times an hour), giving a total score from 29 to 203 points.
      • Cohen-Mansfield J
      Agitated behaviors in the elderly. II. Preliminary results in the cognitively deteriorated.
      ,
      • Cohen-Mansfield J
      • Marx MS
      • Rosenthal AS
      A description of agitation in a nursing home.
      The CMAI was completed by a clinician based on an interview with the patient's caregiver and corroborated by data from a diary in which the caregiver recorded daily observations of all 29 CMAI behaviors (occurrence and time of occurrence). The key secondary efficacy measure was the Clinical Global Impression – Severity of illness (CGI-S)
      • Guy W
      ECDEU Assessment Manual for Psychopharmacology, Revised.
      score as related to agitation. The CGI-S, completed by the clinician, is scored from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). The CMAI and CGI-S were administered at screening, baseline, and Weeks 2, 4, 6, 8, 10, and 12.
      Safety analyses, completed at specified time points, included the assessment of adverse events (AEs), physical and neurologic examinations, vital signs, body weight, waist circumference, clinical laboratory tests (hematology, serum chemistry, and urinalysis), electrocardiograms, suicidality (Sheehan Suicidality Tracking Scale
      • Coric V
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      Sheehan Suicidality Tracking Scale (Sheehan-STS): preliminary results from a multicenter clinical trial in generalized anxiety disorder.
      ), cognitive dysfunction (as measured by the MMSE), and extrapyramidal symptoms (EPS) (the Simpson-Angus Scale,
      • Simpson GM
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      A rating scale for extrapyramidal side effects.
      Abnormal Involuntary Movement Scale,
      • Guy W
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      and Barnes Akathisia Rating Scale
      • Barnes TRE
      A rating scale for drug-induced akathisia.
      ).

      Statistical Analyses

      Sample size was calculated based on an expected treatment effect (drug-placebo difference) of 6.5 points (standard deviation, 16.5) for mean change in CMAI Total score from baseline to Week 12. Allowing 10% of patients to be nonevaluable, a sample size of 132 patients per treatment arm in Study 1 and 130 patients per arm in Study 2 was projected to achieve 85% power at a two-sided alpha level of 0.05.
      Safety analyses were performed in the safety sample, defined as all randomized patients who received at least one dose of study medication. Efficacy analyses were conducted in the efficacy sample, comprising all patients in the safety sample (excluding those randomized to brexpiprazole 0.5 mg in Study 1) who had a baseline and at least one post-baseline efficacy evaluation for CMAI Total score.
      The primary efficacy endpoint was the change from baseline to Week 12 in CMAI Total score, analyzed using mixed model for repeated measures (MMRM) with an unstructured variance covariance matrix, with fixed-class effect terms for treatment, trial center and visit week, an interaction term of treatment by visit week, and the interaction term of baseline CMAI Total score by visit week as a covariate. Cohen's d effect sizes were calculated. The primary comparisons between brexpiprazole and placebo at Week 12 were estimated as the least squares mean difference (hereafter referred to as adjusted mean difference) utilizing the procedure “PROC MIXED” in SAS 9.4 (SAS Institute Inc., Cary, NC). Degrees of freedom for the adjusted mean differences were calculated using the Kenward-Roger approximation. A hierarchical testing procedure was applied to the primary comparisons in Study 1, which were tested at a significance level of 0.05 (two-sided): 1) comparison of brexpiprazole 2 mg versus placebo, and 2) comparison of brexpiprazole 1 mg versus placebo. The formal hierarchical testing procedure was terminated if a p value was non-statistically significant, and p values generated further down the hierarchy were labeled “nominal.”
      The key secondary efficacy endpoint was the change from baseline to Week 12 in CGI-S score as related to agitation, using an MMRM model with corresponding terms to the primary analysis. To maintain the overall experiment-wise Type I error rate at 0.05, a hierarchical testing procedure was employed in which the key secondary comparisons (Study 1: brexpiprazole 2 mg versus placebo, and brexpiprazole 1 mg versus placebo; Study 2: brexpiprazole versus placebo) were tested only if primary comparisons were positive.
      Change from baseline to Week 12 in NPI-NH Agitation/Aggression score (frequency × severity) was also evaluated using an MMRM model, with corresponding terms to the primary analysis.
      Safety and tolerability analyses used descriptive statistics. The Sheehan Suicidality Tracking Scale, MMSE, and EPS scales were analyzed using analysis of covariance (ANCOVA) with treatment and trial center as main effects and baseline value as covariate.
      In Study 1, due to the low number of patients in the brexpiprazole 0.5 mg dose arm, these patients were not included in the efficacy analyses, and were pooled with the 1 mg dose arm in the safety analyses (except for analyses of the Sheehan Suicidality Tracking Scale, MMSE, and EPS scales).
      In Study 2, post hoc analyses were conducted to investigate the effect of dose on the results of this trial. Due to flexible dosing, the effects of a particular brexpiprazole dose could not be directly assessed; therefore, dose analyses were performed based on titration status, that is, whether or not the dose was increased to 2 mg/day (or equivalent placebo) at the Week 4 visit. Patients who discontinued prior to Week 4 were excluded from the post hoc analyses. Post hoc efficacy analyses were performed using the same statistical approaches as for the primary and key secondary analyses.

