A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia

Abstract

The objective of this study was to evaluate the efficacy, safety and tolerability of brexpiprazole versus placebo in adults with acute schizophrenia. This was a 6-week, multicenter, placebo-controlled double-blind phase 3 study. Patients with acute schizophrenia were randomized to brexpiprazole 1, 2 or 4 mg, or placebo (2:3:3:3) once daily. The primary endpoint was changed from baseline at week 6 in Positive and Negative Syndrome Scale (PANSS) total score; the key secondary endpoint was Clinical Global Impressions—Severity (CGI-S) at week 6.

Brexpiprazole 4 mg showed statistically significant improvement versus placebo (treatment difference: − 6.47, p = 0.0022) for the primary endpoint. Improvement compared with placebo was also seen for the key secondary endpoint (treatment difference: − 0.38, p = 0.0015), and on multiple secondary efficacy outcomes. Brexpiprazole 1 and 2 mg also showed numerical improvements versus placebo, although p > 0.05. The most common treatment-emergent adverse events were headache, insomnia and agitation; incidences of akathisia were lower in the brexpiprazole treatment groups (4.2%–6.5%) versus placebo (7.1%). Brexpiprazole treatment was associated with moderate weight gain at week 6 (1.23–1.89 kg versus 0.35 kg for placebo); there were no clinically relevant changes in laboratory parameters and vital signs. In conclusion, brexpiprazole 4 mg is an efficacious and well-tolerated treatment for acute schizophrenia in adults.

Clinical Trials.gov NCT01393613; BEACON trial.

Introduction

Schizophrenia is a chronic, severe, progressive and debilitating mental illness (Messias et al., 2007, McGrath et al., 2008) that substantially contributes to disability (Whiteford et al., 2013). In the Global Burden of Disease Study 2010, schizophrenia ranked sixteenth world-wide (ninth in North America), regarding Years Lived with Disability (Vos et al., 2012) and, of 289 studied diseases and injuries, was the illness with the highest disability weighting (Salomon et al., 2012).

Individuals with schizophrenia experience striking and well-known positive symptoms (hallucinations, delusions, thought disorders) but also typically experience negative symptoms (e.g. social withdrawal and lack of emotion, energy and motivation), cognitive symptoms and behavioral changes. Symptoms experienced by patients with schizophrenia can negatively impact their ability to maintain personal relationships, engage productively in work and care for themselves (Lieberman et al., 2001, Bobes et al., 2007, Stip and Tourjman, 2010). Current second-generation antipsychotic treatments for schizophrenia are efficacious for positive symptoms with low propensity to cause extrapyramidal symptoms (EPS) (Kane and Correll, 2010). While these drugs have represented an important advance in treating schizophrenia, it is still important to develop and offer new drugs with pharmacologies that differ from those of currently available drugs, as physicians and patients seek additions to the current armamentarium. The pharmacological profiles of current second-generation antipsychotics vary with respect to affinity for dopamine and/or serotonin receptor subtypes, and adrenergic, histamine and/or muscarinic receptors (Correll, 2010). The different receptor-binding profiles of current antipsychotics may contribute to variance in associated side effects (Correll, 2010), including hyperprolactinemia (and associated sexual effects), sedation, weight gain and other metabolic effects (De Hert et al., 2012, Leucht et al., 2013). The movement disorder akathisia is another common side effect associated with dopamine receptor antagonists, and may be associated with subjective distress in patients (Kane et al., 2009).

Side effects associated with current schizophrenia treatments can affect the ability of the patient to function and interact with others, potentially affecting their subjective well-being and quality of life (Correll, 2010). Treatment choice among currently available antipsychotics for patients with schizophrenia requires trade-offs between different activating and sedating adverse effects; additional, safe treatment options to compensate for the highly heterogeneous responses between individuals are needed (Correll, 2010). There is a need for better tolerated antipsychotics with broad-based symptom control (positive and negative, as well as cognitive and behavioral) that improve patient functioning by having minimal sedating or activating effects, negligible impacts upon prolactin/sexual functioning and inconsequential neuromotor or cardiovascular adverse effects.

Brexpiprazole, a rationally designed serotonin-dopamine activity modulator, acts as a partial agonist with similar potency at serotonin 5-HT_1A and dopamine D₂ receptors, and a potent antagonist at serotonin 5-HT_2A and noradrenaline α_1B and α_2C receptors (Maeda et al., 2014b). Brexpiprazole's D₂ receptor partial agonism with lower intrinsic activity than the only currently available D₂ partial agonist, aripiprazole (Maeda et al., 2014b), suggests a low potential to induce D₂ agonist-mediated adverse effects such as akathisia, insomnia, restlessness and nausea (Fleischhacker, 2005). Brexpiprazole's potential to induce D₂ antagonist-like adverse effects, such as EPS, hyperprolactinemia and tardive dyskinesia, is also considered to be lower than that of D₂ antagonists (Maeda et al., 2014a). In addition, the balanced binding ratio of brexpiprazole to 5-HT_2A, and 5-HT_1A, relative to D₂, may translate into low incidences of both activation-like and antipsychotic-like adverse effects. Finally, brexpiprazole has moderate affinity, relative to D₂/5-HT_1A receptor affinity, for histamine H₁ (Maeda et al., 2014b), which may result in low levels of sedation.

The objective of this study was to evaluate the efficacy, safety and tolerability of three fixed doses of brexpiprazole (1, 2 and 4 mg) compared with placebo in the treatment of acute schizophrenia in adults. The 1 mg group was included to explore the lower efficacious dose of brexpiprazole.