A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients

Patrick A. Flume; Donald R. VanDevanter; Elizabeth E. Morgan; Michael N. Dudley; Jeffery S. Loutit; Scott C. Bell; Eitan Kerem; Rainald Fischer; Alan R. Smyth; Shawn D. Aaron; Douglas Conrad; David E. Geller; J. Stuart Elborn

doi:10.1016/j.jcf.2015.12.004

A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients

Patrick A. Flume^*, Donald R. VanDevanter, Elizabeth E. Morgan, Michael N. Dudley, Jeffery S. Loutit, Scott C. Bell, Eitan Kerem, Rainald Fischer, Alan R. Smyth, Shawn D. Aaron, Douglas Conrad, David E. Geller, J. Stuart Elborn

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

63 Citations (Scopus)

Abstract

Rationale

For patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF.

Objectives

To compare the safety and efficacy of a 28-day course of treatment with LIS 240 mg or placebo BID in persons ≥ 12 years old with CF and chronic P. aeruginosa infection.

Methods

A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28 days in CF patients ≥ 12 years with chronic P. aeruginosa infection. Time to exacerbation was the primary endpoint. FEV₁ (% predicted) and patient-reported quality of life were among secondary endpoints.

Main results

Baseline demographics for 330 subjects (LIS = 220) were similar although significantly more patients randomized to LIS had experienced multiple exacerbations in the year prior to study entry. There was no statistically significant difference in protocol-defined pulmonary exacerbations between treatment arms. Relative change in FEV₁% predicted from baseline was significantly greater for patients randomized to LIS compared to those randomized to placebo (mean difference 1.31%, p = 0.01 [95% CI 0.27, 2.34%]). LIS was well-tolerated, with dysguesia the most frequent adverse event.

Conclusions

LIS did not demonstrate a difference in time to next exacerbation when compared to placebo. Reasons for this result are discussed but may be due to an imbalance in the frequency of prior pulmonary exacerbations between the two groups. An improvement in FEV₁ (% predicted) at 28 days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa.

Original language	English
Pages (from-to)	495-502
Number of pages	8
Journal	Journal of Cystic Fibrosis
Volume	15
Issue number	4
Early online date	04 Feb 2016
DOIs	https://doi.org/10.1016/j.jcf.2015.12.004
Publication status	Published - 28 Jul 2016

Bibliographical note

Publisher Copyright:
© 2015 European Cystic Fibrosis Society

Keywords

Aerosol
Antibiotics
Cystic fibrosis
Fluoroquinolone
Pseudomonas

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health
Pulmonary and Respiratory Medicine

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Flume, P. A., VanDevanter, D. R., Morgan, E. E., Dudley, M. N., Loutit, J. S., Bell, S. C., Kerem, E., Fischer, R., Smyth, A. R., Aaron, S. D., Conrad, D., Geller, D. E., & Elborn, J. S. (2016). A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. Journal of Cystic Fibrosis, 15(4), 495-502. https://doi.org/10.1016/j.jcf.2015.12.004

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title = "A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients",

abstract = "Rationale For patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF. Objectives To compare the safety and efficacy of a 28-day course of treatment with LIS 240 mg or placebo BID in persons ≥ 12 years old with CF and chronic P. aeruginosa infection. Methods A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28 days in CF patients ≥ 12 years with chronic P. aeruginosa infection. Time to exacerbation was the primary endpoint. FEV1 (% predicted) and patient-reported quality of life were among secondary endpoints. Main results Baseline demographics for 330 subjects (LIS = 220) were similar although significantly more patients randomized to LIS had experienced multiple exacerbations in the year prior to study entry. There was no statistically significant difference in protocol-defined pulmonary exacerbations between treatment arms. Relative change in FEV1% predicted from baseline was significantly greater for patients randomized to LIS compared to those randomized to placebo (mean difference 1.31%, p = 0.01 [95% CI 0.27, 2.34%]). LIS was well-tolerated, with dysguesia the most frequent adverse event. Conclusions LIS did not demonstrate a difference in time to next exacerbation when compared to placebo. Reasons for this result are discussed but may be due to an imbalance in the frequency of prior pulmonary exacerbations between the two groups. An improvement in FEV1 (% predicted) at 28 days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa.",

keywords = "Aerosol, Antibiotics, Cystic fibrosis, Fluoroquinolone, Pseudomonas",

author = "Flume, {Patrick A.} and VanDevanter, {Donald R.} and Morgan, {Elizabeth E.} and Dudley, {Michael N.} and Loutit, {Jeffery S.} and Bell, {Scott C.} and Eitan Kerem and Rainald Fischer and Smyth, {Alan R.} and Aaron, {Shawn D.} and Douglas Conrad and Geller, {David E.} and Elborn, {J. Stuart}",

