An 8 week open-label interventional multicenter study to explore the lung clearance index as endpoint for clinical trials in cystic fibrosis patients ≥8 years of age, chronically infected with Pseudomonas aeruginosa

Sivagurunathan Sutharsan, Susanne Naehrig, Uwe Mellies, Christian Sieder, Jörg Ziegler, Sivagurunathan Sutharsan, Susanne Naehrig, Uwe Mellies, Christian Sieder, Jörg Ziegler

Abstract

Background: Forced expiratory volume in 1 second (FEV1) is the only parameter currently recognized as a surrogate endpoint in cystic fibrosis (CF) trials. However, FEV1 is relatively insensitive to changes in the small airways of patients with milder lung disease. This pilot study aimed to explore the lung clearance index (LCI) as a marker for use in efficacy trials with inhaled antibiotics in CF.

Methods: This open-label, single-arm study enrolled CF patients with Pseudomonas aeruginosa infection, who were treated with tobramycin (28-day on/off regime). FEV1, LCI and bacterial load in sputum (CFU) were assessed at baseline, after 1, 4 and 8 weeks of treatment.

Results: All patients (n = 17) showed elevated LCI of > 11 despite 3 patients having normal FEV1 (> 90% predicted) at baseline. Overall, LCI improved in 8 (47%) patients and FEV1 in 9 (53%) patients. At week 4, LCI improved by 0.88, FEV1 increased by 0.52%, and P. aeruginosa reduced by 30,481.3 CFU/mL. These changes were however statistically non-significant. Six adverse events occurred in 5/17 (29.4%) patients, most of which were mild-to-moderate in severity.

Conclusions: Due to the low evaluable sample size, no specific trend was observed related to the changes between LCI, FEV1 and CFU. Based on the individual data from this study and from recently published literature, LCI has been shown to be a more sensitive parameter than FEV1 for lung function. LCI can be hypothesized to be an appropriate endpoint for efficacy trials in CF patients if the heterogeneity in lung function is limited by enrolling younger patients or patients with more milder lung disease and thus, limiting the ventilation inhomogeneities.

Trial registration: The study is registered with ClinicalTrials.gov, identifier: NCT02248922.

Keywords: Antibiotics; Clinical trials; Cystic fibrosis; Forced expiratory volume in 1 second; Lung clearance index; Pseudomonas aeruginosa; Tobramycin.

Conflict of interest statement

SS has served as an investigator in clinical trials for Galapagos, Proteostasis, Celtaxsys, Flatley, Novartis Pharma GmbH and Vertex Pharmaceuticals Incorporated and has consulted for Teva GmbH, Novartis Pharma GmbH, Chiesi GmbH and Vertex Pharmaceuticals Incorporated. SN and UM have nothing to disclose. CS and JZ are employees of Novartis Pharma GmbH.

Figures

Fig. 1
Fig. 1
Lung function parameters (LCI and FEV1) and CFU at baseline and over time CFU, colony forming units; FEV1, forced expiratory volume in 1 second; LCI, lung clearance index; SD, standard deviation
Fig. 2
Fig. 2
Matched pairs of relative changes in LCI and FEV1 at week 4 from baseline d, difference; FEV1, forced expiratory volume in 1 second; LCI, lung clearance index

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