258 results found
Stanford G, Davies JC, Usmani O, et al., 2020, Investigating outcome measures for assessing airway clearance techniques in adults with cystic fibrosis: protocol of a single-centre randomised controlled crossover trial, BMJ Open Respiratory Research, Vol: 7, ISSN: 2052-4439
INTRODUCTION: Airway clearance techniques (ACTs) are a gold standard of cystic fibrosis management; however, the majority of research evidence for their efficacy is of low standard; often attributed to the lack of sensitivity from outcome measures (OMs) used historically. This randomised controlled trial (RCT) investigates these standard OMs (sputum weight, forced expiratory volume in 1 s) and new OMs (electrical impedance tomography (EIT), multiple breath washout (MBW) and impulse oscillometry (IOS)) to determine the most useful measures of ACT. METHODS AND ANALYSIS: This is a single-centre RCT with crossover design. Participants perform MBW, IOS and spirometry, and then are randomised to either rest or supervised ACT lasting 30-60 min. MBW, IOS and spirometry are repeated immediately afterwards. EIT and sputum are collected during rest/ACT. On a separate day, the OMs are performed with the other intervention. Primary endpoint is difference in change in OMs before and after ACT/rest. Sample size was calculated with 80% power and significance of 5% for each OM (target n=64). ETHICS AND DISSEMINATION: Ethics approval was gained from the London-Chelsea Research Ethics Committee (reference 16/LO/0995, project ID 154635). Dissemination will involve scientific conference presentation and publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ISRCTN11220163 and NCT02721498.
Kaplan S, Lee A, Caine N, et al., 2020, Long-term safety study of colistimethate sodium (Colobreathe®): Findings from the UK Cystic Fibrosis Registry., J Cyst Fibros
BACKGROUND: As part of the risk management plan in Europe, a long-term observational study was conducted to monitor the safety of colistimethate sodium dry powder for inhalation (CMS-DPI) compared to other inhaled antibiotics. METHODS: A cohort of CMS-DPI patients and a matched cohort were identified from the UK Cystic Fibrosis Registry (UKCFR) from 2014-2018. The primary outcome was a composite endpoint, defined as adverse events (AEs) or new cystic fibrosis (CF) complications. Other outcomes included pulmonary exacerbations and treatment discontinuations. RESULTS: Of 1466 and 3503 patients in the CMS-DPI and comparator cohorts, respectively, 82.7% and 79.4% had AEs. Among the most common new CF complications were osteopenia, CF-related diabetes, and increased liver enzymes. The adjusted event rate ratio (ERR) for the primary outcome was 1.25 (95% confidence interval [CI]: 1.18-1.33, p<0.001). After excluding new CF complications, there was no difference between cohorts (ERR=1.04, 95% CI: 0.79-1.38, p=0.785). Pulmonary exacerbations were common in CMS-DPI and comparator cohorts (78.0% and 79.9% of patients, respectively), with adjusted ERR of 1.02 (95% CI: 0.95-1.10, p=0.523). Rates of discontinuation were similar in the CMS-DPI and Tobramycin inhalation powder comparator cohorts (37.8% and 39.8% of patients, respectively). CONCLUSIONS: There was no difference in the rate of adverse events between CMS-DPI and comparator cohorts. The safety profile of CMS-DPI is similar to those of other inhaled antibiotics, supporting its long-term safety in people with CF. The UKCFR has developed a successful model for partnership with industry to conduct long-term studies aimed at assessing drug safety.
