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ABSTRACT: Cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians, affects approximately 70 000 individuals worldwide. In 1998, the Cystic Fibrosis Foundation (CFF) launched the CF Therapeutics Development Network (CF-TDN) as a central element of its Therapeutics Development Programme. Designed to accelerate the clinical evaluation of new therapies needed to fulfil the CFF mission to control and cure CF, the CF-TDN has conducted 75 clinical trials since its inception, and has contributed to studies as varied as initial safety and proof of concept trials to pivotal programmes required for regulatory approval. This review highlights recent and significant research efforts of the CF-TDN, including a summary of contributions to studies involving CF transmembrane conductance regulator (CFTR) modulators, airway surface liquid hydrators and mucus modifiers, anti-infectives, anti-inflammatories, and nutritional therapies. Efforts to advance CF biomarkers, necessary to accelerate the therapeutic goals of the network, are also summarised.
Thorax 10/2012; 67(10):882-90. · 6.84 Impact Factor
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Miriam M Treggiari, George Retsch-Bogart,
Nicole Mayer-Hamblett,
Umer Khan,
Michal Kulich,
Richard Kronmal,
Judy Williams,
Peter Hiatt,
Ronald L Gibson,
Terry Spencer,
David Orenstein,
Barbara A Chatfield,
Deborah K Froh,
Jane L Burns,
Margaret Rosenfeld,
Bonnie W Ramsey
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ABSTRACT: To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection.
Randomized controlled trial.
Multicenter trial in the United States.
Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection.
Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures.
The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures.
The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio, 0.95; 95% confidence interval [CI], 0.54-1.66) or ciprofloxacin and placebo (hazard ratio, 1.45; 95% CI, 0.82-2.54). The odds ratios of P aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 (95% CI, 0.49-1.23) and 1.10 (95% CI, 0.71-1.71) comparing ciprofloxacin vs placebo. Adverse events were similar across groups.
No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits.
ClinicalTrials.gov Identifier: NCT00097773.
Archives of pediatrics & adolescent medicine 09/2011; 165(9):847-56. · 3.73 Impact Factor
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ABSTRACT: The risk of pulmonary exacerbation following Pseudomonas aeruginosa (Pa) acquisition in children with cystic fibrosis (CF) is unknown.
To determine if failure of antibiotic therapy to eradicate Pa and frequency of Pa recurrence are associated with increased exacerbation risk.
The cohort included 282 children with CF who participated in the EPIC trial ages 1-12 with newly acquired Pa, defined as either a first lifetime Pa positive respiratory culture or positive after two years of negative cultures (past isolation of Pa but >2 years prior to the trial). All received antibiotics to promote initial eradication followed by 15 months of intermittent maintenance antibiotics. Quarterly cultures were used to define initial eradication success and subsequent number of Pa recurrences. A standardized symptom-based definition of exacerbation was utilized. Cox proportional hazards models were used to estimate exacerbation risk.
Failure to initially eradicate Pa was associated with exacerbation risk (hazard ratio [HR]: 2.49, 95% confidence interval [CI] 1.26, 4.93). In 245/282 with successful initial eradication during the trial, past isolation of Pa >2 years before the trial was the most significant predictor of exacerbation (HR 1.62, 95% CI 1.12, 2.35). In 37/282 who failed initial eradication, persistent Pa during the maintenance phase (1 or more Pa recurrences after failure to initially eradicate) added even greater exacerbation risk (HR 4.13, 95% CI 1.28, 13.32).
Children with CF who fail to eradicate after initial antibiotic treatment are at higher risk of subsequent exacerbation, suggesting clinical benefit to successful early eradication of Pa infection.
Pediatric Pulmonology 08/2011; 47(2):125-34. · 2.53 Impact Factor
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Margaret Rosenfeld,
Julia Emerson,
Sharon McNamara,
Kelli Joubran, George Retsch-Bogart,
Gavin R Graff,
Hector H Gutierrez,
Jamshed F Kanga,
Thomas Lahiri,
Blake Noyes,
Bonnie Ramsey,
Clement L Ren,
Michael Schechter,
Wayne Morgan,
Ronald L Gibson
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ABSTRACT: The EPIC Observational Study is an ongoing prospective cohort study investigating risk factors for and clinical outcomes associated with early Pseudomonas aeruginosa (Pa) acquisition in young children with cystic fibrosis (CF).
To describe the baseline characteristics of the cohort and evaluate associations between potential risk factors and nutritional and respiratory characteristics at enrollment. We hypothesized that distinct demographic and environmental risk factors could be identified for poorer nutritional status and lung function at enrollment.
During 2004-2006, 1,700 children with CF were enrolled at 59 US CF centers. Children <or=12 years were eligible if they had no prior Pa infection (Pa-Never) or, if prior isolation of Pa from respiratory cultures, at least a 2-year history of Pa negative cultures (Pa-Past).