      RESULTS

      Patients

      Study 1

      In Study 1, the first informed consent form was signed on July 11, 2013 and the last trial observation was on March 15, 2017. A total of 433 patients were randomized to brexpiprazole 2 mg (n = 140), brexpiprazole 1 mg (n = 137), brexpiprazole 0.5 mg (n = 20), or placebo (n = 136; Fig. 1). One patient randomized to placebo did not take a dose, and so the safety sample comprised 432 patients. Of the randomized patients, the study was completed by 122 patients (87.1%) receiving brexpiprazole 2 mg, 121 (88.3%) receiving brexpiprazole 1 mg, 13 (65.0%) receiving brexpiprazole 0.5 mg, and 121 (89.0%) receiving placebo. Besides discontinuation of the 0.5 mg dose arm (as described in the Methods), the most common reasons for discontinuation were adverse events (6.5% of randomized patients) and withdrawal of consent (4.4%; Fig. 1).
      In general, baseline demographic and clinical characteristics were similar across the brexpiprazole 2 mg, brexpiprazole 1 mg, and placebo groups (Table 1). Overall, 65.4% of patients were living in a care facility and 34.6% were living in a community-based setting.
      TABLE 1Baseline Demographic and Clinical Characteristics in Study 1 (Randomized Sample)
      Placebo (n = 136)Brexpiprazole 0.5 mg (n = 20)Brexpiprazole 1 mg (n = 137)Brexpiprazole 2 mg (n = 140)
      Demographic characteristics
      Age (years), mean (SD)74.1 (8.0)73.9 (9.1)73.8 (8.8)73.7 (8.1)
       <65 years, n (%)21 (15.4)5 (25.0)24 (17.5)22 (15.7)
       ≥65, <75 years, n (%)41 (30.1)4 (20.0)35 (25.5)48 (34.3)
       ≥75 years, n (%)74 (54.4)11 (55.0)78 (56.9)70 (50.0)
      BMI (kg/m2), mean (SD)25.3 (4.8)
      n = 135.
      24.8 (4.0)25.4 (5.0)25.1 (4.0)
      Female, n (%)70 (51.5)12 (60.0)78 (56.9)79 (56.4)
      White, n (%)130 (95.6)20 (100.0)134 (97.8)133 (95.0)
      Living situation, n (%)
       Care facility88 (64.7)20 (100.0)89 (65.0)86 (61.4)
       Community-based setting48 (35.3)0 (0.0)48 (35.0)54 (38.6)
      Clinical characteristics
      Time since AD diagnosis (months), mean (SD)32.3 (35.9)27.8 (25.7)36.7 (40.7)31.3 (30.4)
      Time since onset of current agitation episode requiring pharmacotherapy (months), mean (SD)4.7 (6.3)
      n = 135.
      6.8 (13.5)7.0 (17.9)
      n = 135.
      9.3 (22.5)
      n = 138.
      CMAI Total score, mean (SD)72.0 (17.7)64.4 (21.7)70.7 (15.8)71.0 (16.5)
      CGI-S score as related to agitation, mean (SD)4.5 (0.7)4.5 (0.6)4.5 (0.6)4.5 (0.7)
      NPI-NH Agitation/Aggression score, mean (SD)7.9 (2.2)7.4 (2.2)7.3 (1.9)7.3 (2.0)
      MMSE score, n (%)
       Mild (>18)19 (14.0)3 (15.0)7 (5.1)11 (7.9)
       Moderate (13–18)74 (54.4)12 (60.0)76 (55.5)87 (62.1)
       Severe (≤12)43 (31.6)5 (25.0)54 (39.4)42 (30.0)
      Notes: Statistical analysis revealed no significant between-group differences (p <0.05) for any baseline demographic or clinical characteristic (F test for continuous variables and χ2 test for categorical variables), except for NPI-NH Agitation/Aggression score, F(2,410) = 3.42, p = 0.034. Patients in the brexpiprazole 0.5 mg arm were excluded from statistical comparisons. AD: Alzheimer disease; BMI: body mass index; CGI-S: Clinical Global Impression – Severity of illness; CMAI: Cohen-Mansfield Agitation Inventory; MMSE: Mini-Mental State Examination; NPI-NH: Neuropsychiatric Inventory – Nursing Home version; SD: standard deviation.
      a n = 135.
      b n = 138.
      Psychiatric history was similar across treatment groups. Overall, prior depression was reported in 52 patients (12.0%), and prior anxiety was reported in 50 patients (11.5%); other specific psychiatric disorders were reported in <3% of patients, including prior delusions (1.8%), hallucinations (0.7%), and psychotic disorder (2.8%). Prior to the start of the study, 344/432 patients in the safety sample (79.6%) had received treatment for AAD, most commonly (≥10%) risperidone (75 patients [17.4%]), quetiapine (67 [15.5%]), lorazepam (61 [14.1%]), and haloperidol (48 [11.1%]).