Keogh RH, Tanner K, Simmonds NJ, et al., 2020, The changing demography of the cystic fibrosis population: forecasting future numbers of adults in the UK, SCIENTIFIC REPORTS, Vol: 10, Pages: 1-8, ISSN: 2045-2322
Improvements in management of cystic fibrosis (CF) through specialist centres in the UK have been associated with a step-change in life expectancy. With increasing numbers of adult patients there is a need to review health care provision to ensure it is sufficient to meet future needs. We used UK CF Registry data to project the number of patients aged 16–17 and 18 and older up to 2030, and numbers therefore requiring specialist adult CF care. Survival modelling was used to estimate age-specific mortality rates. New-diagnosis rates were estimated using diagnoses observed in the Registry and national population figures. Uncertainty in projections was captured through 95% prediction intervals (PI). The number of adults (aged 18 and older) is expected to increase by 28% from 6,225 in 2017 to 7,988 in 2030 (95% PI 7,803–8,169), assuming current mortality rates. If mortality rates improve at the rate seen over recent years, the projected number increases to 8,579 (95% PI 8,386–8,764). The age distribution is also expected to change, with 36% of CF adults being over 40 in 2030, versus 21% in 2017. There is an urgent requirement to review adult CF health care provision, due to both increasing numbers and the changing care needs of an older population.
Cuthbertson L, Felton I, James P, et al., 2020, The fungal airway microbiome in cystic fibrosis and non-cystic fibrosis bronchiectasis., J Cyst Fibros
BACKGROUND: The prevalence of fungal disease in cystic fibrosis (CF) and non-CF bronchiectasis is increasing and the clinical spectrum is widening. Poor sensitivity and a lack of standard diagnostic criteria renders interpretation of culture results challenging. In order to develop effective management strategies, a more accurate and comprehensive understanding of the airways fungal microbiome is required. The study aimed to use DNA sequences from sputum to assess the load and diversity of fungi in adults with CF and non-CF bronchiectasis. METHODS: Next generation sequencing of the ITS2 region was used to examine fungal community composition (n = 176) by disease and underlying clinical subgroups including allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, non-tuberculous mycobacteria, and fungal bronchitis. Patients with no known active fungal disease were included as disease controls. RESULTS: ITS2 sequencing greatly increased the detection of fungi from sputum. In patients with CF fungal diversity was lower, while burden was higher than those with non-CF bronchiectasis. The most common operational taxonomic unit (OTU) in patients with CF was Candida parapsilosis (20.4%), whereas in non-CF bronchiectasis sputum Candida albicans (21.8%) was most common. CF patients with overt fungal bronchitis were dominated by Aspergillus spp., Exophiala spp., Candida parapsilosis or Scedosporium spp. CONCLUSION: This study provides a framework to more accurately characterize the extended spectrum of fungal airways diseases in adult suppurative lung diseases.
Higgins M, Volkova N, Moy K, et al., 2020, Real-World Outcomes Among Patients with Cystic Fibrosis Treated with Ivacaftor: 2012-2016 Experience., Pulm Ther, Vol: 6, Pages: 141-149
INTRODUCTION: In this long-term, postapproval, observational study, data from the US Cystic Fibrosis Foundation Patient Registry and the UK Cystic Fibrosis Registry were used to evaluate the impact of ivacaftor treatment on cystic fibrosis (CF) by comparing outcomes in ivacaftor-treated patients with those in matched untreated comparator patients. Registry data from up to 5 years of ivacaftor availability in the US and up to 4 years of availability in the UK were evaluated. METHODS: Starting in the first year of ivacaftor availability, ivacaftor-treated patients in each registry were matched 1:5 to comparator patients who never received ivacaftor. Clinical endpoints were evaluated in annual cross-sectional safety analyses. The key endpoints were death, organ transplants, pulmonary exacerbation, and hospitalization. Relative risks and 95% CIs were calculated to compare the ivacaftor and comparator cohorts in each registry. RESULTS: Here, we report the complete and final results of the annual cross-sectional safety analyses across the duration of the study, with up to 5 years of follow-up. Data show a pattern of lower risk of death, transplant, pulmonary exacerbation, and hospitalization among ivacaftor-treated patients in both registries. CONCLUSIONS: Ivacaftor-treated patients had consistently favorable clinical outcomes relative to untreated comparators, and no new safety concerns were identified. While general limitations of observational research apply, these findings support disease modification by CF transmembrane conductance regulator (CFTR) modulator therapy with ivacaftor. Future research of novel CFTR modulators will need to explore alternative methods for comparator selection for evaluation of clinical data given the evolving landscape of CF treatment.