One thousand one hundred seventeen participants (65.7%) were Pa-Never and 583 (34.3%) Pa-Past. Pa-never patients had a lower proportion of CFTR genotypes with both mutations in functional classes I, II, or III), higher lung function and less respiratory symptoms. Diagnosis after newborn or prenatal screening was associated with significantly higher mean weight, height, and FEV(1) at enrollment, while maternal smoking during pregnancy appeared to worsen these parameters.
Children in this cohort with a remote history of Pa infection had a higher proportion of CFTR genotypes associated with severely reduced CFTR function as well as lower lung function and more respiratory symptoms than those without prior Pa infection. These observed differences in respiratory indices may reflect the impact of prior Pa airway infection and/or of CFTR genotype or other genetic factors predisposing both to earlier Pa acquisition and more severe lung disease. Key characteristics associated with nutritional and pulmonary status at enrollment included diagnosis after prenatal or neonatal screening (protective) and in utero cigarette exposure (harmful).
Pediatric Pulmonology 09/2010; 45(9):934-44. · 2.53 Impact Factor
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ABSTRACT: Cystic fibrosis (CF) is a life-shortening disease with significant morbidity. Despite overall improvements in survival, patients with CF experience frequent pulmonary exacerbations and declining lung function, which often accelerates during adolescence. New treatments target steps in the pathogenesis of lung disease, such as the basic defect in CF (CF Transmembrane Conductance Regulator [CFTR]), pulmonary infections, inflammation, and mucociliary clearance. These treatments offer hope but also present challenges to patients, clinicians, and researchers. Comprehensive assessment of efficacy is critical to identify potentially beneficial treatments. Lung function and pulmonary exacerbation are the most commonly used outcome measures in CF clinical research. Other outcome measures under investigation include measures of CFTR function; biomarkers of infection, inflammation, lung injury and repair; and patient-reported outcomes. Molecular diagnostics may help elucidate the complex CF airway microbiome. As new treatments are developed for patients with CF, efforts should be made to balance treatment burden with quality of life. This review highlights emerging treatments, obstacles to optimizing outcomes, and key future directions for research.
Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 10/2009; 9(1):1-16. · 3.19 Impact Factor
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ABSTRACT: The primary cause of morbidity and mortality in patients with cystic fibrosis (CF) is progressive obstructive pulmonary disease due to chronic endobronchial infection, particularly with Pseudomonas aeruginosa (Pa). Risk factors for and clinical impact of early Pa infection in young CF patients are less well understood.
The present studies are designed to evaluate risk factors and outcomes associated with early Pa acquisition, and the benefits and harms of four anti-pseudomonal treatment regimens in young CF patients initiated after the first Pa positive respiratory culture.
The Early Pseudomonas Infection Control (EPIC) program consists of two studies, a randomized multicenter trial in CF patients ages 1-12 years at first isolation of Pa from a respiratory culture, and a longitudinal cohort study enrolling Pa-negative patients. Using a factorial design, trial participants are assigned for 18 months to either anti-pseudomonal treatment on a scheduled quarterly basis (cycled therapy) or based on recovery of Pa from quarterly respiratory cultures (culture-based therapy). The study drugs include inhaled tobramycin (300 mg BID) for 28 days, combined with either oral ciprofloxacin (15-20 mg/kg BID) or oral placebo for 14 days. The primary endpoints of the trial are the time to pulmonary exacerbation requiring IV antibiotics or hospitalization for respiratory symptoms, and the proportion of patients with new Pa-positive respiratory cultures during the study. The broad goals of the observational study are to describe the risk factors and outcomes associated with early acquisition of Pa. 306 patients were randomized in the clinical trial and 1787 were enrolled in the cohort study.
These companion studies will provide valuable epidemiological and microbiological information on early CF lung disease and Pa acquisition, and safety and clinical efficacy data on anti-pseudomonal treatment strategies for early Pa infections in the airways of young children with CF.
Contemporary clinical trials 02/2009; 30(3):256-68. · 1.51 Impact Factor
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ABSTRACT: The primary cause of morbidity and mortality in children with cystic fibrosis (CF) is the progression of obstructive lung disease secondary to chronic endobronchial infection, mainly caused by Pseudomonas aeruginosa (Pa). Initial Pa isolates are typically non-mucoid, usually susceptible to most anti-pseudomonal antibiotics, and potentially amenable to eradication. Preliminary studies of early intervention suggest a "window of opportunity" with anti-pseudomonal antibiotics to eradicate Pa from upper and lower airways. Several large trials in young children with CF are currently ongoing with the goals of (1) investigating if early intervention at the time of initial Pa acquisition is effective and safe and (2) identifying the least invasive and safest treatment regimen to achieve both microbiologic and clinical benefits.
