Do current clinical trials in cystic fibrosis match the priorities of patients and clinicans? A systematic review.

There are many uncertainties regarding Cystic Fibrosis (CF) treatment. Recently, the first James Lind Alliance (JLA) Priority Setting Partnership (PSP) in CF was completed, bringing clinicians, patients and carers together to identify the Top 10 research priorities. Here we investigate how well the current clinical trials landscape reflects these priorities. Trials in CF were identified through searches of research databases (Pubmed, ANZCTR, EU clinical trials register, ClinicalTrials.gov and ISRCTN). Trials meeting inclusion criteria of registered intervention studies in CF published between 01.012016 and 11.09.2017 were matched to the Top 10 priorities. We identified 259 trials, with 193 fulfilling the inclusion criteria. Only 63 (33%) of these matched one or more of the JLA priorities showing that current clinical trials poorly reflect the JLA Top 10. By increasing awareness of the Top 10 priorities, it is hoped that this will fuel future research in areas important to the CF community.

Can exercise replace airway clearance techniques in cystic fibrosis? A survey of patients and healthcare professionals.

Airway clearance techniques (ACTs) are recommended in cystic fibrosis (CF) to prevent accumulation of secretions and lung infection. "Can exercise replace chest physiotherapy for people with CF?" is one of the CF community's top 10 research questions. We conducted an online survey of the CF community to gather data on current ACT use, recommendations, reported adherence levels and exercise strategies used. There were 488 respondents: 194 (40%) people with CF (pwCF), 141 (29%) family and 153 (31%) healthcare professionals (HCPs) (mostly physiotherapists). Only 10/285 (4%) of pwCF do no exercise at present and 163/303 (54%) already incorporate exercise into ACTs. ACTs were omitted by 128/267 (48%) of pwCF when they exercised. Nearly all (110/129, 93%) of HCPs currently recommend exercise to support ACTs. A trial replacing some or all ACTs with exercise, was supported by 80/110 (73%) of HCPs, with an additional 9/110 (8%) willing to consider in selected patients.

Adapting the James Lind Alliance priority setting process to better support patient participation: an example from cystic fibrosis.

PLAIN ENGLISH SUMMARY: Cystic fibrosis (CF) is the commonest life-limiting inherited disorder in the UK. It affects many parts of the body including the lungs and gut leading to increased infection and problems digesting food. People with CF need to undergo many treatments each day throughout their whole lives. These include tablets, inhalers and breathing exercises, which are a huge burden, taking up several hours every dayIt is therefore, really important that the treatments we give are supported by good evidence, usually gathered from clinical trials. Unfortunately, we do not have good evidence for many of the CF treatments. We recently ran an exercise known as a James Lind Alliance Priority Setting Partnership (JLA PSP) to find out which the CF community feel are the top priority research questions. People with CF and those who look after them suggested questions to be answered by clinical trials. Through a series of online surveys and workshops these were then shortlisted to give a final top ten.Due to infection risk people with CF are advised not to mix, this meant we had to do things differently to the usual way JLA PSPs are carried out. We used videoconferencing to enable multiple people with CF to participate. Surveys were accessible online and promoted through social media. ABSTRACT: Background The James Lind Alliance (JLA) method is well recognised for setting research priorities. The JLA approach involves a combination of surveys and workshop interactions between patients, carers and health care professionals to identify and agree on a "top ten" list of research questions. Respiratory infection is one of the hallmarks of cystic fibrosis (CF). To avoid cross infection, patients are advised not to meet face to face, preventing us following standard JLA methodology. Here we describe adaptations made during our recent JLA Priority Setting Partnership (PSP) in CF. Methods We elicited and prioritised research questions, using sequential online surveys, promoted through social media. People with CF participated in steering committee meetings and the final workshop, using videoconferencing. Alterations to workshop methodology enabled participants attending in person and those joining remotely, to contribute equally. We also altered the JLA methodology to include "lone" questions, asked by only one survey respondent. We are now working with the CF community to co-produce research projects that answer these top ten. Results There were 482 respondents, from 23 countries, who submitted 1080 questions. Increases in the number of responses occurred just after promotion on social media. Use of videoconferencing enabled participation of multiple people with CF and ensured participation from anywhere in the world, including hospital inpatients. Inclusion of lone questions resulted in one being included in our top ten. Conclusions There is no "one-size-fits-all" for patient involvement methodologies. Through altering the JLA methods to fit our patient group we achieved wide participation. We believe that methods used in our project may also be applied to future partnerships to increase participation, especially where people may be hospitalised or be unable to travel. The methodology we are developing through the JLA PSP CF2 project may be useful for other PSPs to follow.

