A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients

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

doi:10.1016/j.jcf.2014.12.013

Cited by 64 publications

(51 citation statements)

References 21 publications

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“…Only drugs treating chronic Pseudomonas infection have sought regulatory approval, and relied on reduction in microbial density as a key supportive endpoint (17, 63-65). However in many trials change in FEV 1 is the primary endpoint and this may not always overlap with reductions in Pseudomonas density (66). …”

Section: Biomarkers Of Infectionmentioning

confidence: 99%

Biomarkers for cystic fibrosis drug development

Muhlebach

Clancy

Heltshe

et al. 2016

Journal of Cystic Fibrosis

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Purpose To provide a review of the status of biomarkers in cystic fibrosis drug development, including regulatory definitions and considerations, a summary of biomarkers in current use with supportive data, current gaps, and future needs. Methods Biomarkers are considered across several areas of CF drug development, including cystic fibrosis transmembrane conductance regulator modulation, infection, and inflammation. Results Sweat chloride, nasal potential difference, and intestinal current measurements have been standardized and examined in the context of multicenter trials to quantify CFTR function. Detection and quantification of pathogenic bacteria in CF respiratory cultures (e.g.: Pseudomonas aeruginosa) is commonly used in early phase antimicrobial clinical trials, and to monitor safety of therapeutic interventions. Sputum (e.g.: neutrophil elastase, myeloperoxidase, calprotectin) and blood biomarkers (e.g.: C reactive protein, calprotectin, serum amyloid A) have had variable success in detecting response to inflammatory treatments. Conclusions Biomarkers are used throughout the drug development process in CF, and many have been used in early phase clinical trials to provide proof of concept, detect drug bioactivity, and inform dosing for later-phase studies. Advances in the precision of current biomarkers, and the identification of new biomarkers with ‘omics-based technologies, are needed to accelerate CF drug development.

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Section: Biomarkers Of Infectionmentioning

confidence: 99%

Biomarkers for cystic fibrosis drug development

Muhlebach

Clancy

Heltshe

et al. 2016

Journal of Cystic Fibrosis

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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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“…Clinical trials have however resulted in somewhat conflicting results, [Conrad et al 2015;Dauletbaev et al 2009] so consensus is lacking on the clinical utility of NAC for CF.…”

Section: N-acetyl-l -Cysteinementioning

confidence: 99%

Current and future treatment options for cystic fibrosis lung disease: latest evidence and clinical implications

Edmondson

Davies

2016

Therapeutic Advances in Chronic Disease

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Treatment for cystic fibrosis (CF) has conventionally targeted downstream consequences of the defect such as mucus plugging and infection. More recently, significant advances have been made in treating the root cause of the disease, namely a defective CF transmembrane conductance regulator (CFTR) gene. This review summarizes current pulmonary treatment options and highlights advances in research and development of new therapies

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A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients

Abstract: LIS is a safe and effective therapy for the management of CF patients with chronic P. aeruginosa infection.

Cited by 64 publications

References 21 publications

Biomarkers for cystic fibrosis drug development

Biomarkers for cystic fibrosis drug development

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

Current and future treatment options for cystic fibrosis lung disease: latest evidence and clinical implications

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