Cuthbertson L, Felton I, James P, et al., 2020, The Fungal Airway Microbiome in Cystic Fibrosis and Bronchiectasis, Journal of Cystic Fibrosis, ISSN: 1569-1993
Bilton D, Pressler T, Fajac I, et al., 2020, Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis, JOURNAL OF CYSTIC FIBROSIS, Vol: 19, Pages: 284-291, ISSN: 1569-1993
Mohindru B, Turner D, Sach T, et al., 2020, Health state utility data in cystic fibrosis: a systematic review, PharmacoEconomics - Open, Vol: 4, Pages: 13-25, ISSN: 2509-4254
INTRODUCTION: Cystic fibrosis (CF) is a life-limiting, hereditable condition, with the highest prevalence in Europe. CF treatments have led to improvements in clinical symptoms, disease management and decelerated disease progression. However, little is known about the health state utility (HSU) associated with CF disease states, adverse events, and changes in disease severity. Although HSU data have contributed to existing health economic modelling studies, a lack of such data have been highlighted. This systematic review aims to provide a summary of HSU-related research in CF and highlight related research gaps. METHODS: Online searches were performed in six databases and studies in any of the following categories were included: (1) estimation of HSUs in CF; (2) mapping studies between patient-reported outcome measures (PROMs) and HSUs; (3) economic evaluations on the management of CF that report primary HSU data; and (4) any CF clinical trial that reported HSU as an outcome. RESULTS: A total of 17 studies were reviewed, of which 12 provided HSU values for specific CF populations. The remaining five articles provided HSU data that were broken down by CF relevant health states, including lung transplantations, pulmonary exacerbation (PEx) events and forced expiratory volume in 1 s (FEV1). CONCLUSION: Current HSU data in CF are limited and there is considerable scope for further research, both in providing HSU values for CF and in investigating methods for HSU elicitation/evaluation in CF populations.
Volkova N, Moy K, Evans J, et al., 2020, Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries, JOURNAL OF CYSTIC FIBROSIS, Vol: 19, Pages: 68-79, ISSN: 1569-1993
Taccetti G, Denton M, Hayes K, et al., 2020, A critical review of definitions used to describe Pseudomonas aeruginosa microbiological status in patients with cystic fibrosis for application in clinical trials., J Cyst Fibros, Vol: 19, Pages: 52-67
BACKGROUND: Definition of Pseudomonas aeruginosa (Pa) microbiological status is essential for patients' inclusion in clinical trials. The aim of this study was to agree on the definitions of Pa infection status for initial infection, eradication and chronic infection to be used in clinical trials and to propose additional future study areas. METHODS: An exhaustive literature search was performed. The clinimetric properties of different definitions of Pa microbiological status were evaluated. RESULTS: Historical studies have mostly used culture-based definitions, although some have also involved complementary anti-Pa antibodies. Clinimetric analysis showed great variability in the definitions used, leading to differences in reliability, validity, responsiveness to treatment and correlation with outcome measures. Use of serology for initial Pa infection and successful Pa eradication introduced a greater level of complexity as antibody tests are not standardised. Moreover, the chronology of the immune response to Pa antigenic determinants was not completely clear. Chronic Pa infection was characterized by high levels of antibodies and good concordance between culture results and serology. CONCLUSIONS: Microbiological monitoring, regular sampling from the airways and standardization of culture methods remain essential requisites for microbiological definitions. Despite limitations, serology should be incorporated in the definitions of initial infection and eradication used in clinical trials to better classify patients at enrolment, mainly in non-expectorating children. This requires standardization of serological testing.
