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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 (% 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.
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THORAXJNL2012202230F4: 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.

Mentions: A subgroup of subjects in the European trial (n=49) were enrolled into an open-label extension study to evaluate the safety, tolerability and efficacy of six repeat cycles of Arikace treatment (560 mg daily for 28 days) followed by 56 days off treatment. Baseline characteristics of this group are included in table 3, and changes in FEV1% predicted, P aeruginosa sputum CFUs/g, and the distribution of median MIC50 of Pseudomonas isolates are shown in figures 4, 5, and online supplementary figure S3, respectively. Repeat dosing with Arikace was well tolerated with four subjects discontinuing study drug over six cycles and 15 subjects experiencing SAEs (pulmonary exacerbations requiring treatment with antibiotics). Online supplementary table S7 summarises the AEs reported during the open-label extension. Of 49 subjects, 48 experienced at least one AE, with approximately one-third experiencing an SAE (none related to study drug). The majority of reported AEs (59%) were mild and most were classified as either infectious or respiratory. Of the 351 total AEs reported, 33 were categorised as possibly or probably related to study drug, and there were no deaths. FEV1% predicted (figure 4) demonstrated rapid and sustained increases for each treatment cycle, with an estimated mean increase of FEV1 (%) of 7.9% from baseline to end of the 28-day dosing period for the six cycles (p<0.0001), and a mean increase of 5.7% from baseline to end of day 84 (56 days post-treatment) across all six cycles (p=0.0001). P aeruginosa CFU/g were reduced across the treatment cycles (log10 CFUs of −0.53 at day 28 of the first treatment cycle (p=0.025)), with an estimated mean change in log10 CFUs of −0.60 from baseline over all measurements (p=0.003) across all six treatment cycles (figure 5). Median MIC50 values for P aeruginosa isolates demonstrated no significant change over all cycles (see online supplementary figure S3).


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

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

THORAXJNL2012202230F4: 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.
Mentions: A subgroup of subjects in the European trial (n=49) were enrolled into an open-label extension study to evaluate the safety, tolerability and efficacy of six repeat cycles of Arikace treatment (560 mg daily for 28 days) followed by 56 days off treatment. Baseline characteristics of this group are included in table 3, and changes in FEV1% predicted, P aeruginosa sputum CFUs/g, and the distribution of median MIC50 of Pseudomonas isolates are shown in figures 4, 5, and online supplementary figure S3, respectively. Repeat dosing with Arikace was well tolerated with four subjects discontinuing study drug over six cycles and 15 subjects experiencing SAEs (pulmonary exacerbations requiring treatment with antibiotics). Online supplementary table S7 summarises the AEs reported during the open-label extension. Of 49 subjects, 48 experienced at least one AE, with approximately one-third experiencing an SAE (none related to study drug). The majority of reported AEs (59%) were mild and most were classified as either infectious or respiratory. Of the 351 total AEs reported, 33 were categorised as possibly or probably related to study drug, and there were no deaths. FEV1% predicted (figure 4) demonstrated rapid and sustained increases for each treatment cycle, with an estimated mean increase of FEV1 (%) of 7.9% from baseline to end of the 28-day dosing period for the six cycles (p<0.0001), and a mean increase of 5.7% from baseline to end of day 84 (56 days post-treatment) across all six cycles (p=0.0001). P aeruginosa CFU/g were reduced across the treatment cycles (log10 CFUs of −0.53 at day 28 of the first treatment cycle (p=0.025)), with an estimated mean change in log10 CFUs of −0.60 from baseline over all measurements (p=0.003) across all six treatment cycles (figure 5). Median MIC50 values for P aeruginosa isolates demonstrated no significant change over all cycles (see online supplementary figure S3).

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