Tobramycin inhalation powder manufactured by improved process in cystic fibrosis: the randomized EDIT trial

Abstract

Background:

Tobramycin inhalation powder (TIP) was reported to be effective in two Phase III studies in patients with cystic fibrosis (CF) chronically infected with Pseudomonas aeruginosa (Pa). The EDIT study evaluated the efficacy and safety of TIP manufactured by an improved process in CF subjects aged 6–21 years.

Methods:

CF patients with a forced expiratory volume in 1 second (FEV₁) ≥25% to ≤80% predicted, positive Pa cultures and inhaled antipseudomonal therapy naïve (or at least for past 4 months) were enrolled into this double-blind, multicenter trial. Patients were randomized to receive TIP or placebo (1:1) twice daily for one treatment cycle (28.5 days on drug, 28 days off drug). The primary endpoint was relative change in FEV₁ percentage predicted from baseline to day 29. A pre-specified sensitivity analysis evaluated absolute change in FEV₁% predicted. Other endpoints included Pa sputum density and safety.

Results:

A total of 62 patients out of a target of 100 (mean age 12.9 years, baseline FEV₁ 59.2% predicted, Pa sputum density 7.4 log₁₀ colony forming units [CFU] per gram) were randomized. Mean treatment differences (TIP - placebo) were 5.9% (p = 0.148) and 4.4% (p < 0.05) for relative and absolute change in FEV₁% predicted respectively. TIP significantly reduced Pa sputum density by −1.2 log₁₀ CFU (p = 0.002). Treatment with TIP was well tolerated.

Conclusions:

Relative change in FEV₁% predicted with TIP treatment was in the expected range based on the literature, but did not reach statistical significance versus placebo. Placebo control and use of treatment naïve patients led to significant recruitment challenges and an underpowered study with consequent impact on the generated data. However, significant improvements in other outcomes including absolute change in FEV₁% predicted and reduction in Pa sputum density indicate that TIP is efficacious and well tolerated in CF patients.

ClinicalTrials.gov identifier:

ClinicalTrials.gov identifier: NCT00918957.

Keywords::

• Cystic fibrosis
• Dry powder inhaler
• Inhalation therapy
• Pseudomonas lung infection
• Tobramycin

Transparency

Declaration of funding

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

Declaration of financial/other relationships

A.G.C. and I.G. received reimbursement from Novartis to cover their costs as clinical investigators for this study. M.W.K. has consulting relationships with Aradigm, CSL-Behring, Genentech, GlaxoSmithKline, KaloBios, Gilead Sciences, Insmed, Novartis Pharmaceuticals and Vertex Pharmaceuticals. G.A., F.B. and M.H. are employees of Novartis. S.P. and K.T. were employees of Novartis at the time this study was conducted.

CMRO peer reviewers on this manuscript have received honoraria for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

The authors were assisted in the preparation of the manuscript by Mary Sayers, professional medical writer contracted to CircleScience (Macclesfield, UK), and Mark Fedele (Novartis). Writing support was funded by the study sponsor.

Previous presentation: The 35th European Cystic Fibrosis Conference, Dublin, Ireland, 6–9 June 2012. Abstract publication: Galeva I, Konstan MW, Higgins M et al. A challenging double-blind, placebo-controlled study of tobramycin inhalation powder in cystic fibrosis: results of the EDIT trial. J Cyst Fibros 2012;11(Suppl 1):S12.

Notes

¹Tobi is a registered trade name of Novartis Pharma AG, Basel, Switzerland

²TIP is a registered trade name of Novartis Pharma AG, Basel, Switzerland