Keogh RH, Seaman S, Gran J, et al., 2019, EMULATING A TARGET TRIAL USING THE UK CYSTIC FIBROSIS REGISTRY: THE CAUSAL EFFECT OF DNASE ON 5-YEAR SURVIVAL, Publisher: WILEY, Pages: S235-S235, ISSN: 8755-6863
Flume P, Bilton D, Charlton B, et al., 2019, INHALED DRY POWDER MANNITOL IMPROVES LUNG FUNCTION IN ADULTS WITH CYSTIC FIBROSIS - AN INTEGRATED ANALYSIS, Publisher: WILEY, Pages: S329-S330, ISSN: 8755-6863
Archangelidi O, Carr SB, Simmonds NJ, et al., 2019, Non-invasive ventilation and clinical outcomes in cystic fibrosis: Findings from the UK CF registry, Journal of Cystic Fibrosis, Vol: 18, Pages: 665-670, ISSN: 1569-1993
Background: Non-invasive ventilation (NIV) for respiratory failure and airway clearance is an established intervention in cystic fibrosis (CF), but its therapeutic benefit on lung function and survival remains under-investigated. Methods: Using data from the UK CF Registry between 2007 and 2015, we explored the patterns of NIV use, and assessed changes in mean percent predicted FEV1 (ppFEV1) prior to and after NIV use, and the survival of patients on NIV. Results: Among 11,079 patients, 1107 had at least one record of NIV treatment. Incidence and prevalence of NIV was lower in children and followed non-linear temporal patterns. Adjusting for other risk factors, ppFEV1 rose by 0.70 (95%CI: -0.83, 2.24) after first NIV use in children. In adults with a low ppFEV1 (<40%) at initiation of treatment, NIV increased mean ppFEV1 by 2.60 (95% CI: 0.93, 4.27). Our analysis showed that NIV initiation is associated with an increased risk of death/transplant in both children (HR = 2.47; 95%CI: 1.20–5.08) and adults (HR = 1.96; 95% CI: 1.63–2.36) but effect was attenuated in children with low ppFEV1 (<40%). Conclusions: NIV usage in CF improves spirometric values but does not benefit survival. Further studies are required to better understand survival outcomes and ultimately improve NIV outcomes in CF.
Kaplan S, Bilton D, Charman SC, et al., 2019, Safety of Colobreathe: findings from the UK cystic fibrosis registry, Publisher: WILEY, Pages: 430-430, ISSN: 1053-8569
Mohindru B, Turner D, Sach T, et al., 2019, Health economic modelling in Cystic Fibrosis: a systematic review, Journal of Cystic Fibrosis, Vol: 18, Pages: 452-460, ISSN: 1569-1993
INTRODUCTION: Cystic Fibrosis (CF) is a heritable chronic condition. Due to the genetic and progressive nature of CF, a number of interventions are available for the condition. In the United Kingdom (U.K.) average annual cost of CF treatment is between €49,000 to €76,000 (2012) per patient . A review of health economic modelling studies is warranted to provide decision makers and researchers with an in depth understanding of modelling practices in CF and guidance for future research. METHODS: Online searches were performed in the 5 databases, studies were included if they were: a) Model based economic evaluation for management of Cystic Fibrosis. Articles were restricted to English language only, but no restriction was applied on publication year. RESULTS: Nine studies were reviewed, most were Markov cohort models. Models evaluated pharmaceutical interventions and drug adherence. Modelling structure was consistent across most articles and a range of sources were used to populate the models. Cost and utility data were based on different sources and elicitation methods respectively. The majority of models failed to incorporate significant health events which impact both cost and disease progression. CONCLUSION: In our review we observed a lack of, application of European Medicines Agency (EMA) guidelines for clinical trial endpoints, model structure justifications and lastly, health-related quality of life derived utility information around important clinical events. Future work around conceptual modelling of CF progression, utility valuation of significant health events and meeting EMA guidelines for trial reporting is encouraged.
