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

Clancy JP, Dupont L, Konstan MW, Billings J, Fustik S, Goss CH, Lymp J, Minic P, Quittner AL, Rubenstein RC, Young KR, Saiman L, Burns JL, Govan JR, Ramsey B, Gupta R, Arikace Study Gro - Thorax (2013)

Bottom Line: Primary outcomes included safety and tolerability.Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021).Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. john.clancy@cchmc.org

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.

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Related in: MedlinePlus

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).
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THORAXJNL2012202230F2: 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).

Mentions: Pulmonary function data are summarised in figure 2. Due to the short duration of the placebo-controlled trial (28 days of dosing), data in the figure are presented as mean raw litre flows and SD (reduced risk of height measurement errors that can occur when reporting the FEV1% predicted). FEV1 in the placebo, 70 and 140 mg dose groups demonstrated no consistent trends over the 28-day treatment period. By contrast, the 280 mg and 560 mg dose groups demonstrated rapid, sustained and significant increases in FEV1 at days 14 and 28 compared with pretreatment values and placebo. In the 280 mg dose group, the change in FEV1 from baseline was higher at day 28 compared with placebo (0.101L±0.128 vs 0.011L±0.101; p=0.009), returning to pretreatment values by day 56 (28 days off study drug). In the 560 mg dose group, the change in FEV1 from baseline was higher at day 28 compared with placebo (0.081L±0.161 vs 0.011L ± 0.101; p=0.033), persisting through day 56 (0.093L±0.203 vs −0.032L±0.119; p=0.003). This corresponded to an % FEV1 predicted treatment effect at day 56 of 12.5%.


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

Clancy JP, Dupont L, Konstan MW, Billings J, Fustik S, Goss CH, Lymp J, Minic P, Quittner AL, Rubenstein RC, Young KR, Saiman L, Burns JL, Govan JR, Ramsey B, Gupta R, Arikace Study Gro - Thorax (2013)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756431&req=5

THORAXJNL2012202230F2: 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).
Mentions: Pulmonary function data are summarised in figure 2. Due to the short duration of the placebo-controlled trial (28 days of dosing), data in the figure are presented as mean raw litre flows and SD (reduced risk of height measurement errors that can occur when reporting the FEV1% predicted). FEV1 in the placebo, 70 and 140 mg dose groups demonstrated no consistent trends over the 28-day treatment period. By contrast, the 280 mg and 560 mg dose groups demonstrated rapid, sustained and significant increases in FEV1 at days 14 and 28 compared with pretreatment values and placebo. In the 280 mg dose group, the change in FEV1 from baseline was higher at day 28 compared with placebo (0.101L±0.128 vs 0.011L±0.101; p=0.009), returning to pretreatment values by day 56 (28 days off study drug). In the 560 mg dose group, the change in FEV1 from baseline was higher at day 28 compared with placebo (0.081L±0.161 vs 0.011L ± 0.101; p=0.033), persisting through day 56 (0.093L±0.203 vs −0.032L±0.119; p=0.003). This corresponded to an % FEV1 predicted treatment effect at day 56 of 12.5%.

Bottom Line: Primary outcomes included safety and tolerability.Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021).Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. john.clancy@cchmc.org

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.

Show MeSH
Related in: MedlinePlus