Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial

Abstract

Tobramycin inhalation solution is used to treat chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients. We evaluated the efficacy and safety of a novel, light-porous particle, dry-powder formulation of tobramycin, which was developed to improve delivery efficiency to the airways and substantially reduce the delivery time. In this randomized, double-blind study, patients with CF (age 6-21 years) received tobramycin inhalation powder (112 mg tobramycin) twice daily (n = 46) or placebo (n = 49) via the T-326 Inhaler for one cycle, followed by two open-label cycles (all patients). Cycles were 28 days on, 28 days off treatment. The primary endpoint was change in forced expiratory volume in 1 sec (FEV1) % predicted from baseline to Day 28 of Cycle 1. The study was terminated early based on positive results in the interim analysis. Tobramycin inhalation powder significantly improved FEV1 % predicted versus placebo at Day 28 (difference 13.3, 95% CI: 5.31-21.28; P = 0.0016). Similar changes in FEV1 were seen in patients switching from placebo to tobramycin inhalation powder in Cycle 2; improvements were maintained over time. Tobramycin inhalation powder also reduced sputum P. aeruginosa density, respiratory-related hospitalization and antipseudomonal antibiotic use versus placebo. The most common adverse event was cough; the frequency of cough was higher in patients receiving placebo (26.5%) versus tobramycin inhalation powder (13.0%) in Cycle 1. Tobramycin inhalation powder was not associated with ototoxicity or nephrotoxicity. Administration time was between 4 and 6 min. In conclusion, tobramycin inhalation powder was effective and well tolerated in CF patients, and may offer an important treatment option to decrease the treatment burden of CF pseudomonas lung infections.

Keywords: Pseudomonas aeruginosa; cystic fibrosis; tobramycin inhalation powder.

Fig. 1

Tobramycin inhalation powder: a novel, light-porous-particle formulation of tobramycin delivered via a simple passive inhaler. a) Hollow, porous particles of tobramycin inhalation powder; b) the T-326 Inhaler

Fig. 2

Study disposition (all randomized patients) *Includes moved, intolerant of inhaler, non-compliance and self discontinuation; TIP = tobramycin inhalation powder

Fig. 3

Relative change from baseline (95% confidence intervals) in forced expiratory volume in 1 second (FEV₁) % predicted over three cycles in patients receiving tobramycin inhalation powder (112 mg tobramycin) (mITT population) Grey dotted line = placebo [placebo for Cycle 1, TIP for Cycles 2 and 3]; black line = TIP [for all 3 cycles]; TIP = tobramycin inhalation powder

Fig. 4

Mean Pseudomonas aeruginosa densities of all phenotypes (mucoid, non-mucoid and small colony variant) over three cycles of treatment in patients receiving tobramycin inhalation powder (112 mg tobramycin) (all treated patients) Grey dotted line = placebo [placebo for Cycle1, TIP for Cycles 2 and 3]; black line = TIP [for all 3 cycles]; TIP = tobramycin inhalation powder; CFU = colony forming unit

Fig. 4

Mean Pseudomonas aeruginosa densities of all phenotypes (mucoid, non-mucoid and small colony variant) over three cycles of treatment in patients receiving tobramycin inhalation powder (112 mg tobramycin) (all treated patients) Grey dotted line = placebo [placebo for Cycle1, TIP for Cycles 2 and 3]; black line = TIP [for all 3 cycles]; TIP = tobramycin inhalation powder; CFU = colony forming unit