Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection

Abstract

Rationale: Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition.

Objectives: To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa.

Methods: 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R).

Results: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs -0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49).

Conclusions: Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

Trial registration: ClinicalTrials.gov NCT00558844 NCT00777296.

Keywords: Bacterial Infection; Cystic Fibrosis; Respiratory Infection.

Figure 1

Patient enrolment across the two Arikace studies. In the European study, 75 patients were screened, and 66 were randomised. In the US study, 56 patients were screened, and 46 were randomised. *Across all randomised subjects, seven subjects withdrew consent prior to dosing. Data shown is for the 105 subjects dosed at least once with Arikace or placebo.

Figure 2

Change in FEV₁ (L) from baseline through day 56. Filled squares, solid line=Arikace 560 mg, *p=0.033 at day 28, *p=0.003 at day 56 (compared with placebo). Filled triangles, solid line=Arikace 280 mg, *p=0.009 at day 28 (compared with placebo). Open squares, dashed line=Arikace 140 mg. Open diamonds, dashed line=Arikace 70 mg. Open circles, dashed line=placebo. The values above the abscissa are the number of subjects in each dose cohort providing data at each time point (70 mg/140 mg/280 mg/560 mg/placebo).

Figure 3

Change in sputum density of Pseudomonas aeruginosa (log₁₀ CFU/g) from baseline through day 35. Filled squares, solid line=Arikace 560 mg, *p=0.007 at day 28, *p=0.021 at day 35. Filled triangles, solid line=Arikace 280 mg. Open squares, dashed line=Arikace 140 mg. Open diamonds, dashed line=Arikace 70 mg. Open circles, dashed line=placebo. The values above the abscissa are the number of subjects in each dose cohort providing data at each time point (70 mg/140 mg/280 mg/560 mg/placebo).

Figure 4

Change in FEV₁ (% predicted) from baseline through cycle 6 of Arikace. Each cycle consisted of 28 days of once daily Arikace (560 mg) followed by 56 days off study drug. Each shaded box is a treatment cycle. Study days (every 2 weeks) are as shown on the abscissa, with the number of subjects at each time point as noted immediately above the study days. *p<0.0001 for FEV₁ at end of treatment following six cycles compared with baseline; **p=0.0001 for FEV₁ at 56 days post-treatment following six cycles compared with baseline.

Figure 5

Change in sputum density of Pseudomonas aeruginosa (log₁₀ CFU/g) from baseline through cycle 6 of Arikace. Each set of three bars is the change in sputum P aeruginosa density compared with baseline (day 1 of cycle 1) for days 1 (white), 14 (gray), and 28 (black) of each respective Arikace cycle. *p=0.003 for change in CFU across all of the Arikace treatment cycles relative to baseline (cycle 1, day 1).