Changes in respiratory symptoms during 48-week treatment with ARD-3150 (inhaled liposomal ciprofloxacin) in bronchiectasis: results from the ORBIT-3 and -4 studies

Abstract

It is not known if inhaled antibiotics improve respiratory symptoms in patients with bronchiectasis. In the recent phase-3 ORBIT trials, 48 weeks' treatment with ARD-3150 (inhaled liposomal ciprofloxacin) did not significantly improve symptoms using the prespecified method of analysis comparing baseline symptoms to those after 48 weeks, when patients had been off treatment for 28 days. This method of analysis does not take account of possible improvements in symptoms while on active treatment.A post hoc analysis of two identical randomised trials of ARD-3150 (ORBIT-3 and -4) administered 28 days on and 28 days off in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. The quality-of-life bronchiectasis respiratory symptom scale (QOL-B-RSS), which has a one-week recall period, was administered every 28 days. We examined whether respiratory symptoms improved during on-treatment periods and the relationship of changes in QOL-B-RSS to changes in bacterial load using a mixed-model repeated measures approach.ARD-3150 treatment resulted in a significant improvement in respiratory symptoms during the on-treatment periods with concordant results between ORBIT-3 (estimate 1.4 points, se 0.49; p=0.004) and ORBIT-4 (estimate 1.1 point, se 0.41; p=0.006). The proportion of patients achieving a symptom improvement above the minimum clinically important difference was higher with ARD-3150 compared with placebo during on-treatment cycles (p=0.024). Changes in respiratory symptoms were correlated with changes in bacterial load in the treatment group (r=-0.89, p<0.0001). Individual estimates for decrements in the QOL-B RSS during exacerbation were -9.4 points (se 0.91) in ORBIT-3 and -10.8 points (0.74) in ORBIT-4 (both p<0.0001).Inhaled ARD-3150 resulted in significant improvements in respiratory symptoms during the on-treatment periods which were lost during off-treatment periods. These results supports the concept that reducing bacterial load can improve respiratory symptoms in patients with bronchiectasis.

Trial registration: ClinicalTrials.gov NCT01515007 NCT02104245.

Conflict of interest statement

Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, GlaxoSmithKline, Grifols, Insmed and Boehringer Ingelheim, personal fees from Chiesi, grants from Gilead, outside the submitted work. Conflict of interest: D. Cipolla has patents US 10,420,765, US 9,987,227, US 9,968,555, US 9,844,548, US 9,545,401, US 9,259,424, US 9,078,897, US 9,028,864, US 8,414,915, US 8,268,347, US 8,119,156, and US 8,071,127 issued. Conflict of interest: B. Thompson reports personal fees for consultancy from Aradigm, during the conduct of the study. Conflict of interest: A.M. Davis is an employee of Grifols. Conflict of interest: A. O'Donnell reports personal fees from Aradigm, during the conduct of the study. Conflict of interest: G. Tino has nothing to disclose. Conflict of interest: I. Gonda reports personal fees from Aradigm Corporation, during the conduct of the study; hold shares in Aradigm Corporation, outside the submitted work; and has two patents licensed with Aradigm Corporation. Conflict of interest: C. Haworth reports personal fees for research from Aradigm, personal fees for consultancy and lectures from Grifols, during the conduct of the study; personal fees for consultancy and lectures from Zambon/Profile, personal fees for consultancy from Chiesi, Gilead and GSK, grants and personal fees for consultancy and lectures from Insmed, grants from Novartis, grants and personal fees for lectures from TEVA, outside the submitted work. Conflict of interest: J. Froehlich is an employee of Aradigm.

Copyright ©ERS 2020.