Stanford G, Parrott H, Bilton D, et al., 2019, A randomised crossover trial evaluating the short-term effects of non-invasive ventilation as an adjunct to airway clearance techniques in adults with cystic fibrosis, BMJ Open Respiratory Research, Vol: 6, ISSN: 2052-4439
Introduction Non-invasive ventilation (NIV) is used in cystic fibrosis (CF) to support airway clearance techniques (ACTs) by augmenting tidal volumes and reducing patient effort. However, the evidence base for this is limited. We hypothesised that NIV, in addition to usual ACT, would increase sputum clearance. In addition, we investigated ease of sputum clearance (EoC), work of breathing (WoB) and NIV tolerability.Methods Adults with CF (16+ years) at the end of hospitalisation for a pulmonary exacerbation were randomised to a cross-over trial of NIV-supported ACT or ACT alone in two consecutive days. No other changes to standard care were made. The primary outcome was the total 24-hour expectorated sputum wet weight after the intervention. Spirometry was completed pre-treatment and post-treatment. Oxygen saturations were measured pre-treatment, during treatment and post-treatment. EoC and WoB were assessed using Visual Analogue Scale.Results 14 subjects completed the study (7 male, mean age 35 [SD 17] years, mean forced expiratory volume in 1 s [FEV1] 49  % predicted). The difference between treatment regimens was −0.98 g sputum (95% CI −11.5 to 9.6, p=0.84) over 24 hours. During treatment oxygen saturations were significantly higher with NIV-supported ACT (mean difference 2.0, 95% CI 0.9 to 2.6, p=0.0004). No other significant differences were found in post-treatment FEV1, EoC, WoB, oxygen saturations or subject preference.Conclusions There was no difference in treatment effect between NIV-supported ACT and ACT alone, although the study was underpowered. Oxygen saturations were significantly higher during NIV-supported ACT, but with no effect on post-treatment saturations. NIV was well tolerated.
Keogh RH, Bilton D, Cosgriff R, et al., 2019, Results from an online survey of adults with cystic fibrosis: Accessing and using life expectancy information, PLOS ONE, Vol: 14, ISSN: 1932-6203
Toledano M, Mukherjee S, Howell J, et al., 2019, The emerging burden of liver disease in cystic fibrosis patients: a UK nationwide study, PLoS ONE, Vol: 14, ISSN: 1932-6203
ObjectiveCystic fibrosis associated liver disease (CFLD) is the third largest cause of mortality in CF. Our aim was to define the burden of CFLD in the UK using national registry data and identify risk factors for progressive disease.MethodsA longitudinal population-based cohort study was conducted. Cases were defined as all patients with CFLD identified from the UK CF Registry, 2008–2013 (n = 3417). Denominator data were derived from the entire UK CF Registry. The burden of CFLD was characterised. Regression analysis was undertaken to identify risk factors for cirrhosis and progression.ResultsPrevalence of CFLD increased from 203.4 to 228.3 per 1000 patients during 2008–2013. Mortality in CF patients with CFLD was more than double those without; cirrhotic patients had higher all-cause mortality (HR 1.54, 95% CI 1.09 to 2.18, p = 0.015). Median recorded age of cirrhosis diagnosis was 19 (range 5–53) years. Male sex, Pseudomonas airway infection and CF related diabetes were independent risk factors for cirrhosis. Ursodeoxycholic acid use was associated with prolonged survival in patients without cirrhosis.ConclusionsThis study highlights an important changing disease burden of CFLD. The prevalence is slowly increasing and, importantly, the disease is not just being diagnosed in childhood. Although the role of ursodeoxycholic acid remains controversial, this study identified a positive association with survival.
Haworth CS, Bilton D, Chalmers JD, et al., 2019, Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials., The Lancet. Respiratory medicine, Vol: 7, Pages: 213-226, ISSN: 2213-2600
