Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial

Abstract

Background: The delivery of antipseudomonal antibiotics by inhalation to Pseudomonas aeruginosa-infected subjects with non-cystic fibrosis (CF) bronchiectasis is a logical extension of treatment strategies successfully developed in CF bronchiectasis. Dual release ciprofloxacin for inhalation (DRCFI) contains liposomal ciprofloxacin, formulated to optimise airway antibiotic delivery.

Methods: Phase II, 24-week Australian/New Zealand multicentre, randomised, double-blind, placebo-controlled trial in 42 adult bronchiectasis subjects with ≥2 pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive P aeruginosa at screening. Subjects received DRCFI or placebo in three treatment cycles of 28 days on/28 days off. The primary outcome was change in sputum P aeruginosa bacterial density to the end of treatment cycle 1 (day 28), analysed by modified intention to treat (mITT). Key secondary outcomes included safety and time to first pulmonary exacerbation-after reaching the pulmonary exacerbation endpoint subjects discontinued study drug although remained in the study.

Results: DRCFI resulted in a mean (SD) 4.2 (3.7) log10 CFU/g reduction in P aeruginosa bacterial density at day 28 (vs -0.08 (3.8) with placebo, p=0.002). DRCFI treatment delayed time to first pulmonary exacerbation (median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol). DRCFI was well tolerated with a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events.

Conclusions: Once-daily inhaled DRCFI demonstrated potent antipseudomonal microbiological efficacy in adults with non-CF bronchiectasis and ciprofloxacin-sensitive P aeruginosa. In this modest-sized phase II study, DRCFI was also well tolerated and delayed time to first pulmonary exacerbation in the per protocol population.

Keywords: Bronchiectasis; Respiratory Infection.

Figure 1

Trial flow diagram (AE, adverse event; CFUs, colony forming units; DRCFI, dual release ciprofloxacin for inhalation; mITT, modified intention to treat; PEx, pulmonary exacerbation; after randomisation, n refers to the number of subjects continuing to receive trial medication, although all subjects were encouraged to continue trial assessments until completion at day 168).

Figure 2

Change in mean sputum Pseudomonas aeruginosa bacterial density across the 24 weeks of the study comparing DRCFI and placebo groups in the modified intention to treat (mITT) population. (Dotted line represents placebo, solid line represents DRCFI; note that data presented here are from both subjects who remained on trial drug and those who had withdrawn from trial drug due to pulmonary exacerbation; *p<0.05, **p<0.01, ***p<0.001 comparing DRCFI and placebo groups for change in bacterial density from baseline; CFU, colony forming unit; DRCFI, dual release ciprofloxacin for inhalation.)

Figure 3

Kaplan–Meier curves comparing DRCFI and placebo groups for time to first pulmonary exacerbation in the modified intention to treat (mITT) population. (Dotted line represents DRCFI, solid line represents placebo; median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol, by log-rank test; DRCFI, dual release ciprofloxacin for inhalation.)