Early anti-pseudomonal acquisition in young patients with cystic fibrosis: Rationale and design of the EPIC clinical trial and observational study,☆,☆☆
Introduction
Cystic fibrosis (CF), an autosomal recessive disease lacking a curative therapy, has a current median survival of over 36 years, and affects approximately 25,000–30,000 individuals in the United States and 70,000 people worldwide [1], [2], [3]. The primary cause of morbidity and mortality in patients with CF is progressive obstructive pulmonary disease associated with chronic Pseudomonas aeruginosa (Pa) endobronchial bacterial infection and an intense neutrophil-dominated host inflammatory response [4], [5]. Pa, a ubiquitous environmental bacterium, is the most important pathogen in CF lung disease. Pa infection can begin very early in life, and the prevalence of Pa in respiratory cultures increases with age, from 10–30% at ages 0–5 years to 80% at ages ≥ 18 years [1]. Unlike established Pa infection, features of early Pa infection, including susceptibility to antibiotics, non-mucoid phenotype, and low bacterial density, appear to provide a “window of opportunity” during which time anti-pseudomonal therapy may be effective in eradicating Pa [6], [7], [8]. Over time, the distinct microenvironment in the CF airways allows selection of Pa uniquely adapted for chronic, persistent infection. These organisms are mucoid, form biofilms, become increasingly antibiotic-resistant, are present at high density, and are virtually impossible to eradicate. Chronic Pa infection is clearly associated with poorer clinical outcomes among patients with CF [9], [10], [11], [12]. The risk factors for and clinical impact of early Pa infection are even less understood, yet are of great import to clinicians caring for young patients with CF. Preliminary data suggest a favorable effect of aggressive treatment at first isolation of Pa from respiratory cultures, but data from large randomized trials are lacking [5], [12], [13], [14].
Thus, we designed a randomized trial in children with CF to investigate the benefits and harms of aggressive, early anti-pseudomonal interventions with the goal of delaying or preventing chronic Pa infection and its clinical consequences. Companion to this clinical trial is the first large, multicenter, longitudinal observational study of early lung disease in CF, which enrolled young Pa-negative patients and clinical trial participants. The goal of the observational study is to determine improved strategies for prevention and treatment of early Pa infection.
In order to assess the clinical and microbiologic efficacy of early anti-pseudomonal therapy, and more thoroughly address issues of safety and antimicrobial resistance, the Early Pseudomonas Infection Control multi-center clinical trial (EPIC-CT) and an observational study (EPIC-OBS) target children with CF younger than 12 years of age.
The EPIC-OBS serves both as a freestanding epidemiologic study of risk factors associated with early Pa airway infection, and as an adjunct to the EPIC-CT by providing pre-study data on risk factors potentially affecting response to the trial regimens and post-enrollment follow-up for the clinical trial participants for up to five years (Fig. 1).
The EPIC-CT was designed to allow the randomized controlled evaluation of early intervention with inhaled and oral anti-pseudomonal therapy in young patients with CF at first isolation of Pa from respiratory cultures. Participants meeting the eligibility criteria were offered the opportunity to be enrolled in the clinical trial and initiate or continue simultaneous participation in the observational study. The clinical trial assigned children to two different antimicrobial treatment strategies: (1) Cycled antibiotic therapy, i.e., treatment provided in quarterly cycles regardless of findings from respiratory cultures obtained quarterly, and (2) antibiotic therapy based upon cultures, i.e., treatment based on recovery of Pa from respiratory cultures obtained at scheduled quarterly intervals throughout the 18-month study period (Fig. 2).
To summarize, the overall objectives of the clinical trial are to compare the clinical and microbiological efficacy and safety of cycled therapy versus culture-based therapy, initiated at the time of early Pa infection of the respiratory tract and given over an 18-month study period. Because a true placebo group receiving no anti-pseudomonal antibiotic therapy was not feasible at the time of study initiation in 2004, clinical trial participants will be also compared with two external controls, a concurrent cohort (derived from the EPIC Observational study) that will allow the evaluation of the generalizability of the clinical trial results, and a historical group that will allow the evaluation of low versus high intensity exposure to antipseudomonal antibiotics. This historical group, derived from an existing patient registry and covering a period ranging from 1997–1999, had significantly less exposure to inhaled tobramycin prior to the commercial product's (TOBI) FDA approval in 1998. Children in the historical group will be matched 2:1 for age and gender to each EPIC-CT participant.
Section snippets
Objectives and aims of EPIC-OBS
The primary aim of EPIC-OBS is the identification of risk factors associated with early age at first isolation of Pa from respiratory cultures and with the early emergence of mucoid and antibiotic-resistant strains of Pa, in particular, modifiable exposures, such as environmental tobacco smoke, breastfeeding and daycare. The EPIC-OBS also aims to describe the longitudinal changes in clinical endpoints (e.g., lung function, growth, exacerbation frequency) associated with initial acquisition of Pa
Objectives of EPIC-CT
The primary objectives of the clinical trial are to investigate if an intensive quarterly anti-pseudomonal strategy (cycled therapy) reduces pulmonary exacerbations and the isolation of Pa from respiratory cultures, compared with a strategy of anti-pseudomonal administration solely based upon recovery of positive respiratory cultures collected quarterly (culture-based therapy). The specific primary aim is twofold and includes a clinical and a microbiological endpoint. The clinical endpoint is
Discussion
The major objective of EPIC-CT is to help define a safe, effective and systematic approach to the treatment of first isolation of Pa from young CF patients. These young patients potentially have the most to gain from aggressive early intervention, but also the most to lose in terms of cumulative drug toxicities and acquisition of resistant pathogens. If the study demonstrates both a microbiologic effect and clinical efficacy of aggressive therapy without significant adverse events or high rates
Acknowledgements
The research for this article was supported in part by the Cystic Fibrosis Foundation grants number EPIC0K0 and OBSERV04K0, the National Heart Lung and Blood Institute (NHLBI) and National Institute for Digestive Disorders and Kidney (NIDDK) grant number U01-HL080310, and the National Center for Research Resources (NCRR) grant number ULI-RR2501401. Study drugs and devices were supplied free of charges by Novartis Pharmaceutical Corp. (inhaled tobramycin) and Bayer Healthcare AG (oral
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Financial support: The research for this article was supported in part by the Cystic Fibrosis Foundation grants number EPIC0K0 and OBSERV04K0, the National Heart Lung and Blood Institute (NHLBI) and National Institute for Digestive Disorders and Kidney (NIDDK) grant number U01-HL080310, and the National Center for Research Resources (NCRR) grant number ULI-RR2501401. Study drugs and devices were supplied free of charges by Novartis Pharmaceutical Corp. (inhaled tobramycin) and Bayer Healthcare AG (oral ciprofloxacin and oral placebo), compressors and nebulizers were provided by PARI Respiratory Equipment Inc.
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ClinicalTrial.gov numbers: NCT00676169; NCT00097773.
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Participating clinical sites and investigators are listed in Appendix A.