The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison.

BACKGROUND: Circadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity. AIM: To investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission. METHODS: Children (age 5-18years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000h. Serum tobramycin levels were drawn at 1h and between 3.5 and 5h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800h in the evening until 1200h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin. RESULTS: Eighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%). CONCLUSIONS: Renal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245).

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 FEV(1) (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.

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.

Guideline on the design and conduct of cystic fibrosis clinical trials: the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN).

We describe the rationale for disease specific research networks in general as well as the aims and function of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) specifically. The ECFS-CTN was founded in 2009 with the aim of improving the quality and quantity of clinical research in the area of cystic fibrosis (CF) in Europe. A network of 18 clinical trial sites in 8 European countries was established according to uniform state-of-the-art quality criteria. To support the ECFS-CTN in the acquisition, planning and conduct of clinical trials, the network is equipped with a coordinating centre, steering and executive committees, and committees for protocol review, standardization, training and networking as well as a data safety monitoring board. A strong partnership with European CF patient parent organizations aims to increase awareness of the need for efficient clinical research and the participation of patients in clinical trials.

Oral versus i.v. antibiotics for community-acquired pneumonia in children: a cost-minimisation analysis.

Community-acquired pneumonia represents a high financial burden to healthcare providers. This manuscript seeks to estimate and compare the costs of treating children hospitalised with community-acquired pneumonia, with oral and intravenous antibiotics, thus determining which treatment is cost minimising. A cost-minimisation analysis was undertaken alongside a randomised controlled non-blinded equivalence trial. 232 children (from eight paediatric centres in England) diagnosed with pneumonia, who required admission to hospital, were randomised to receive oral amoxicillin or i.v. benzyl penicillin. The analysis considered the cost to the health service, patients and society, from pre-admission until the child was fully recovered. Oral amoxicillin and i.v. benzyl penicillin have equivalent efficacy. Children treated with i.v. antibiotics were found to have significantly longer in-patient stays (3.12 versus 1.93 days; p<0.001). i.v. treatment was found to be more expensive than oral treatment ( pound1,256 versus pound769; difference pound488; 95% CI: pound233- pound750), such that treatment of community-acquired pneumonia with oral amoxicillin would result in savings of between pound473 and pound518 per child (euro545 and euro596 per child) admitted. The findings demonstrate that oral amoxicillin is a cost-effective treatment for the majority of children admitted to hospital with pneumonia.

Respiratory medicines for children: current evidence, unlicensed use and research priorities.

This European Respiratory Society task force has reviewed the evidence for paediatric medicines in respiratory disease occurring in adults and children. We describe off-licence use, research priorities and ongoing studies. Off-licence and off-label prescribing in children is widespread and potentially harmful. Research areas in asthma include novel formulations and regimens, and individualised prescribing. In cystic fibrosis, future studies will focus on screened infants and robust outcome measures are needed. Other areas include new enzyme and antibiotic formulations and the basic defect. Research into pneumonia should include evaluation of new antibacterials and regimens, rapid diagnostic tests and, in pleural infection, antibiotic penetration, fibrinolytics and surveillance. In uncommon conditions, such as primary ciliary dyskinesia, congenital pulmonary abnormalities or neuromuscular disorders, drugs indicated for other conditions (e.g. dornase alfa) are commonly used and trials are needed. In neuromuscular disorders, the beta-agonists may enhance muscle strength and are in need of evaluation. Studies of antibiotic prophylaxis, immunoglobulin and antifungal drugs are needed in immune deficiency. We hope that this summary of the evidence for respiratory medicines in children, highlighting gaps and research priorities, will be useful for the pharmaceutical industry, the paediatric committee of the European Medicines Agency, academic investigators and the lay public.

Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

BACKGROUND: People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. SEARCH STRATEGY: We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: August 2005. SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy and/or toxicity, in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The two authors independently selected the studies to be included in the review and assessed methodological quality of each study. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. MAIN RESULTS: Eleven studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants were included in this review. All studies compared once-daily dosing with thrice-daily dosing. There was no significant difference between treatment groups in: forced expiratory volume at one second, weighted mean difference (WMD) 0.33 (95% confidence interval (CI) -2.81 to 3.48); forced vital capacity, WMD 0.29 (95% CI -6.58 to 7.16); % weight for height, WMD -0.82 (95% CI -3.77 to 2.13); body mass index, WMD 0.00 (95% CI -0.42 to 0.42); or in the incidence of ototoxicity, relative risk 0.56 (95% CI 0.04 to 7.96). The percentage change in creatinine significantly favoured once-daily treatment in children, WMD -8.20 (95% CI -15.32 to -1.08), but showed no difference in adults, WMD 3.25 (95% CI -1.82 to 8.33). AUTHORS' CONCLUSIONS: Once and three times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

