PLACID study: A randomized trial comparing the efficacy and safety of inhaled loxapine versus intramuscular aripiprazole in acutely agitated patients with schizophrenia or bipolar disorder

Abstract

The aim of the study was to investigate the efficacy and safety of inhaled loxapine compared with the intramuscular (IM) antipsychotic aripiprazole in acutely agitated patients with schizophrenia or bipolar I disorder. PLACID was an assessor-blind, parallel-group trial conducted in 23 centres in the Czech Republic, Germany, Spain, and Russia. Patients (aged 18-65 years) diagnosed with schizophrenia or bipolar I disorder experiencing acute agitation (Clinical Global Impression [CGI]-Severity score ≥ 4) while hospitalized or attending an emergency room were randomized to receive up to two doses of inhaled loxapine 9.1 mg or IM aripiprazole 9.75 mg (≥ 2 h between doses) during the 24-h study period. The primary efficacy endpoint was time to response (CGI-Improvement score 1 [very much improved] or 2 [much improved]). The primary analysis included randomized patients who provided informed consent (full analysis set [FAS]); the safety analysis included all patients who received study medication. The FAS comprised 357 patients (enrolled December 2, 2014 - October 31, 2016). The between-treatment difference in median time to CGI-Improvement response was 10 min (95% CI 0.0-30.0); p = 0.0005) in favour of inhaled loxapine (median [95% CI]: 50 min [30.0-50.0] vs 60 min [50.0-90.0] with IM aripiprazole); the difference was significant at 10 min (responders: 14% [loxapine] vs 4% [aripiprazole]; p = 0.001). There were no safety issues. Inhaled loxapine reduced agitation faster than IM aripiprazole, supporting its use as a first-line option for managing acute agitation in patients with schizophrenia or bipolar disorder.

Inhaled Loxapine for the Management of Acute Agitation in Bipolar Disorder and Schizophrenia: Expert Review and Commentary in an Era of Change

“…Most recently, loxapine has been evaluated in a phase IIIb head-to-head study with IM aripiprazole as a comparator agent [ 40 , 41 ]. The PLACID study was performed at 23 centres in the Czech Republic, Germany, Spain and Russia and included 357 adults (aged 18–65 years) with a confirmed diagnosis of schizophrenia or bipolar disorder who presented with acute agitation while hospitalised or while attending an emergency room.…”

“…Among the 357 patients included in the efficacy analysis, 297 had a diagnosis of schizophrenia and 60 had a diagnosis of bipolar I disorder [ 41 ]. The majority ( n = 236) were considered to be moderately and markedly agitated at baseline with nine patients considered to be severely agitated.…”

“…The mean time to CGI-I response was significantly shorter ( p = 0.0005) among patients treated with inhaled loxapine (median 50 min; 95% confidence interval 30.0–50.0) than with IM aripiprazole (median 60 min; 95% confidence interval 50.0–90.0) [ 41 ]. When evaluated separately, the time to CGI-I response remained statistically significantly in favour of inhaled loxapine for patients diagnosed with schizophrenia compared with those treated with IM aripiprazole (50 min vs. 60 min, p = 0.0028), but failed to achieve statistical significance among those with a diagnosis of bipolar disorder (30 min vs. 50 min, p = 0.06), likely owing to the small sample size of this cohort ( n = 60).…”

“…The results of the PLACID study have shown, for the first time, that an inhaled medication—loxapine—is more effective in relieving the symptoms of acute agitation in patients with schizophrenia or bipolar disorder than an IM medication—aripiprazole [ 41 ]. The rapid relief of acute agitation in the emergency psychiatric setting is essential to minimise the risks of self-harm and violence to others or to property.…”

“…The rapid relief of acute agitation in the emergency psychiatric setting is essential to minimise the risks of self-harm and violence to others or to property. The PLACID study employed a pragmatic approach and was conducted in real-world settings, both hospital and emergency room, enrolling patients who would likely receive the medication in routine medical practice [ 41 ].…”