Pediatric Pulmonology 10/2007; 42(9):751-6. · 2.53 Impact Factor
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Ronald L Gibson,
Julia Emerson,
Nicole Mayer-Hamblett,
Jane L Burns,
Sharon McNamara,
Frank J Accurso,
Michael W Konstan,
Barbara A Chatfield, George Retsch-Bogart,
David A Waltz,
James Acton,
Pamela Zeitlin,
Peter Hiatt,
Richard Moss,
Judy Williams,
Bonnie W Ramsey
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ABSTRACT: Among young children with cystic fibrosis (CF), Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality. Early intervention strategies include tobramycin solution for inhalation (TSI), which can eradicate lower airway Pa from cultures obtained at the end of 28 days of treatment in young children.
We conducted an open label, sequential cohort study of TSI in young children with CF to investigate duration of antimicrobial treatment effect. The primary outcome was lower airway Pa eradication per bronchoalveolar lavage (BAL) fluid culture. Sequential treatment cohorts varied by duration of treatment (28 or 56 days) and timing of follow-up BAL (at Days 56, 84, or 112). Subjects (N = 36) were treated with TSI, 300 mg twice daily, for 28 days or 56 days per cohort assignment.
Among 31 evaluable subjects, culture based, lower airway Pa eradication was observed in the majority of subjects for up to 1-3 months following TSI treatment: 75% in Cohort 28/56 (days of treatment/day of follow-up BAL), 63% in Cohort 28/84, 82% in Cohort 56/112, and 75% in Cohort 28/112. Non-mucoid Pa at baseline and/or exotoxin A seronegativity were associated with higher rates of eradication. There was a less pronounced effect of TSI treatment on Pa eradication from oropharyngeal cultures in all cohorts. TSI treatment was associated with reduced neutrophilic airway inflammation and was not related to any serious adverse events.
TSI monotherapy is safe and can eradicate lower airway Pa for up to 3 months after treatment in young children with CF.
Pediatric Pulmonology 08/2007; 42(7):610-23. · 2.53 Impact Factor
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Robin Deterding, George Retsch-Bogart,
Laura Milgram,
Ron Gibson,
Cori Daines,
Pamela L Zeitlin,
Carlos Milla,
Bruce Marshall,
Lisa Lavange,
Jean Engels,
Dave Mathews,
Joann Gorden,
Amy Schaberg,
Judy Williams,
Bonnie Ramsey
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ABSTRACT: Denufosol tetrasodium (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease.
Pediatric Pulmonology 05/2005; 39(4):339-48. · 2.53 Impact Factor
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Richard B Moss,
Nicole Mayer-Hamblett,
Jeffrey Wagener,
Cori Daines,
Kathryn Hale,
Richard Ahrens,
Ronald L Gibson,
Paula Anderson, George Retsch-Bogart,
Samya Z Nasr,
Imre Noth,
David Waltz,
Pamela Zeitlin,
Bonnie Ramsey,
Karen Starko
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ABSTRACT: Interferon gamma-1b (IFN-gamma1b) is a pleiotropic cytokine with immunomodulatory activities that could decrease bacterial burden, inflammation, and obstruction in patients with CF. Patients with CF (> or =12 years old, FEV1 > or =40% predicted) were randomly assigned to sequential dose cohorts inhaling 500 microg IFN-gamma1b, 1,000 microg IFN-gamma1b, or placebo by Respirgard II nebulizer thrice weekly for 12 weeks. Sputum bacterial density and spirometry were measured. Safety, antibiotic use, hospitalization, and sputum neutrophils, elastase, DNA, IL-8, and myeloperoxidase were also evaluated. Sixty-six patients (mean age, 24 years, with mean baseline FEV1 of 74 +/- 20 (SD) percent predicted) were studied. One patient had bronchospasm after the first dose of IFN-gamma1b; the overall withdrawal rate was 15% (5 in the placebo group, 2 in the 500-microg IFN-gamma1b group, and 3 in the 1,000 microg IFN-gamma1b group). The 500-microg IFN-gamma1b dose was well-tolerated, but the 1,000-mug dose cohort, who had a higher baseline bacterial density than placebo patients (mean difference, 1.2 log(10) CFU/g sputum, 95% confidence interval (CI), 0.1,2.8, P=0.04), had 24% more hospitalizations for exacerbation than placebo patients (95% CI, 2,45%, P=0.05). There was a 0.12-l difference between the 500-microg IFN-gamma1b and placebo groups with respect to the 12-week change in FEV1 (active group minus placebo group, 95% CI, -0.03,0.26, P=0.11), as compared to a 0.01-l difference between the 1,000-microg IFN-gamma1b and placebo groups (95% CI, -0.16,0.17, P=0.96). No effects of IFN-gamma1b were seen in sputum bacterial density or inflammatory biomarkers at 12 weeks. Aerosolized IFN-gamma1b did not improve pulmonary function, reduce sputum bacterial density, or affect inflammatory sputum markers in patients with mild-moderate lung disease.
