Publications
451 results found
McNally P, O'Rourke J, Fantino E, et al., 2018, Pooling of bronchoalveolar lavage in children with cystic fibrosis does not adversely affect the microbiological yield or sensitivity in detecting pulmonary inflammation, Journal of Cystic Fibrosis, Vol: 17, Pages: 391-399, ISSN: 1569-1993
BACKGROUND: Bronchoalveolar lavage (BAL) is a potentially useful outcome measure for clinical trials in children with CF but its use is limited by variations in approach internationally. We sought to determine if pooling adversely affected the diagnostic properties of BAL. METHODS: Children undergoing bronchoscopy for clinical reasons were included. A multi-step study protocol ensured BAL was collected and analysed both separately and as a pooled fluid. RESULTS: Eighty-five children (53 CF, 32 control) were recruited. There was a high level of concordance between pooled and non-pooled samples in terms of organism identification (76%). There was good agreement (Bland Altman) between the two methods in terms of detection of inflammation independent of centre, microbiological concordance or disease status. Bi-directional variability in IL-8 levels between pooled and non-pooled samples was seen. Free neutrophil elastase (NE) was detected in 4 cases in pooled lavage when absent in non-pooled lavage. Levels of interleukin-8 (IL-8) were similar between the two groups with pooled samples showing a greater spread of values. CONCLUSIONS: Pooling of BAL in children does not negatively impact on either the detection of pulmonary infection or inflammation or the observed relationship between infection and inflammation. Intra-patient variability in BAL IL-8 levels suggests regional differences in inflammation.
Brugha RE, Edmondson C, Davies J, 2018, Outdoor Air Pollution and Cystic Fibrosis, Paediatric Respiratory Reviews, ISSN: 1526-0542
Saleh AD, Clarke NK, Meng C, et al., 2017, DEVELOPMENT OF ASSAYS TO ASSESS SAFETY AND EFFICACY OF LENTIVIRAL GENE THERAPY FOR CYSTIC FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A57-A57, ISSN: 0040-6376
Edmondson C, Murphy R, Moffitt K, et al., 2017, IT IS POSSIBLE TO DETECT ACTIVE NEUTROPHIL ELASTASE IN EXHALED BREATH CONDENSATE OF PATIENTS WITH CYSTIC FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A219-A219, ISSN: 0040-6376
Rowe SM, Daines C, Ringshausen FC, et al., 2017, Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis, New England Journal of Medicine, Vol: 377, Pages: 2024-2035, ISSN: 0028-4793
BACKGROUNDCystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR.METHODSWe conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor–ivacaftor, ivacaftor monotherapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period.RESULTSThe number of analyzed intervention periods was 162 for tezacaftor–ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor–ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor–ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%).CONCLUSI
Christiansen SH, Murphy RA, Juul-Madsen K, et al., 2017, The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria., Scientific Reports, Vol: 7, ISSN: 2045-2322
Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. Glatiramer acetate (GA) is a widely used and safe formulation for treatment of multiple sclerosis. It contains a large diversity of essentially isomeric polypeptides with the cationic and amphiphilic character of many antimicrobial peptides (AMP). Here, we report that GA is antibacterial, targeting Gram-negative organisms with higher activity towards Pseudomonas aeruginosa than the naturally-occurring AMP LL-37 in human plasma. As judged from flow cytometric assays, bacterial killing by GA occurred within minutes. Laboratory strains of Escherichia coli and P. aeruginosa were killed by a process of condensing intracellular contents. Efficient killing by GA was also demonstrated in Acinetobacter baumannii clinical isolates and approximately 50% of clinical isolates of P. aeruginosa from chronic airway infection in CF patients. By contrast, the Gram-positive Staphylococcus aureus cells appeared to be protected from GA by an increased formation of nm-scale particulates. Our data identify GA as an attractive drug repurposing candidate to treat infections with Gram-negative bacteria.
Davies G, Stocks J, Thia LP, et al., 2017, Pulmonary function deficits in newborn screened infants with cystic fibrosis managed with standard UK care are mild and transient, European Respiratory Journal, Vol: 50, ISSN: 0903-1936
With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV0.5), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45–1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV0.5 on all test occasions, precluding the ability to identify “high-risk” infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up.