      During the study, a total of 323/432 patients in the safety sample (74.8%) used one or more medications for AD: 101/140 (72.1%) in the brexpiprazole 2 mg group, 107/137 (78.1%) in the brexpiprazole 1 mg group, and 104/135 (77.0%) in the placebo group. Specific AD medications taken by ≥10% of patients were memantine (195 [45.1%]), donepezil (120 [27.8%]), and rivastigmine (51 [11.8%]). Lorazepam, permitted only during the first 4 weeks of the study, was given to 48 patients (11.1%) during the study: 2 (10.0%) in the brexpiprazole 0.5 mg group, 15 (10.9%) in the brexpiprazole 1 mg group, 10 (7.1%) in the brexpiprazole 2 mg group, and 21 (15.6%) in the placebo group.

      Study 2

      In Study 2, the first informed consent form was signed on October 28, 2013 and the last trial observation was on March 30, 2017. A total of 270 patients were randomized to brexpiprazole 0.5–2 mg/day (n = 133) or placebo (n = 137; Fig. 2). One patient randomized to brexpiprazole did not take a dose, and so the safety sample comprised 269 patients. Of the randomized patients, the study was completed by 117 (88.0%) receiving brexpiprazole 0.5–2 mg/day and 121 (88.3%) receiving placebo. The most common reasons for discontinuation were AEs (4.1% of randomized patients) and withdrawal of consent (3.7%; Fig. 2).
      Baseline demographic and clinical characteristics were similar between the brexpiprazole 0.5–2 mg and placebo groups (Table 2). Overall, 54.8% of patients were living in a care facility and 45.2% were living in a community-based setting.
      TABLE 2Baseline Demographic and Clinical Characteristics in Study 2 (Randomized Sample)
      Placebo (n = 137)Brexpiprazole 0.5–2 mg (n = 133)
      Demographic characteristics
      Age (years), mean (SD)74.0 (7.8)73.5 (8.5)
       <65 years, n (%)19 (13.9)24 (18.0)
       ≥65, <75 years, n (%)49 (35.8)46 (34.6)
       ≥75 years, n (%)69 (50.4)63 (47.4)
      BMI (kg/m2), mean (SD)25.8 (4.7)25.2 (4.2)
      n = 132.
      Female, n (%)88 (64.2)82 (61.7)
      White, n (%)129 (94.2)128 (96.2)
      Living situation, n (%)
       Care facility75 (54.7)73 (54.9)
       Community-based setting62 (45.3)60 (45.1)
      Clinical characteristics
      Time since AD diagnosis (months), mean (SD)32.1 (27.2)28.2 (28.3)
      Time since onset of current agitation episode requiring pharmacotherapy (months), mean (SD)4.5 (7.1)5.2 (16.5)
      n = 132.
      CMAI Total score, mean (SD)68.5 (15.9)71.4 (16.7)
      CGI-S score as related to agitation, mean (SD)4.5 (0.7)4.5 (0.8)
      NPI-NH Agitation/Aggression score, mean (SD)7.4 (1.8)7.5 (1.9)
      MMSE score, n (%)
       Mild (>18)34 (24.8)28 (21.1)
       Moderate (13–18)65 (47.4)64 (48.1)
       Severe (≤12)38 (27.7)41 (30.8)
      Notes: Statistical analysis revealed no significant between-group differences (p <0.05) for any baseline demographic or clinical characteristic (F test for continuous variables and χ2 test for categorical variables). AD: Alzheimer disease; BMI: body mass index; CGI-S: Clinical Global Impression – Severity of illness; CMAI: Cohen-Mansfield Agitation Inventory; MMSE: Mini-Mental State Examination; NPI-NH: Neuropsychiatric Inventory – Nursing Home version; SD: standard deviation.
      a n = 132.
      With regard to psychiatric history, prior depression was reported in 22 patients (8.1%), and prior anxiety was reported in 20 patients (7.4%); other specific psychiatric disorders were reported in <2% of patients, including prior hallucinations (0.7%) and psychotic disorder (1.5%). Prior to the start of the study, 179/269 patients in the safety sample (66.5%) had received treatment for AAD, most commonly (≥10%) risperidone (39 patients [14.5%]), chlorprothixene (38 [14.1%]), haloperidol (31 [11.5%]), and quetiapine (27 [10.0%]).
      During the study, a total of 224/269 patients in the safety sample (83.3%) used one or more medications for AD: 108/132 (81.8%) in the brexpiprazole 0.5–2 mg group and 116/137 (84.7%) in the placebo group. Specific AD medications taken by ≥10% of patients were memantine (139 [51.7%]) and donepezil (84 [31.2%]). Lorazepam, permitted only during the first 4 weeks of the study, was given to six patients (2.2%) during the study: two (1.5%) in the brexpiprazole 0.5–2 mg group and four (2.9%) in the placebo group.
      The mean of each patient's last brexpiprazole dose was 1.54 mg/day (n = 132). At Week 4, 77/127 patients (60.6%) in the brexpiprazole group were titrated to the maximum dose (2 mg), compared with 74/134 patients (55.2%) in the placebo group.