note = "Publisher Copyright: {\textcopyright} 2015 European Cystic Fibrosis Society",

year = "2016",

month = jul,

day = "28",

doi = "10.1016/j.jcf.2015.12.004",

language = "English",

volume = "15",

pages = "495--502",

journal = "Journal of Cystic Fibrosis",

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Flume, PA, VanDevanter, DR, Morgan, EE, Dudley, MN, Loutit, JS, Bell, SC, Kerem, E, Fischer, R, Smyth, AR, Aaron, SD, Conrad, D, Geller, DE & Elborn, JS 2016, 'A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients', Journal of Cystic Fibrosis, vol. 15, no. 4, pp. 495-502. https://doi.org/10.1016/j.jcf.2015.12.004

A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. / Flume, Patrick A.; VanDevanter, Donald R.; Morgan, Elizabeth E. et al.
In: Journal of Cystic Fibrosis, Vol. 15, No. 4, 28.07.2016, p. 495-502.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients

AU - Flume, Patrick A.

AU - VanDevanter, Donald R.

AU - Morgan, Elizabeth E.

AU - Dudley, Michael N.

AU - Loutit, Jeffery S.

AU - Bell, Scott C.

AU - Kerem, Eitan

AU - Fischer, Rainald

AU - Smyth, Alan R.

AU - Aaron, Shawn D.

AU - Conrad, Douglas

AU - Geller, David E.

AU - Elborn, J. Stuart

PY - 2016/7/28

Y1 - 2016/7/28

N2 - Rationale For patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF. Objectives To compare the safety and efficacy of a 28-day course of treatment with LIS 240 mg or placebo BID in persons ≥ 12 years old with CF and chronic P. aeruginosa infection. Methods A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28 days in CF patients ≥ 12 years with chronic P. aeruginosa infection. Time to exacerbation was the primary endpoint. FEV1 (% predicted) and patient-reported quality of life were among secondary endpoints. Main results Baseline demographics for 330 subjects (LIS = 220) were similar although significantly more patients randomized to LIS had experienced multiple exacerbations in the year prior to study entry. There was no statistically significant difference in protocol-defined pulmonary exacerbations between treatment arms. Relative change in FEV1% predicted from baseline was significantly greater for patients randomized to LIS compared to those randomized to placebo (mean difference 1.31%, p = 0.01 [95% CI 0.27, 2.34%]). LIS was well-tolerated, with dysguesia the most frequent adverse event. Conclusions LIS did not demonstrate a difference in time to next exacerbation when compared to placebo. Reasons for this result are discussed but may be due to an imbalance in the frequency of prior pulmonary exacerbations between the two groups. An improvement in FEV1 (% predicted) at 28 days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa.

AB - Rationale For patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF. Objectives To compare the safety and efficacy of a 28-day course of treatment with LIS 240 mg or placebo BID in persons ≥ 12 years old with CF and chronic P. aeruginosa infection. Methods A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28 days in CF patients ≥ 12 years with chronic P. aeruginosa infection. Time to exacerbation was the primary endpoint. FEV1 (% predicted) and patient-reported quality of life were among secondary endpoints. Main results Baseline demographics for 330 subjects (LIS = 220) were similar although significantly more patients randomized to LIS had experienced multiple exacerbations in the year prior to study entry. There was no statistically significant difference in protocol-defined pulmonary exacerbations between treatment arms. Relative change in FEV1% predicted from baseline was significantly greater for patients randomized to LIS compared to those randomized to placebo (mean difference 1.31%, p = 0.01 [95% CI 0.27, 2.34%]). LIS was well-tolerated, with dysguesia the most frequent adverse event. Conclusions LIS did not demonstrate a difference in time to next exacerbation when compared to placebo. Reasons for this result are discussed but may be due to an imbalance in the frequency of prior pulmonary exacerbations between the two groups. An improvement in FEV1 (% predicted) at 28 days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa.

KW - Aerosol

KW - Antibiotics

KW - Cystic fibrosis

KW - Fluoroquinolone

KW - Pseudomonas

U2 - 10.1016/j.jcf.2015.12.004

DO - 10.1016/j.jcf.2015.12.004

M3 - Article

C2 - 26852040

AN - SCOPUS:84957049727

SN - 1569-1993

VL - 15

SP - 495

EP - 502

JO - Journal of Cystic Fibrosis

JF - Journal of Cystic Fibrosis

IS - 4

ER -

Flume PA, VanDevanter DR, Morgan EE, Dudley MN, Loutit JS, Bell SC et al. A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. Journal of Cystic Fibrosis. 2016 Jul 28;15(4):495-502. Epub 2016 Feb 4. doi: 10.1016/j.jcf.2015.12.004