Matthew N. Hurley

Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study.

Objective To examine compliance with mandatory reporting of summary clinical trial results (within one year of completion of trial) on ClinicalTrials.gov for studies that fall under the recent Food and Drug Administration Amendments Act (FDAAA) legislation. Design Registry based study of clinical trial summaries. Data sources ClinicalTrials.gov, searched on 19 January 2011, with cross referencing with Drugs@FDA to determine for which trials mandatory reporting was required within one year. Selection criteria Studies registered on ClinicalTrials.gov with US sites which completed between 1 January and 31 December 2009. Main outcome measure Proportion of trials for which results had been reported. Results The ClinicalTrials.gov registry contained 83 579 entries for interventional trials, of which 5642 were completed within the timescale of interest. We identified trials as falling within the mandatory reporting rules if they were covered by the FDAAA (trials of a drug, device, or biological agent, which have at least one US site, and are of phase II or later) and if they investigated a drug that already had approval from the Food and Drug Administration. Of these, 163/738 (22%) had reported results within one year of completion of the trial compared with 76/727 (10%) trials that were not subject to mandatory reporting (95% confidence interval for the difference in proportions 7.8% to 15.5%; χ2 test, P=2.6×10−9). Later phase trials were more likely to report results (P=4.4×10−11), as were industry funded trials (P=2.2×10−16). Conclusion Most trials subject to mandatory reporting did not report results within a year of completion.

Results of antibiotic susceptibility testing do not influence clinical outcome in children with cystic fibrosis

Introduction Patients with CF experience pulmonary exacerbations. These are often initially empirically treated with intravenous antibiotics, with antibiotic choice refined after susceptibility testing. Methods We completed a 5-year retrospective review of children attending the Paediatric CF Unit, Nottingham. The respiratory sampling, antibiotic prescribing and susceptibility testing guidance were audited. Episodes were classified according to the concordance between the antibiotics prescribed and antibiotic susceptibility testing. Results Of 52 patients who had previously isolated Pseudomonas aeruginosa, 103 antibiotic courses were commenced that coincided with an isolation of P. aeruginosa. P. aeruginosa was fully susceptible, partially susceptible or fully resistant on 33%, 44.7% or 16.5% of occasions respectively. The antibiotic prescriptions were never changed following antibiotic susceptibility testing. We found no association between change in FEV1 (p = 0.54), change in BMI (p = 0.12) or time to next exacerbation (p = 0.66) and concordance between antibiotic susceptibility and the antibiotics administered. Conclusion This study contributes to mounting evidence questioning the utility of routine antibiotic susceptibility testing.

Novel approaches to the treatment of Pseudomonas aeruginosa infections in cystic fibrosis

Pseudomonas aeruginosa chronically infects patients with cystic fibrosis and is associated with greater morbidity. There has been limited progress on the clinical development of new antibiotics with novel modes of action. This review addresses some of the latest research developments on the exploitation of candidate adjuvant therapeutic agents that may act alongside conventional antibiotics as an alternative therapeutic strategy. After considering key mechanisms this opportunistic pathogen employs to control virulence, the progress of various strategies including the inhibition of quorum sensing, efflux pumps and lectins, and the use of iron chelators, bacteriophages, immunisation and immunotherapy is reviewed. Both therapeutic approaches in early development and clinical phase are discussed.

Rate of improvement of CF life expectancy exceeds that of general population--observational death registration study.

Background It is unclear why cystic fibrosis (CF) survival has improved. We wished to quantify increases in CF median age of death in the context of general population survival improvement. Method Death registration data analysis (US, England & Wales (E&W)—1972–2009). Results CF median age of death is higher in US than E&W and greater for males, opposite to that of death from all causes. CF median age of death has increased by 0.543 life years per year (E&W, US combined (95% confidence interval 0.506, 0.582)). The difference in median age at death between those dying from all causes and CF decreased in both territories. CF median age of death for males is greater than for females in both territories. This gap has not narrowed. Conclusion The median age of death of people with CF is improving more rapidly than that of the general population in US and E&W.

The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers

There remain many treatment uncertainties in cystic fibrosis (CF). With limited resources, research should focus on questions which are most important to the CF community. We conducted a James Lind Alliance Priority Setting Partnership in CF. Research questions were elicited and then prioritised in successive surveys. A workshop agreed the final top 10. Online methods avoided cross infection and widened participation. The elicitation survey had 482 respondents (1080 questions) and prioritisation survey 677 respondents. Participants were drawn equally from the patient and clinical communities globally. We have achieved a consensus on 10 research priorities which will be attractive to funders.

Delayed publication of clinical trials in cystic fibrosis

Background When the publication of important trial data is delayed, or data are never published, this will prevent the proper practice of evidence based medicine through robust systematic reviews. Clinical trial registries allow researchers to interrogate the trial protocol and afford the opportunity to identify studies that have been completed and so determine the time lag between completion and publication. Methods We searched ClinicalTrials.gov with the keywords ‘cystic fibrosis’. Intervention trials which had completed 1st Jan 1998–31st Dec 2010 were selected. Time to publication in a peer-reviewed journal was calculated. Survival analyses using the log rank test were undertaken. Results We identified 142 records. Of these, 62 had full paper publications. The median time to publication was 3.25 years. Phase of study (phase one studies more delayed, p = 0.024) but not source of funding (p = 0.34) was associated with time to publication. Conclusions Clinical trials in cystic fibrosis take a considerable amount of time to report their findings. More importantly, a large number of trials fail to report at all.