      Efficacy

      Study 1

      On the primary efficacy endpoint of change in CMAI Total score from baseline to Week 12, the brexpiprazole 2 mg group demonstrated statistically significantly greater improvement compared with the placebo group (Fig. 3; Table 3). The brexpiprazole 1 mg group did not show meaningful separation from placebo on the primary efficacy endpoint (Fig. 3; Table 3), and the formal hierarchical testing procedure was terminated for both dose arms.
      FIGURE 3
      FIGURE 3Primary endpoint in Study 1: effects of brexpiprazole on symptoms of agitation (CMAI Total).
      Notes: MMRM analysis. Mean (SD) CMAI Total score at baseline: placebo, 72.2 (17.9); brexpiprazole 1 mg, 70.5 (16.0); brexpiprazole 2 mg, 71.0 (16.6). CMAI: Cohen-Mansfield Agitation Inventory; MMRM: mixed model for repeated measures; SD: standard deviation; SE: standard error. *t(316) = −2.06, p = 0.040 versus placebo.
      TABLE 3Effects of Brexpiprazole on Efficacy Endpoints in Study 1 (Efficacy Sample)
      Treatment Difference at Week 12 Versus Placebo
      NBaseline, Mean (SD)Change From Baseline at Week 12, Adjusted Mean (SE)Adjusted Mean Difference (95% CLs)Test Statistic and p ValueCohen's d Effect Size
      Primary endpoint: CMAI Total
      Brexpiprazole 2 mg13871.0 (16.6)−21.6 (1.3)−3.77 (−7.38, −0.17)t(316) = −2.06, p = 0.040−0.25
      Brexpiprazole 1 mg13470.5 (16.0)−17.6 (1.3)0.23 (−3.40, 3.86)t(314) = 0.12, p = 0.900.02
      Placebo13172.2 (17.9)−17.8 (1.3)
      Key secondary endpoint: CGI-S as related to agitation
      Brexpiprazole 2 mg1384.51 (0.70)−1.27 (0.08)−0.16 (−0.39, 0.06)t(337) = −1.42, p = 0.16
      Nominal p value.
      −0.17
      Brexpiprazole 1 mg1344.53 (0.62)−1.02 (0.08)0.09 (−0.14, 0.32)t(335) = 0.77, p = 0.44
      Nominal p value.
      0.09
      Placebo1314.50 (0.66)−1.11 (0.08)
      NPI-NH Agitation/Aggression domain
      Brexpiprazole 2 mg1387.25 (1.94)−4.23 (0.25)−0.55 (−1.25, 0.15)t(324) = −1.55, p = 0.12−0.19
      Brexpiprazole 1 mg1347.31 (1.91)−3.78 (0.26)−0.10 (−0.80, 0.60)t(321) = −0.28, p = 0.78−0.03
      Placebo1317.81 (2.18)−3.68 (0.26)
      Notes: MMRM analyses. p values from t test (degrees of freedom provided). CGI-S: Clinical Global Impression – Severity of illness; CLs: confidence limits; CMAI: Cohen-Mansfield Agitation Inventory; MMRM: mixed model for repeated measures; NPI-NH: Neuropsychiatric Inventory – Nursing Home version; SD: standard deviation; SE: standard error.
      a Nominal p value.
      On the key secondary efficacy endpoint of change in CGI-S score as related to agitation from baseline to Week 12, the brexpiprazole 2 mg group demonstrated a greater numerical improvement (non-statistically significant) than the placebo group (Fig. 4; Table 3). No meaningful separation was observed between brexpiprazole 1 mg and placebo on the key secondary efficacy endpoint (Fig. 4; Table 3). Brexpiprazole 2 mg also demonstrated a greater numerical improvement than placebo in terms of change from baseline to Week 12 in NPI-NH Agitation/Aggression score (Table 3).
      FIGURE 4
      FIGURE 4Key secondary endpoint in Study 1: effects of brexpiprazole on symptoms of agitation (CGI-S as related to agitation).
      Notes: MMRM analysis. Mean (SD) CGI-S score at baseline: placebo, 4.5 (0.7); brexpiprazole 1 mg, 4.5 (0.6); brexpiprazole 2 mg, 4.5 (0.7). CGI-S: Clinical Global Impression – Severity of illness; MMRM: mixed model for repeated measures; SD: standard deviation; SE: standard error.

