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.; Dudley, Michael N.; Loutit, Jeffery S.; Bell, Scott C.; Kerem, Eitan; Fischer, Rainald; Smyth, Alan; Aaron, Shawn D.; Conrad, Douglas; Geller, David E.; Elborn, J. Stuart

doi:10.1016/j.jcf.2015.12.004

Cited by 63 publications

(40 citation statements)

References 20 publications

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“…Flume et al compared the safety and efficacy of a 28-day course of levofloxacin inhalation solution to placebo in a multinational, randomized, double-blind trial in 330 patients with CF. Although there was an improvement in the relative change in FEV 1 percent predicted from baseline (mean difference 1.31%, p = 0.01), there was in the patients randomized to levofloxacin compared to the placebo arm [64]. Possible explanations for these results include insufficient antibiotic concentrations, dissimilarities in the study populations or an inappropriate definition of an exacerbation.…”

Section: Cystic Fibrosismentioning

confidence: 99%

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases

Maselli

Keyt

Restrepo

2017

IJMS

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The management of patients with chronic respiratory diseases affected by difficult to treat infections has become a challenge in clinical practice. Conditions such as cystic fibrosis (CF) and non-CF bronchiectasis require extensive treatment strategies to deal with multidrug resistant pathogens that include Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, Burkholderia species and non-tuberculous Mycobacteria (NTM). These challenges prompted scientists to deliver antimicrobial agents through the pulmonary system by using inhaled, aerosolized or nebulized antibiotics. Subsequent research advances focused on the development of antibiotic agents able to achieve high tissue concentrations capable of reducing the bacterial load of difficult-to-treat organisms in hosts with chronic respiratory conditions. In this review, we focus on the evidence regarding the use of antibiotic therapies administered through the respiratory system via inhalation, nebulization or aerosolization, specifically in patients with chronic respiratory diseases that include CF, non-CF bronchiectasis and NTM. However, further research is required to address the potential benefits, mechanisms of action and applications of inhaled antibiotics for the management of difficult-to-treat infections in patients with chronic respiratory diseases.

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Section: Cystic Fibrosismentioning

confidence: 99%

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases

Maselli

Keyt

Restrepo

2017

IJMS

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“…The 240 mg BID group had the greatest reduction in PA density at day 28, with a −1.19 (log CFU/g sputum) difference vs. the placebo. The MPEX-209 study compared MP-376 to a tobramycin solution for inhalation (TIS) in people with CF who had chronic PA lung infection [37,41]. This study showed that LVX was not inferior to TIS as measured by lung function.…”

Section: Efficacymentioning

confidence: 96%

“…The inhaled LVX aqueous solution initially called MP-376 (brand name Quinsair ® in Europe, or Aeroquin™ in the USA) is a FQ formulation originally developed for the long-term treatment of lung infections caused by PA in cystic fibrosis (CF) patients [32,[37][38][39][40][41][42][43]. This formulation is the first FQ-inhaled formulation approved in the European Union and Canada.…”

Section: Pharmaceutical Properties-developmentmentioning

confidence: 99%

Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

Brillault

Tewes

2020

Pharmaceutics

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Pulmonary drug delivery is a promising strategy to treat lung infectious disease as it allows for a high local drug concentration and low systemic side effects. This is particularly true for low-permeability drugs, such as tobramycin or colistin, that penetrate the lung at a low rate after systemic administration and greatly benefit from lung administration in terms of the local drug concentration. However, for relatively high-permeable drugs, such as fluoroquinolones (FQs), the rate of absorption is so high that the pulmonary administration has no therapeutic advantage compared to systemic or oral administration. Formulation strategies have thus been developed to decrease the absorption rate and increase FQs’ residence time in the lung after inhalation. In the present review, some of these strategies, which generally consist of either decreasing the lung epithelium permeability or decreasing the release rate of FQs into the epithelial lining fluid after lung deposition, are presented in regards to their clinical aspects.

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“…This 28-day on/off regimen, which was selected in an attempt to reduce emergence of tobramycin resistance [16], became the approved indication for inhaled tobramycin and eventually a standard of care in North America. Subsequent inhaled aztreonam [17,18] and inhaled levofloxacin [19,20] development programs have reinforced the “on/off” inhaled antipseudomonal antibiotic treatment paradigm. Initially, this “on/off” period treatment paradigm facilitated creative study designs utilizing placebo controls: patients could be randomized to a new inhaled antibiotic or placebo in the off period following a standard 28-day “on” treatment (in essence a randomized treatment withdrawal design).…”

Section: Efficacy Of Chronic Inhaled Antibiotic Treatmentsmentioning

confidence: 99%

Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies

VanDevanter

Mayer-Hamblett

2017

Current Opinion in Pulmonary Medicine

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Purpose of review Evolving cystic fibrosis (CF) ‘standards of care’ have influenced recent CF clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection. Recent findings Three CF therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced CF Transmembrane Conductance Regulator [CFTR] protein function) differ with respect to the duration for which recognized ‘standards of care’ have been available. However, developers of new therapies in all three areas are affected by similar challenge: standards of care have become so strongly entrenched that traditional placebo-controlled studies in CF populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active comparator trial designs, which have substantial challenges of their own. Foremost among these are the selection of ‘valid’ active comparator(s), estimation of a comparator’s current clinical efficacy (required for testing non-inferiority hypotheses), and effective blinding of commercially available comparators. Summary Recent and future CF clinical trial designs will have to creatively address this collateral result of successful past development of effective CF therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies.

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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

Cited by 63 publications

References 20 publications

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases

Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies

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