Long-term safety of tobramycin inhalation powder in patients with cystic fibrosis: phase IV (ETOILES) study

Abstract

Objective: Long-term treatment with inhaled antibiotics is recommended for chronic Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients. The ETOILES study (Clinicaltrials.gov identifier: NCT01519661) evaluated the safety of tobramycin inhalation powder (TIP) for 1 year.

Research design and methods: This single-arm, open-label, multicenter, phase IV trial, enrolled CF patients aged ≥6 years, with baseline FEV₁ ≥25%–≤75% predicted and Pa infection, and assessed the safety of TIP over six cycles in terms of the incidence of treatment-emergent adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included presence of airway reactivity, relative change in FEV₁% predicted, and change in sputum Pa density (log₁₀ colony forming units/g sputum).

Results: A total of 157 patients were enrolled, and 96 patients (61.1%) completed the study. The most commonly reported AE was infective pulmonary exacerbation of CF (55.4%). Cough was reported as an AE in 23.6% of patients; a majority were mild or moderate and two were severe (1.3%). SAEs were reported by 31.2% of patients. No deaths were reported during the study. There were no clinically meaningful changes reported in airway reactivity. Most frequently reported post-inhalation event was cough at all time points; however, it was of short duration (<4 minutes) and decreased over the course of the study, possibly due to patients becoming more experienced with the administration of TIP. The post-inhalation events resolved without intervention in most cases. FEV₁% predicted remained stable from Cycles 1 to 4 and tended to decrease thereafter, although it was not statistically significant (change from baseline to study end mean [SD] = −1.9% [14.55]; P = 0.199).

Conclusions: This was one of the largest studies with long-term TIP exposure. The majority of patients enrolled were adults with more advanced CF lung disease than those in previous TIP studies. No new emerging safety signals were seen and efficacy was sustained during the year.

Keywords:

• Cystic fibrosis
• Dry powder inhaler (DPI)
• Pseudomonas aeruginosa
• Safety
• Tobramycin

Transparency

Declaration of funding

The study was sponsored by Novartis Pharma AG. Novartis, the manufacturer of TIP, was responsible for the design of the study and analysis of the data and, in collaboration with the other authors, was involved in interpretation and presentation of the data for this report.

Declaration of financial/other relationships

G.A., A.V., W.C. and L.D. have disclosed that they are full-time employees of Novartis. U.S. has disclosed that she has no significant relationships with or financial interests in any commercial companies related to this study or article. I.V.-L. has disclosed that she is a consultant for Novartis and has received clinical trial funding from Celtaxsys and Vertex.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors would like to acknowledge the contribution for a part of the statistical analysis by Marc Vandemeulebroecke, who was an employee of Novartis at the time this study was conducted. The authors were assisted in the preparation of the manuscript by Shaswati Khan (Novartis).

Previous presentation: Primary results for this work were presented as posters at: the 37th European Cystic Fibrosis Conference, Gothenburg, Sweden, 11–14 June 2014; and the 28th Annual North American Cystic Fibrosis Conference, Atlanta, GA, USA, 9–11 October 2014.