      Study 2

      On the primary efficacy endpoint of change in CMAI Total score from baseline to Week 12, the brexpiprazole 0.5–2 mg group did not achieve statistical superiority relative to the placebo group (Fig. 5a; Table 4), and the formal hierarchical testing procedure was terminated. In post hoc efficacy analyses, the subgroup of patients who were titrated to the maximum brexpiprazole dose (2 mg) at Week 4 showed improvement in CMAI Total score compared with similarly titrated placebo patients (Fig. 5b; Table 4). For those patients who were not titrated to brexpiprazole 2 mg (or equivalent placebo) at Week 4, there was no clinically meaningful separation versus placebo (Table 4).
      FIGURE 5
      FIGURE 5Primary endpoint in Study 2: effects of brexpiprazole on symptoms of agitation (CMAI Total) in a) total efficacy sample and b) subgroup titrated to 2 mg (or equivalent placebo) at Week 4 (post hoc analysis).
      Notes: MMRM analysis. Mean (SD) CMAI Total score at baseline: a) placebo, 68.6 (16.0); brexpiprazole 0.5–2 mg, 71.5 (16.8); b) placebo, 68.3 (16.2); brexpiprazole, 69.2 (15.4). CMAI: Cohen-Mansfield Agitation Inventory; MMRM: mixed model for repeated measures; SD: standard deviation; SE: standard error. *p <0.05, **p <0.01 versus placebo. Specifically, the test statistics (with degrees of freedom) and p values were: a) Week 8, t(235) = −2.63, p = 0.0091; Week 10, t(230) = −2.03, p = 0.044; b) Week 6, t(137) = −2.50, p = 0.014; Week 8, t(140) = −2.48, p = 0.015; Week 10, t(143) = −2.83, p = 0.0053; Week 12, t(144) = −2.54, p = 0.012.
      TABLE 4Effects of Brexpiprazole on Efficacy Endpoints in Study 2 (Efficacy Sample)
      Treatment Difference at Week 12 Versus Placebo
      NBaseline, Mean (SD)Change From Baseline at Week 12, Adjusted Mean (SE)Adjusted Mean Difference (95% CLs)Test Statistic and p ValueCohen's d Effect Size
      Primary endpoint: CMAI Total
      Brexpiprazole 0.5–2 mg13171.5 (16.8)−18.9 (1.2)−2.34 (−5.49, 0.82)t(230) = −1.46, p = 0.15−0.18
      Placebo13568.6 (16.0)−16.5 (1.1)
      Key secondary endpoint: CGI-S as related to agitation
      Brexpiprazole 0.5–2 mg1314.54 (0.77)−1.32 (0.09)−0.31 (−0.55, −0.06)t(222) = −2.42, p = 0.016
      Nominal p value.
      −0.30
      Placebo1354.51 (0.74)−1.02 (0.09)
      NPI-NH Agitation/Aggression domain
      Brexpiprazole 0.5–2 mg1317.53 (1.89)−4.07 (0.23)−0.87 (−1.50, −0.24)t(202) = −2.73, p = 0.0068−0.34
      Placebo1357.43 (1.82)−3.19 (0.23)
      Post hoc analyses
      Titrated to 2 mg (or equivalent placebo) at Week 4: CMAI Total
      Brexpiprazole7769.2 (15.4)−17.8 (1.4)−5.06 (−8.99, −1.13)t(144) = −2.54, p = 0.012−0.41
      Placebo7468.3 (16.2)−12.8 (1.4)
      Not titrated to 2 mg (or equivalent placebo) at Week 4: CMAI Total
      Brexpiprazole5074.8 (18.1)−19.3 (2.0)1.57 (−3.64, 6.78)t(73) = 0.60, p = 0.550.11
      Placebo6069.0 (16.1)−20.8 (1.8)
      Titrated to 2 mg (or equivalent placebo) at Week 4: CGI-S as related to agitation
      Brexpiprazole774.57 (0.73)−1.34 (0.12)−0.60 (−0.93, −0.27)t(141) = −3.63, p < 0.001−0.59
      Placebo744.55 (0.71)−0.74 (0.12)
      Not titrated to 2 mg (or equivalent placebo) at Week 4: CGI-S as related to agitation
      Brexpiprazole504.46 (0.81)−1.28 (0.14)0.06 (−0.32, 0.43)t(82) = 0.29, p = 0.770.06
      Placebo604.43 (0.77)−1.33 (0.13)
      Notes: MMRM analyses. p values from t test (degrees of freedom provided). CGI-S: Clinical Global Impression – Severity of illness; CLs: confidence limits; CMAI: Cohen-Mansfield Agitation Inventory; MMRM: mixed model for repeated measures; NPI-NH: Neuropsychiatric Inventory – Nursing Home version; SD: standard deviation; SE: standard error.
      a Nominal p value.
      On the key secondary efficacy endpoint of change in CGI-S score as related to agitation from baseline to Week 12, the brexpiprazole 0.5–2 mg group demonstrated a greater improvement than the placebo group (Fig. 6a; Table 4). In post hoc analyses, the subgroup titrated to brexpiprazole 2 mg at Week 4 showed greater improvement in CGI-S score than similarly titrated placebo patients (Fig. 6b; Table 4), whereas those patients who were not titrated to brexpiprazole 2 mg at Week 4 showed no clinically meaningful separation versus similarly titrated placebo (Table 4).
      FIGURE 6
      FIGURE 6Key secondary endpoint in Study 2: effects of brexpiprazole on symptoms of agitation (CGI-S as related to agitation) in a) total efficacy sample and b) subgroup titrated to 2 mg (or equivalent placebo) at Week 4 (post hoc analysis).
      Notes: MMRM analysis. Mean (SD) CGI-S score at baseline: a) placebo, 4.5 (0.7); brexpiprazole 0.5–2 mg, 4.5 (0.8); b) placebo, 4.6 (0.7); brexpiprazole, 4.6 (0.7). CGI-S: Clinical Global Impression – Severity of illness; MMRM: mixed model for repeated measures; SD: standard deviation; SE: standard error. *p <0.05, **p <0.01, ***p <0.001 versus placebo. Specifically, the test statistics (with degrees of freedom) and p values were: a) Week 10, t(233) = −2.21, p = 0.028; Week 12, t(222) = −2.42, p = 0.016; b) Week 4, t(131) = −2.78, p = 0.0063; Week 6, t(138) = −2.12, p = 0.036; Week 10, t(141) = −2.71, p = 0.0076; Week 12, t(141) = −3.63, p = 0.0004.
      Brexpiprazole 0.5–2 mg also demonstrated a greater improvement than placebo for change in NPI-NH Agitation/Aggression score (Table 4).