Pediatric Pulmonology 04/2005; 39(3):209-18. · 2.53 Impact Factor
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Richard B. Moss MD,
Nicole Mayer-Hamblett PhD,
Jeffrey Wagener MD,
Cori Daines MD,
Kathryn Hale MD,
Richard Ahrens MD,
PhD Ronald L. Gibson MD,
Paula Anderson MD,
George Retsch-Bogart MD,
Samya Z. Nasr MD, [......],
Richard Ahrens,
Ronald L. Gibson,
Paula Anderson, George Retsch‐Bogart,
Samya Z. Nasr,
Imre Noth,
David Waltz,
Pamela Zeitlin,
Bonnie Ramsey,
Karen Starko
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ABSTRACT: Interferon gamma-1b (IFN-γ1b) is a pleiotropic cytokine with immunomodulatory activities that could decrease bacterial burden, inflammation, and obstruction in patients with CF. Patients with CF (≥12 years old, FEV1 ≥40% predicted) were randomly assigned to sequential dose cohorts inhaling 500 μg IFN-γ1b, 1,000 μg IFN-γ1b, or placebo by Respirgard II® nebulizer thrice weekly for 12 weeks. Sputum bacterial density and spirometry were measured. Safety, antibiotic use, hospitalization, and sputum neutrophils, elastase, DNA, IL-8, and myeloperoxidase were also evaluated. Sixty-six patients (mean age, 24 years, with mean baseline FEV1 of 74 ± 20 (SD) percent predicted) were studied. One patient had bronchospasm after the first dose of IFN-γ1b; the overall withdrawal rate was 15% (5 in the placebo group, 2 in the 500-μg IFN-γ1b group, and 3 in the 1,000 μg IFN-γ1b group). The 500-μg IFN-γ1b dose was well-tolerated, but the 1,000-μg dose cohort, who had a higher baseline bacterial density than placebo patients (mean difference, 1.2 log10 CFU/g sputum, 95% confidence interval (CI), 0.1,2.8, P = 0.04), had 24% more hospitalizations for exacerbation than placebo patients (95% CI, 2,45%, P = 0.05). There was a 0.12-l difference between the 500-μg IFN-γ1b and placebo groups with respect to the 12-week change in FEV1 (active group minus placebo group, 95% CI, −0.03,0.26, P = 0.11), as compared to a 0.01-l difference between the 1,000-μg IFN-γ1b and placebo groups (95% CI, −0.16,0.17, P = 0.96). No effects of IFN-γ1b were seen in sputum bacterial density or inflammatory biomarkers at 12 weeks. Aerosolized IFN-γ1b did not improve pulmonary function, reduce sputum bacterial density, or affect inflammatory sputum markers in patients with mild-moderate lung disease. Pediatr Pulmonol. 2005; 39:209–218. © 2004 Wiley-Liss, Inc.
Pediatric Pulmonology 02/2005; 39(3):209 - 218. · 2.53 Impact Factor
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Ronald L Gibson,
Julia Emerson,
Sharon McNamara,
Jane L Burns,
Margaret Rosenfeld,
Ann Yunker,
Nicole Hamblett,
Frank Accurso,
Mark Dovey,
Peter Hiatt,
Michael W Konstan,
Richard Moss, George Retsch-Bogart,
Jeffrey Wagener,
David Waltz,
Robert Wilmott,
Pamela L Zeitlin,
Bonnie Ramsey
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ABSTRACT: We conducted a double-blind, placebo-controlled, multicenter, randomized trial to test the hypothesis that 300 mg of tobramycin solution for inhalation administered twice daily for 28 days would be safe and result in a profound decrease in Pseudomonas aeruginosa (Pa) density from the lower airway of young children with cystic fibrosis. Ninety-eight subjects were to be randomized; however, the trial was stopped early because of evidence of a significant microbiological treatment effect. Twenty-one children under age 6 years were randomized (8 active; 13 placebo) and underwent bronchoalveolar lavage at baseline and on Day 28. There was a significant difference between treatment groups in the reduction in Pa density; no Pa was detected on Day 28 in 8 of 8 active group patients compared with 1 of 13 placebo group patients. We observed no differences between treatment groups for clinical indices, markers of inflammation, or incidence of adverse events. No abnormalities in serum creatinine or audiometry and no episodes of significant bronchospasm were observed in association with active treatment. We conclude that 28 days of tobramycin solution for inhalation of 300 mg twice daily is safe and effective for significant reduction of lower airway Pa density in young children with cystic fibrosis.
American Journal of Respiratory and Critical Care Medicine 04/2003; 167(6):841-9. · 11.08 Impact Factor