BACKGROUND: Lower respiratory tract infection with Pseudomonas aeruginosa (P. aeruginosa) occurs in most people with cystic fibrosis. Once chronic infection is established, P. aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. OBJECTIVES: To determine whether antibiotic treatment of early P. aeruginosa infection in children and adults with cystic fibrosis eradicates the organism and improves clinical and microbiological outcome. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of most recent search: May 2004 SELECTION CRITERIA: We included randomised controlled trials of people with cystic fibrosis, in whom P. aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo or usual treatment (or both) or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls. DATA COLLECTION AND ANALYSIS: Both authors independently assessed selected trials, assessed methodological quality and extracted data. MAIN RESULTS: The search identified 15 trials. Three trials (69 participants) were eligible for inclusion. There is evidence from two randomised controlled trials, of questionable methodological quality, that treatment of early P. aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo and that this effect may persist for up to 12 months, however incomplete data from one of the trials precludes an accurate analysis. One randomised controlled trial of oral ciprofloxacin and nebulised colisitin versus usual treatment was identified. This trial was of poor methodological quality. The results suggested treatment of early infection results in microbiological eradication of P. aeruginosa more often than usual treatment, after two years, RR 0.24 (95% CI 0.06 to 0.96). There is insufficient evidence to determine whether antibiotic strategies for the eradication of early P. aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. AUTHORS' CONCLUSIONS: From the three trials included in this review, there is some evidence that antibiotic treatment of early P. aeruginosa results in short-term eradication but it remains uncertain whether there is clinical benefit to people with cystic fibrosis.

Parental attitudes: antenatal diagnosis of cystic fibrosis.

In order to understand attitudes to antenatal diagnosis of cystic fibrosis (CF), we interviewed parents from 19 families, who already had one child with CF. Nine women had chorion villus sampling in a subsequent pregnancy and 6/19 said they would consider termination of pregnancy if the result confirmed CF. These results differ from the results of antenatal screening studies of previously unaffected families, where most couples opt for termination.

Paradoxical embolism in a boy with cystic fibrosis and a stroke.

An 11 year old boy with cystic fibrosis suffered a stroke, producing right sided weakness. Four years previously a totally implantable venous access device (Port-a-Cath) had been inserted. Magnetic resonance angiography revealed a filling defect in the left middle cerebral artery. Transoesophageal echocardiography demonstrated a thrombus attached to the tip of the Port-a-Cath and also the presence of a patent foramen ovale. After an initial period of anticoagulation the defect was closed using a septal occlusion device introduced via a cardiac catheter. The boy's neurological signs completely resolved and he remains free from further thromboembolic episodes. Whilst pulmonary embolism has been described before in relation to a totally implantable venous access device, this is believed to be the first description of a paradoxical embolism in relation to such a device.

The laryngeal mask airway in fibreoptic bronchoscopy.

A large series of patients is reported in whom the laryngeal mask airway was used to perform fibreoptic bronchoscopy. It allows direct visualisation of the airways during spontaneous respiration. It has enabled bronchoalveolar lavage and bronchography to be performed in children as young as 6 months and transbronchial biopsies in children as young as 4 years.

Effect of respiratory virus infections including rhinovirus on clinical status in cystic fibrosis.

One hundred and eight patients with cystic fibrosis were investigated over one year to determine whether an association existed between rhinovirus or other respiratory virus infection and clinical status. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), Shwachman score, Chrispin-Norman chest radiograph score, and percentage weight for height were recorded at the beginning and end of the study; days of intravenous antibiotics were noted. Nasopharyngeal aspirates were taken for viral studies during respiratory exacerbations. Serum was collected at enrollment and 2-6 weeks after each respiratory exacerbation. One hundred and fifty seven exacerbations occurred in 76 patients. Respiratory virus infection was detected in 44 exacerbations and rhinovirus was present in 16% (25/157) of exacerbations. Patients with one or more respiratory virus infections were compared with those who had none. When all respiratory virus infections were considered, patients had a significantly greater deterioration in Shwachman score and received significantly more days of intravenous antibiotics. When rhinovirus was considered separately, patients received significantly more days of intravenous antibiotics, but showed no deterioration in clinical status. However, patients infected with another respiratory virus had a significant decline in FEV1, with trends towards significance for decline in FVC and Shwachman score.