      Safety and Tolerability

      Study 1

      The incidence of treatment-emergent AEs (TEAEs) over 12 weeks was 65.0% in the brexpiprazole 2 mg group, 49.0% in the brexpiprazole 0.5–1 mg group, and 45.9% in the placebo group. TEAEs with incidence ≥5% among patients receiving brexpiprazole 2 mg were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%); and among patients receiving brexpiprazole 0.5–1 mg was headache (7.6%; Table 5). The majority of TEAEs were mild or moderate in severity. The incidence of serious TEAEs was 9.3% with brexpiprazole 2 mg, 10.2% with brexpiprazole 0.5–1 mg, and 5.2% with placebo. Serious TEAEs reported by more than 1 patient receiving brexpiprazole were urinary tract infection (4 patients with brexpiprazole versus 1 patient with placebo), Alzheimer's type dementia (2 versus 0), agitation (3 versus 0), and chronic obstructive pulmonary disease (2 versus 0). Only one serious TEAE (agitation, brexpiprazole 0.5 mg) was considered related to study drug. Discontinuation due to TEAEs occurred in 4.3% of patients in the brexpiprazole 2 mg group, 8.9% in the brexpiprazole 0.5–1 mg group, and 5.2% in the placebo group. The only TEAEs that led to discontinuation in more than 1 patient receiving brexpiprazole were agitation (4 patients with brexpiprazole versus 1 with placebo) and QTc interval prolongation (2 versus 0).
      TABLE 5Treatment-Emergent Adverse Events in Study 1 (Safety Sample)
      MedDRA Preferred TermPlacebo (n = 135)Brexpiprazole 0.5–1 mg (n = 157)Brexpiprazole 2 mg (n = 140)All Brexpiprazole (n = 297)
      At least one TEAE62 (45.9)77 (49.0)91 (65.0)168 (56.6)
      Discontinued due to TEAE7 (5.2)14 (8.9)6 (4.3)20 (6.7)
      TEAEs occurring in ≥5% of patients in any treatment group
       Headache11 (8.1)12 (7.6)13 (9.3)25 (8.4)
       Insomnia6 (4.4)7 (4.5)8 (5.7)15 (5.1)
       Urinary tract infection2 (1.5)3 (1.9)7 (5.0)10 (3.4)
       Dizziness4 (3.0)1 (0.6)8 (5.7)9 (3.0)
      Notes: Data are number of patients (%) with a TEAE at any time post-baseline. MedDRA: Medical Dictionary for Regulatory Activities; TEAE: treatment-emergent adverse event.
      There were no clinically meaningful between-group mean differences in other safety assessments, including suicidality, EPS, QTc interval, body weight, metabolic parameters, and cognitive dysfunction (Table 6). No patients experienced akathisia as a TEAE.
      TABLE 6Suicidality, EPS, QT Interval, Body Weight, Metabolic Parameters, and Cognitive Dysfunction in Study 1 (Safety Sample)
      Placebo (n = 135)Brexpiprazole 0.5–1 mg (n = 157)Brexpiprazole 2 mg (n = 140)
      Sheehan-STS Total score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      −0.01 (n = 129)0.01 (n = 130)
      Patients in the brexpiprazole 0.5 mg arm were not included in this analysis.
      −0.02 (n = 135)
       Adjusted mean difference versus placebo (95% CLs)0.02 (−0.03, 0.07)−0.01 (−0.06, 0.04)
       Test statistic and p valuet(343) = 0.76, p = 0.45t(343) = −0.43, p = 0.66
      Treatment-emergent suicidal ideation, n (%)
      At any time post-baseline.
      1 (0.7)0 (0.0)0 (0.0)
      SAS Total score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      0.00 (n = 132)0.03 (n = 137)
      Patients in the brexpiprazole 0.5 mg arm were not included in this analysis.
      0.50 (n = 139)
       Adjusted mean difference versus placebo (95% CLs)0.04 (−0.36, 0.44)0.50 (0.11, 0.90)
       Test statistic and p valuet(357) = 0.20, p = 0.85t(357) = 2.50, p = 0.013
      AIMS Movement rating score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      ,
      Defined as the sum of items 1–7 (facial and oral, extremity, and trunk movements).
      −0.07 (n = 132)−0.05 (n = 134)
      Patients in the brexpiprazole 0.5 mg arm were not included in this analysis.
      −0.08 (n = 137)
       Adjusted mean difference versus placebo (95% CLs)0.02 (−0.08, 0.12)−0.01 (−0.11, 0.09)
       Test statistic and p valuet(352) = 0.36, p = 0.72t(352) = −0.15, p = 0.88
      BARS Global score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      −0.05 (n = 132)−0.06 (n = 137)
      Patients in the brexpiprazole 0.5 mg arm were not included in this analysis.
      −0.03 (n = 139)
       Adjusted mean difference versus placebo (95% CLs)0.00 (−0.06, 0.05)0.02 (−0.03, 0.08)
       Test statistic and p valuet(357) = −0.14, p = 0.89t(357) = 0.76, p = 0.45
      At least one EPS-related TEAE, n (%)
      At any time post-baseline.
      3 (2.2)5 (3.2)9 (6.4)
       Hypertonia1 (0.7)1 (0.6)2 (1.4)
       Muscle spasms0 (0.0)1 (0.6)2 (1.4)
       Bradykinesia0 (0.0)0 (0.0)2 (1.4)
       Tremor1 (0.7)2 (1.3)1 (0.7)
       Extrapyramidal disorder0 (0.0)1 (0.6)1 (0.7)
       Parkinsonism0 (0.0)0 (0.0)1 (0.7)
       Psychomotor hyperactivity0 (0.0)0 (0.0)1 (0.7)
       Hypokinesia1 (0.7)1 (0.6)0 (0.0)
       Dyskinesia1 (0.7)0 (0.0)0 (0.0)
      QTcF (ms), change from baseline
      Mean change from baseline to last evaluable value.
      2.7 (n = 133)−0.4 (n = 155)−1.3 (n = 138)
      QTcF prolongation (new onset, >450 ms), n (%)
      At any time post-baseline.
      17 (12.8) (n = 133)10 (6.5) (n = 155)15 (10.9) (n = 138)
      Body weight (kg), change from baseline
      Mean change from baseline to last evaluable value.
      −0.3 (n = 134)−0.10.2
      Weight increase ≥7% from baseline, n (%)
      At any time post-baseline.
      1 (0.7) (n = 134)3 (1.9)3 (2.1)
      Weight decrease ≥7% from baseline, n (%)
      At any time post-baseline.
      6 (4.5) (n = 134)6 (3.8)4 (2.9)
      Fasting metabolic parameters (mg/dL), change from baseline
      Mean change from baseline to last evaluable value.
       Glucose2.80 (n = 108)−2.61 (n = 132)−0.04 (n = 115)
       HDL cholesterol−0.25 (n = 106)−1.36 (n = 131)−1.56 (n = 115)
       LDL cholesterol−3.81 (n = 104)4.62 (n = 131)0.96 (n = 114)
       Total cholesterol−4.77 (n = 106)4.79 (n = 131)−0.05 (n = 115)
       Triglycerides−0.16 (n = 106)10.86 (n = 131)5.62 (n = 115)
      MMSE score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      −0.07 (n = 127)0.00 (n = 123)
      Patients in the brexpiprazole 0.5 mg arm were not included in this analysis.
      0.22 (n = 133)
       Adjusted mean difference versus placebo (95% CLs)0.07 (−0.46, 0.60)0.28 (−0.23, 0.79)
       Test statistic and p valuet(332) = 0.26, p = 0.79t(332) = 1.08, p = 0.28
      Notes: p values from t test (degrees of freedom provided). ANCOVA: analysis of covariance; AIMS: Abnormal Involuntary Movement Scale; BARS: Barnes Akathisia Rating Scale; CLs: confidence limits; EPS: extrapyramidal symptoms; HDL: high-density lipoprotein; LDL: low-density lipoprotein; MMSE: Mini-Mental State Examination; QTcF: QT interval as corrected by Fridericia's formula; SAS: Simpson-Angus Scale; STS: Suicidality Tracking Scale; TEAE: treatment-emergent adverse event.
      a Adjusted mean change from baseline to last evaluable value (ANCOVA).
      b Patients in the brexpiprazole 0.5 mg arm were not included in this analysis.
      c At any time post-baseline.
      d Defined as the sum of items 1–7 (facial and oral, extremity, and trunk movements).
      e Mean change from baseline to last evaluable value.
      Five patients died during the study, all in the brexpiprazole groups—one receiving brexpiprazole 2 mg (end-stage AD), two receiving brexpiprazole 1 mg (aspiration pneumonia, airway obstruction), and two receiving brexpiprazole 0.5 mg (intracranial hemorrhage, acute purulent meningoencephalitis). None of the deaths were considered related to treatment.