Early Respiratory Bacterial Detection and Antistaphylococcal Antibiotic Prophylaxis in Young Children with Cystic Fibrosis

Rationale: Consensus is lacking regarding antistaphylococcal antibiotic prophylaxis use for young children with cystic fibrosis. Prophylaxis is recommended in the United Kingdom, but it is recommended against in the United States. Objectives: To test the hypothesis that antistaphylococcal antibiotic prophylaxis is associated with a decreased risk of Staphylococcus aureus acquisition but no increased risk of Pseudomonas aeruginosa acquisition. Methods: We undertook a longitudinal observational study of children with cystic fibrosis who were recruited from birth (or from their first registry entry in the period) and followed until the age of 4 years (1,500 d) using 2000‐2009 data from the UK Cystic Fibrosis Trust and Cystic Fibrosis Foundation registries. Children were excluded if they had a positive culture result for S. aureus or P. aeruginosa, or if they were receiving inhaled antibiotics, at the first encounter. Time to first S. aureus and P. aeruginosa detection in the UK/U.S. cohorts was compared using a Cox proportional hazards model. A UK‐based analysis compared the same for those receiving flucloxacillin with those who received no prophylaxis. We included the following covariates: sex, age at registry entry, dornase alfa use, genotype, and center size. Results: The primary analysis comprised 1,074 UK and 3,677 U.S. children. The risk of first detection was greater in U.S. children than in UK children for S. aureus (hazard ratio [HR], 5.79; 95% confidence interval [CI], 4.85, 6.90; P < 0.001) and P. aeruginosa (HR, 1.92; 95% CI, 1.65, 2.24; P < 0.001). In the UK analysis, we compared 278 children receiving flucloxacillin and 306 receiving no prophylaxis. Flucloxacillin was not associated with a reduced risk of S. aureus detection (HR, 1.22; 95% CI, 0.74, 2.0; P = 0.43), but it was associated with an increased risk of P. aeruginosa detection (HR, 2.53; 95% CI, 1.71, 3.74; P < 0.001). None of the covariates significantly affected the risk estimate in either analysis. Conclusions: The risk of first detection of S. aureus and P. aeruginosa was greater in the United States than in the United Kingdom. In the United Kingdom, the risk of first P. aeruginosa detection was increased among those receiving flucloxacillin compared with those who received no prophylaxis. These observational findings should be examined in randomized controlled trials.

Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis1

Figure 1. Pseudomonas aeruginosa swarming. Antibiotic resistance increasingly poses a challenge to the successful treatment of many infections and this is particularly the case for the treatment of lung infections with Pseudomonas aeruginosa (see Figure 1) in cystic fibrosis, a bacterium with inherent antibiotic tolerance that may acquire antibiotic resistance rapidly. While early infections may be eradicated if treated early, the establishment of chronic infection which cannot be cleared with current antibiotic therapies, is inevitable. As there has been limited progress in the development of new antibiotics to which conventional antibiotic-resistant strains may be sensitive, new approaches that may act to re-sensitise bacteria to coadministered antibiotics without selecting for resistance are needed. We examined randomised and quasi-randomised controlled trials of the use of antibiotic adjuvants for the treatment of acute pulmonary exacerbations or the treatment of chronic infection. Pulmonary exacerbations, lung function and quality of life were our primary outcomes. We identified eighteen studies, the methodological quality of which was largely poor. The results of five studies recently completed or ongoing are awaited. Three studies were eligible for inclusion individually examining the effect of b-carotene, zinc or garlic supplementation. For each of these interventions there was no statistically significant effect in any of the primary outcomes of the review and so we cannot recommend their use. There is a need for further development of these strategies and for them to be evaluated in well-designed

382 Quantifying publication bias in cystic fibrosis clinical trials

Background: The practice of evidence-based medicine depends upon the publication of high quality clinical studies. However, publication bias may act to exclude some trials from contributing to the knowledge base. The influence of such biases upon the evidence base is often unknown as clinicians have no way of knowing the results of unreported studies. ClinicalTrials.gov was commissioned in 2000. In 2005 the ICMJE announced that publication of trials would be limited to trials registered with a public registry prior to commencing. Aim: We aimed to quantify reporting biases present within the CF literature. Method: We interrogated ClinicalTrials.gov using ‘cystic fibrosis’ as the keyword, limited to interventional studies that had been closed. We searched PubMed, the Cochrane Central Register of Controlled Trials and Google Scholar for publications using ClinicalTrials.gov ID, study title and Chief Investigator name. We documented publication date and study sponsor. A survival analysis was performed using R (version 2.12.1). Results: In total 142 studies were identified (completed 1998–2010) of which 59 were published. Median time to publication was 2.09 years.

95 An audit of the investigation, antibiotic management and clinical outcome of pulmonary exacerbations in patients with cystic fibrosis

95 An audit of the investigation, antibiotic management and clinical outcome of pulmonary exacerbations in patients with cystic fibrosis M.N. Hurley1,2, A.H.A. Ariff3, A. Smyth1,2,4. 1University of Nottingham, Child Health, Nottingham, United Kingdom; 2Nottingham Respiratory Biomedical Research Unit, Nottingham, United Kingdom; 3University of Nottingham, Medical School, School of Clinical Sciences, Nottingham, United Kingdom; 4Trent Local Children’s Research Network, Nottingham, United Kingdom