BACKGROUND:In patients with non-cystic fibrosis bronchiectasis, lung infection with Pseudomonas aeruginosa is associated with frequent pulmonary exacerbations and admission to hospital for treatment, reduced quality of life, and increased mortality. Although inhaled antibiotics are conditionally recommended for long-term management of non-cystic fibrosis bronchiectasis with frequent exacerbations, there is no approved therapy. We investigated the safety and efficacy of inhaled liposomal ciprofloxacin (ARD-3150) in two phase 3 trials. METHODS:ORBIT-3 and ORBIT-4 were international, randomised, double-blind, placebo-controlled, phase 3 trials run concurrently in similar geographical regions. Eligible patients had non-cystic fibrosis bronchiectasis, had had at least two pulmonary exacerbations treated with antibiotics in the previous 12 months, and had a history of chronic P aeruginosa lung infection. Patients were randomly assigned (2:1) to receive either ARD-3150 or placebo. ARD-3150 (3 mL liposome encapsulated ciprofloxacin 135 mg and 3 mL free ciprofloxacin 54 mg) or 6 mL placebo (3 mL dilute empty liposomes mixed with 3 mL of saline) was self-administered once daily for six 56-day treatment cycles, for 48 weeks. The primary endpoint was time to first pulmonary exacerbation from the date of randomisation to week 48. We did primary and secondary efficacy, safety, and microbiology analyses on the full analysis population, which comprised all randomised patients who received at least one dose of study drug. ORBIT-3 and ORBIT-4 are registered with ClinicalTrials.gov, numbers NCT01515007 and NCT02104245, respectively. FINDINGS:Between March 31, 2014, and Aug 19, 2015, we screened 514 patients in ORBIT-3 and 533 patients in ORBIT-4. The full analysis populations consisted of 278 patients in ORBIT-3 (183 patients received at least one dose of ARD-3150 and 95 received placebo) and 304 patients in ORBIT-4 (206 patients received at least one dose of ARD-3150 and 98 received
Boyle M, Moore JE, Whitehouse JL, et al., 2019, The diagnosis and management of respiratory tract fungal infection in cystic fibrosis: A UK survey of current practice, MEDICAL MYCOLOGY, Vol: 57, Pages: 155-160, ISSN: 1369-3786
Newsome SJ, Daniel RM, Carr SB, et al., 2019, Investigating the effects of long-term dornase alfa use on lung function using registry data, JOURNAL OF CYSTIC FIBROSIS, Vol: 18, Pages: 110-117, ISSN: 1569-1993
MacDougall A, Archangelidi O, Carr SB, et al., 2018, TRAJECTORIES OF EARLY GROWTH AND FIRST LUNG FUNCTION TEST: A REGISTRY ANALYSIS, Publisher: WILEY, Pages: 394-394, ISSN: 8755-6863
Carr SB, Leadbetter J, Caine N, et al., 2018, FIVE-YEAR POST-AUTHORISATION SAFETY STUDY OF INHALED MANNITOL IN THE UK, Publisher: WILEY, Pages: 332-332, ISSN: 8755-6863
Boyle M, Moore JE, Whitehouse JL, et al., 2018, Laboratory Diagnosis and Characterization of Fungal Disease in Patients with Cystic Fibrosis (CF): A Survey of Current UK Practice in a Cohort of Clinical Microbiology Laboratories, MYCOPATHOLOGIA, Vol: 183, Pages: 723-729, ISSN: 0301-486X
Bessonova L, Volkova N, Higgins M, et al., 2018, Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor, THORAX, Vol: 73, Pages: 731-740, ISSN: 0040-6376
Bilton D, Caine N, Cunningham S, et al., 2018, Use of a rare disease patient registry in long-term post-authorisation drug studies: a model for collaboration with industry, LANCET RESPIRATORY MEDICINE, Vol: 6, Pages: 495-496, ISSN: 2213-2600
Stephenson AL, Bilton D, 2018, The impact of National Cystic Fibrosis Registries: A review series, JOURNAL OF CYSTIC FIBROSIS, Vol: 17, Pages: 287-288, ISSN: 1569-1993
Keogh RH, Szczesniak R, Taylor-Robinson D, et al., 2018, Up-to-date and projected estimates of survival for people with cystic fibrosis using baseline characteristics: A longitudinal study using UK patient registry data, JOURNAL OF CYSTIC FIBROSIS, Vol: 17, Pages: 218-227, ISSN: 1569-1993
Hippolyte SS, Simmonds NJ, Bilton D, et al., 2017, DIABETES AND PSEUDOMONAS, A TERRIBLE COMBINATION? EXAMINING THE UK CYSTIC FIBROSIS REGISTRY FOR A SEX DIFFERENCE IN OUTCOMES (2008-2013), Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A2-A3, ISSN: 0040-6376
Hippolyte SS, Simmonds NJ, Bilton D, et al., 2017, ARE GIRLS ALWAYS THINNER THAN BOYS? USING UK CYSTIC FIBROSIS (CF) REGISTRY DATA (2008-2013) TO EXAMINE WEIGHT CHANGES BETWEEN THE SEXES FROM CHILDHOOD AND BEYOND, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A76-A77, ISSN: 0040-6376
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