      Study 2

      There was no notable difference in the incidence of TEAEs over 12 weeks between the brexpiprazole 0.5–2 mg group (56.8%) and the placebo group (58.4%). TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5–2 mg were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%; Table 7a). The majority of TEAEs were mild or moderate in severity. The incidence of serious TEAEs was 5.3% with brexpiprazole 0.5–2 mg and 4.4% with placebo. The only serious TEAE reported by more than 1 patient receiving brexpiprazole was seizure (3 patients with brexpiprazole; 0 patients with placebo). One of these cases was reported as non-serious by the investigator and upgraded to serious by the sponsor. All three cases of seizure were considered by the investigator to be possibly related to study drug and led to study discontinuation. Discontinuation due to TEAEs occurred in 6.8% of patients receiving brexpiprazole 0.5–2 mg and 0.7% of patients receiving placebo, with seizure being the only TEAE that led to discontinuation in more than 1 patient receiving brexpiprazole.
      TABLE 7Treatment-Emergent Adverse Events in Study 2
      a) In the Safety Sample
      MedDRA Preferred TermPlacebo (n = 137)Brexpiprazole 0.5–2 mg (n = 132)
      At least one TEAE80 (58.4)75 (56.8)
      Discontinued due to TEAE1 (0.7)9 (6.8)
      TEAEs occurring in ≥5% of patients in either treatment group
       Headache17 (12.4)10 (7.6)
       Somnolence5 (3.6)8 (6.1)
       Dizziness7 (5.1)6 (4.5)
      b) By Titration Status
      Titrated to 2 mg (or Equivalent Placebo) at Week 4Not Titrated to 2 mg (or Equivalent Placebo) at Week 4
      MedDRA Preferred TermPlacebo (n = 74)Brexpiprazole (n = 77)Placebo (n = 60)Brexpiprazole (n = 50)
      At least one TEAE42 (56.8)41 (53.2)37 (61.7)31 (62.0)
      Discontinued due to TEAE0 (0.0)5 (6.5)0 (0.0)1 (2.0)
      TEAEs occurring in ≥5% of patients in any treatment subgroup
       Headache6 (8.1)6 (7.8)11 (18.3)4 (8.0)
       Somnolence2 (2.7)6 (7.8)3 (5.0)2 (4.0)
       Dizziness3 (4.1)4 (5.2)4 (6.7)2 (4.0)
       Nausea2 (2.7)4 (5.2)0 (0.0)0 (0.0)
       Nasopharyngitis4 (5.4)2 (2.6)2 (3.3)2 (4.0)
       Decreased appetite4 (5.4)2 (2.6)0 (0.0)1 (2.0)
       Fall2 (2.7)1 (1.3)3 (5.0)1 (2.0)
       Urinary incontinence1 (1.4)1 (1.3)1 (1.7)3 (6.0)
       Arthralgia0 (0.0)1 (1.3)4 (6.7)1 (2.0)
       Tremor4 (5.4)0 (0.0)1 (1.7)3 (6.0)
       Rhinitis3 (4.1)0 (0.0)3 (5.0)0 (0.0)
       Respiratory tract infection0 (0.0)0 (0.0)1 (1.7)3 (6.0)
      Notes: Data are number of patients (%) with a TEAE at any time post-baseline. MedDRA: Medical Dictionary for Regulatory Activities; TEAE: treatment-emergent adverse event.
      In post hoc safety analyses, there was no indication that the overall TEAE profile was different in patients titrated to brexpiprazole 2 mg at Week 4 (Table 7b).
      There were no clinically meaningful between-group mean differences in other safety assessments in the total safety sample, including suicidality, EPS, QTc interval, body weight, metabolic parameters, and cognitive dysfunction (Table 8).
      TABLE 8Suicidality, EPS, QT Interval, Body Weight, Metabolic Parameters, and Cognitive Dysfunction in Study 2 (Safety Sample)
      Placebo (n = 137)Brexpiprazole 0.5–2 mg (n = 132)
      Sheehan-STS Total score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      0.01 (n = 134)0.04 (n = 127)
       Adjusted mean difference versus placebo (95% CLs)0.03 (−0.01, 0.07)
       Test statistic and p valuet(217) = 1.28, p = 0.20
      Treatment-emergent suicidal ideation, n (%)
      At any time post-baseline.
      0 (0.0)0 (0.0)
      SAS Total score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      −0.440.08
       Adjusted mean difference versus placebo (95% CLs)0.52 (0.20, 0.83)
       Test statistic and p valuet(225) = 3.21, p = 0.0015
      AIMS Movement rating score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      ,
      Defined as the sum of items 1–7 (facial and oral, extremity, and trunk movements).
      −0.04 (n = 136)−0.05 (n = 130)
       Adjusted mean difference versus placebo (95% CLs)−0.01 (−0.10, 0.08)
       Test statistic and p valuet(222) = −0.24, p = 0.81
      BARS Global score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      −0.010.00
       Adjusted mean difference versus placebo (95% CLs)0.02 (−0.03, 0.06)
       Test statistic and p valuet(225) = 0.74, p = 0.46
      At least one EPS-related TEAE, n (%)
      At any time post-baseline.
      8 (5.8)11 (8.3)
       Tremor5 (3.6)3 (2.3)
       Akathisia1 (0.7)3 (2.3)
       Dyskinesia0 (0.0)2 (1.5)
       Hypokinesia0 (0.0)2 (1.5)
       Muscle rigidity2 (1.5)1 (0.8)
       Extrapyramidal disorder0 (0.0)1 (0.8)
       Parkinsonism0 (0.0)1 (0.8)
       Akinesia1 (0.7)0 (0.0)
      QTcF (ms), change from baseline
      Mean change from baseline to last evaluable value.
      0.10.3 (n = 131)
      QTcF prolongation (new onset, >450 ms), n (%)
      At any time post-baseline.
      15 (10.9)12 (9.2) (n = 131)
      Body weight (kg), change from baseline
      Mean change from baseline to last evaluable value.
      −0.10.2
      Weight increase ≥7% from baseline, n (%)
      At any time post-baseline.
      2 (1.5)2 (1.5)
      Weight decrease ≥7% from baseline, n (%)
      At any time post-baseline.
      4 (2.9)0 (0.0)
      Fasting metabolic parameters (mg/dL), change from baseline
      Mean change from baseline to last evaluable value.
       Glucose0.11 (n = 125)2.58 (n = 120)
       HDL cholesterol−0.10 (n = 124)0.75 (n = 118)
       LDL cholesterol2.38 (n = 123)−4.19 (n = 118)
       Total cholesterol1.25 (n = 124)−2.67 (n = 118)
       Triglycerides4.80 (n = 124)1.50 (n = 118)
      MMSE score, change from baseline
      Adjusted mean change from baseline to last evaluable value (ANCOVA).
      0.08 (n = 130)−0.36 (n = 124)
       Adjusted mean difference versus placebo (95% CLs)−0.44 (−0.94, 0.06)
       Test statistic and p valuet(210) = −1.72, p = 0.087
      Notes: p values from t test (degrees of freedom provided). ANCOVA: analysis of covariance; AIMS: Abnormal Involuntary Movement Scale; BARS: Barnes Akathisia Rating Scale; CLs: confidence limits; EPS: extrapyramidal symptoms; HDL: high-density lipoprotein; LDL: low-density lipoprotein; MMSE: Mini-Mental State Examination; QTcF: QT interval as corrected by Fridericia's formula; SAS: Simpson-Angus Scale; STS: Suicidality Tracking Scale; TEAE: treatment-emergent adverse event.
      a Adjusted mean change from baseline to last evaluable value (ANCOVA).
      b At any time post-baseline.
      c Defined as the sum of items 1–7 (facial and oral, extremity, and trunk movements).
      d Mean change from baseline to last evaluable value.
      One patient died during the study, from respiratory insufficiency due to pneumonia, having been randomized to the placebo group. In addition, 1 patient died 2 days after the 30-day follow-up period, from a spontaneous subdural hematoma with secondary brain edema, having been randomized to the brexpiprazole group. Neither of these deaths were considered related to study drug.

