Safety and tolerability of inhaled loxapine in subjects with asthma and chronic obstructive pulmonary disease--two randomized controlled trials

Abstract

Background: Loxapine, a first-generation antipsychotic, delivered with a novel inhalation delivery device developed for the acute treatment of agitation in patients with schizophrenia or bipolar disorder was evaluated in subjects with asthma or chronic obstructive pulmonary disease (COPD).

Methods: Separate randomized, double-blind, parallel-arm, placebo-controlled trials compared two administrations of inhaled loxapine (10 mg) 10 hr apart with placebo in 52 subjects with asthma and in 53 subjects with COPD. A thermally-generated drug aerosol of loxapine was delivered to the deep lung for rapid systemic absorption. Controller medications were continued throughout the study, but quick-relief bronchodilators were withheld from 6-8 hr before through 34 hr after dose 1, unless indicated as rescue.

Results: All airway adverse events (AEs) were of mild or moderate severity. Symptomatic bronchospasm occurred in 53.8% of subjects with asthma after inhaled loxapine and 11.5% after placebo; and in 19.2% of COPD subjects after inhaled loxapine and 11.1% after placebo. Subjects required inhaled albuterol as follows: asthma: 53.8% after inhaled loxapine and 11.5% after placebo; and COPD: 23.1% after inhaled loxapine and 14.8% after placebo. Respiratory signs/symptoms requiring treatment responded to rescue bronchodilator [forced expiratory volume in 1 sec (FEV(1)) return to within 10% of baseline] within 1 hr in 11 of 15 events in asthma subjects and four of seven events in COPD subjects, the remainder by the last spirometry.

Conclusions: In subjects with either asthma or COPD, FEV(1) decline and bronchospasm can occur following inhaled loxapine, but more frequently in asthmatic subjects. Most subjects with bronchospasm responded to rescue bronchodilator within 1 hr. No treatment-related serious AE occurred. Although inhaled loxapine is contraindicated in patients with active airways disease per the current approved US labeling, these studies demonstrated that rescue bronchodilator mitigated the symptomatic bronchospasms that may occur in case of inadvertent use.

Trial registration: ClinicalTrials.gov NCT00889837 NCT00890175.

Keywords: ADASUVE; COPD; aerosol; agitation; asthma; inhaled loxapine; randomized; safety.

FIG. 1.

Study design schematic.

FIG. 2.

Staccato drug-device combination product.

FIG. 3.

Disposition of study participants (asthma and COPD studies).

FIG. 4.

Sedation VAS change from baseline (LSMean, 90% CI): (A) Subjects with asthma. (B) Subjects with COPD.

FIG. 5.

FEV₁ % change from baseline, dropouts censored (means±1 SEM). (A) Subjects with asthma. (B) Subjects with COPD. FEV₁ baseline means for placebo and loxapine, respectively, were 3.33 L and 2.93 L for asthma and 1.60 L and 1.55 L for COPD subjects.

FIG. 6.

FEV₁ response to albuterol in the individual subjects (A) with asthma and (B) with COPD. Time 0 in this figure is the time of first albuterol administration and could have occurred anywhere during the study.