      DISCUSSION

      These two randomized controlled trials, conducted in parallel, are among the first to directly address agitation as a therapeutic endpoint in AD using a fully powered, placebo-controlled design. In Study 1, brexpiprazole at a fixed dose of 2 mg/day demonstrated superior efficacy versus placebo in patients with AAD, as measured by change in CMAI Total score over 12 weeks (primary endpoint). The brexpiprazole 1 mg/day dose did not separate from placebo. In Study 2, flexibly dosed brexpiprazole in the range of 0.5–2 mg/day did not achieve statistical superiority over placebo on the primary endpoint. Post hoc analyses of Study 2 data showed that patients who were titrated to brexpiprazole 2 mg/day at Week 4 demonstrated superiority over matched placebo patients. Those who remained at 1 mg/day or lower did not separate from placebo. Taken together, data from the two studies suggest that 2 mg/day may be an effective dose of brexpiprazole for the treatment of AAD.
      On the key secondary endpoint of change in CGI-S score as related to agitation over 12 weeks, a numerical benefit was observed for brexpiprazole 2 mg in Study 1, although statistical significance versus placebo was not reached. In Study 2, brexpiprazole was superior to placebo by 0.31 points in the total sample, and by 0.60 points in the post hoc analysis of patients titrated to 2 mg/day at the end of Week 4. Change in NPI-NH Agitation/Aggression domain score followed this same pattern of greater benefit in Study 2 than Study 1. We hypothesize that lack of statistical separation on the CGI-S in Study 1 compared with Study 2 may be because investigators in the flexible-dose study (Study 2) were required to use their clinical judgment of efficacy and tolerability at each time point in order to select a dosing option, and thereby gave a more considered CGI-S rating, whereas fixed dosing required no such clinical judgment. CMAI scores were not similarly affected because of the CMAI's greater objectivity and the corroboration of ratings using diary data. The NPI-NH also requires a judgment of severity based on informant feedback, and therefore, it is perhaps not surprising that the changes in NPI-NH Agitation/Aggression domain score followed changes in CGI-S score more closely than changes in the strictly frequency-based CMAI.
      As well as benefiting patients, brexpiprazole's potential to reduce agitation may provide important benefits for caregivers and healthcare systems, since both caregiver burden and health and social care costs increase with agitation severity.
      • Allegri RF
      • Sarasola D
      • Serrano CM
      • et al.
      Neuropsychiatric symptoms as a predictor of caregiver burden in Alzheimer's disease.
      ,
      • Morris S
      • Patel N
      • Baio G
      • et al.
      Monetary costs of agitation in older adults with Alzheimer's disease in the UK: prospective cohort study.
      In AAD—a clinical condition with a high unmet need for safe and effective pharmacologic treatments—the present studies suggest that brexpiprazole 2 mg/day is a promising therapeutic candidate. Cohen's d effect sizes for brexpiprazole 2 mg versus placebo were 0.25–0.41 for improvement in CMAI Total score, indicating a clinically meaningful effect, supported by meaningful effect sizes on the CGI-S. The results also support the agitation features in the IPA definition, and the use of the CMAI in clinical trials of AAD. A third Phase 3 study is currently underway based on these learnings (NCT03548584).
      Concerns over safety and tolerability are an important consideration in the prescribing of pharmacologic agents to treat agitation in dementia.
      • Reus VI
      • Fochtmann LJ
      • Eyler AE
      • et al.
      The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia.
      ,
      • Rabins PV
      • Blacker D
      • Rovner BW
      • et al.
      American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. Second edition.
      To maximize safety and tolerability in the present study, a slow brexpiprazole titration schedule was implemented, reaching the highest permitted dose (2 mg/day) after a 4-week titration period. In safety analyses, it is standard to include all patients who took at least one dose of study drug. Thus, safety analyses generally included the 0.5 mg dose arm from Study 1, which was discontinued (and excluded from efficacy analyses) in response to other data indicating that this dose was nonefficacious. Overall, brexpiprazole 0.5–2 mg was safe and well tolerated in patients with AAD, as has been observed in schizophrenia and major depressive disorder,
      • Kane JM
      • Skuban A
      • Hobart M
      • et al.
      Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia.
      ,
      • Nelson JC
      • Zhang P
      • Skuban A
      • et al.
      Overview of short-term and long-term safety of brexpiprazole in patients with major depressive disorder and inadequate response to antidepressant treatment.
      with the notable difference that no patients in Study 1, and only 2.3% of patients in Study 2, experienced akathisia while on brexpiprazole. TEAEs generally did not lead to discontinuation, and completion rates were high and comparable between groups. Death rates were low on brexpiprazole (0.0–1.7% during the studies) and placebo (0.0–0.7%), and no deaths were considered related to brexpiprazole treatment. The incidence of TEAEs related to EPS was low, and changes in EPS rating scale scores, metabolic parameters, and MMSE scores were minimal. While it may appear that brexpiprazole offers safety advantages over previously studied antipsychotics,
      • Schneider LS
      • Dagerman KS
      • Insel P
      Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.
      ,
      • Schneider LS
      • Dagerman K
      • Insel PS
      Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials.
      ,
      • Farlow MR
      • Shamliyan TA
      Benefits and harms of atypical antipsychotics for agitation in adults with dementia.
      • Fraser LA
      • Liu K
      • Naylor KL
      • et al.
      Falls and fractures with atypical antipsychotic medication use: a population-based cohort study.
      • Vigen CLP
      • Mack WJ
      • Keefe R
      • et al.
      Cognitive effects of atypical antipsychotic medications in patients with Alzheimer's disease: outcomes from CATIE-AD.
      • Lipkovich I
      • Ahl J
      • Nichols R
      • et al.
      Weight changes during treatment with olanzapine in older adult patients with dementia and behavioral disturbances.
      the present brexpiprazole AAD studies included relatively young patients (mean age: 74 years), and excluded patients with a history of stroke, and patients with probable vascular or mixed dementia. Comparisons with other agents and other trials are therefore limited.
      Approximately two-thirds of patients in the current studies were living in a care facility, with the remaining third in a community-based setting. While increasing generalizability, variations in treatment setting—as well as the international nature of the studies—may have influenced the results. In large, multisite studies, it is difficult to isolate the impact of different standards of care in different countries on the overall treatment effect.
      • Cummings J
      • Reynders R
      • Zhong K
      Globalization of Alzheimer's disease clinical trials.
      Patients must have trialed a nonpharmacologic intervention prior to study entry, and such interventions will also differ between countries. In addition, CMAI ratings will be affected by the different types of informants between patients in a care facility and those in the community. Finally, as with all controlled clinical trials, the exclusion of patients with certain comorbidities and the restrictions placed upon concomitant therapies will limit the generalizability of the findings, since the observed safety profile may not reflect that of the patient population who would receive the drug in clinical practice.
      In conclusion, the results of these two clinical trials suggest that brexpiprazole 2 mg/day has the potential to be an efficacious, safe, and well-tolerated treatment for AAD. Moreover, the studies show that the CMAI is sensitive to drug treatment effects and thus a potentially useful endpoint in future clinical trials aimed at treating AAD.

      Disclosure

      These studies were supported by Otsuka Pharmaceutical Development & Commercialization Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).
      Writing support was provided by Chris Watling, PhD, assisted by his colleagues at Cambridge Medical Communication Ltd (Cambridge, UK), and funded by Otsuka Pharmaceutical Development & Commercialization Inc. and H. Lundbeck A/S.
      Dr. Grossberg serves as a consultant to: Acadia, Alkahest, Allergan, Avanir, Axona, Axovant, BioXcel, GE, Genentech, Novartis, Lundbeck, Otsuka, Roche, and Takeda. He has received research support from Janssen, Roche, and NIA, and has been on Speaker's Bureau for Acadia, and safety monitoring committees for EryDel, Merck, and Newron.
      Drs. Kohegyi, Mergel, Hobart, Slomkowski, Baker, and McQuade are full-time employees of Otsuka Pharmaceutical Development & Commercialization Inc.
      Drs. Josiassen and Meulien are full-time employees of H. Lundbeck A/S.
      Dr. Cummings has provided consultancy to Acadia, Actinogen, AgeneBio, Alkahest, Alzheon, Avanir, Axsome, Biogen, BiOasis, Bracket, Cogniciti, Cortexyme, Demiurge, Diadem, EIP, Eisai, Genentech, Green Valley, Grifols, Idorsia, Hisun, Karuna, Kyowa-Kirin, Lilly, Lundbeck, MedAvante, Merck, Novartis, Otsuka, Pfizer, Proclera, QR, Resverlogix, Roche, Samus, Samumed, Suven, Takeda, Toyama, and United Neuroscience. He has stock options with Prana, Neurokos, Adamas, MedAvante, and QR Pharma, and holds the copyright to the Neuropsychiatric Inventory. Dr. Cummings is supported by Keep Memory Alive (KMA) and NIH/NIGMS COBRE award P20GM109025.
      Previous presentation: Presented at the Annual Meeting of the American Association for Geriatric Psychiatry (AAGP); Honolulu, Hawaii; March 15–18, 2018.

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