Wen KY, Cameron L, Chappell J, et al., 2017, A Cell-Free Biosensor for Detecting Quorum Sensing Molecules in P. aeruginosa-Infected Respiratory Samples., ACS Synthetic Biology, Vol: 6, Pages: 2293-2301, ISSN: 2161-5063
Synthetic biology designed cell-free biosensors are a promising new tool for the detection of clinically relevant biomarkers in infectious diseases. Here, we report that a modular DNA-encoded biosensor in cell-free protein expression systems can be used to measure a bacterial biomarker of Pseudomonas aeruginosa infection from human sputum samples. By optimizing the cell-free system and sample extraction, we demonstrate that the quorum sensing molecule 3-oxo-C12-HSL in sputum samples from cystic fibrosis lungs can be quantitatively measured at nanomolar levels using our cell-free biosensor system, and is comparable to LC-MS measurements of the same samples. This study further illustrates the potential of modular cell-free biosensors as rapid, low-cost detection assays that can inform clinical practice.
Donaldson SH, Pilewski JM, Griese M, et al., 2017, Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR., American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 214-224, ISSN: 1073-449X
RATIONALE: Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. OBJECTIVES: To evaluate safety and efficacy of tezacaftor monotherapy and tezacaftor/ivacaftor combination therapy in subjects with CF homozygous for F508del or compound heterozygous for F508del and G551D. METHODS: This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 mg to 150 mg) qday alone or in combination with ivacaftor 150 mg q12h in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D taking physician prescribed ivacaftor received tezacaftor 100 mg qday. MEASUREMENTS AND MAIN RESULTS: Primary endpoints were safety through day 56 and change in sweat chloride from baseline through day 28. Secondary endpoints included change in percent predicted FEV1 (ppFEV1) from baseline through day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor 100 mg qday/ivacaftor 150 mg q12h resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV¬1 in subjects homozygous for F508del and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV¬1 in subjects compound heterozygous for F508del and G551D from baseline through day 28 (P < 0.05 for all). CONCLUSIONS: These results support continued clinical development of tezacaftor 100 mg qday in combination with ivacaftor 150 mg q12h in subjects with CF. Clinical trial registration available at www.clinicaltrials.gov, ID NCT0153167.
Conrath K, Gesson C, Allamassey L, et al., 2017, GLPG1837 IN SUBJECTS WITH CYSTIC FIBROSIS AND THE S1251N OR G551D MUTATION: RESULTS FROM PHASE 2A STUDIES (SAPHIRA 1 AND 2), North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S312-S312, ISSN: 8755-6863
Edmondson C, Murphy R, Moffitt K, et al., 2017, ACTIVE NEUTROPHIL ELASTASE CAN BE DETECTED IN EXHALED BREATH CONDENSATE OF PATIENTS WITH CYSTIC FIBROSIS, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S316-S316, ISSN: 8755-6863
Davies J, 2017, PSEUDOMONAL/VIRAL INTERACTIONS IN AIRWAY INFECTION, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S166-S167, ISSN: 8755-6863
Rowe SM, Davies J, 2017, CFTR MODULATION WITH TEZACAFTOR/IVACAFTOR IN PATIENTS HETEROZYGOUS FOR F508DEL AND A RESIDUAL FUNCTION MUTATION, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S175-S176, ISSN: 8755-6863
Taylor-Cousar JL, Derichs N, Tullis DE, et al., 2017, SAFETY, TOLERABILITY AND EARLY SIGNS OF EFFICACY WITH RIOCIGUAT FOR THE TREATMENT OF ADULT PHE508DEL HOMOZYGOUS CYSTIC FIBROSIS PATIENTS: SAFETY DATA FROM THE RIO-CF STUDY, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S307-S307, ISSN: 8755-6863
Elborn JS, Davies J, 2017, Clinical trial research in focus: ensuring new cystic fibrosis drugs fulfil their potential, LANCET RESPIRATORY MEDICINE, Vol: 5, Pages: 681-683, ISSN: 2213-2600
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Davies JC, 2017, Invasive and Non-invasive Methods to Assess Responses to Respiratory Treatments in Early Childhood, PEDIATRIC PULMONOLOGY, Vol: 52, Pages: S20-S22, ISSN: 8755-6863
Flume PA, Wainwright CE, Elizabeth Tullis D, et al., 2017, Recovery of lung function following a pulmonary exacerbation in patients with cystic fibrosis and the G551D-CFTR mutation treated with ivacaftor, Journal of Cystic Fibrosis, Vol: 17, Pages: 83-88, ISSN: 1569-1993
BACKGROUND: Pulmonary exacerbations (PEx) are associated with acute loss of lung function that is often not recovered after treatment. We investigated lung function recovery following PEx for ivacaftor- and placebo-treated subjects. METHODS: Short- and long-term pulmonary function recovery data after PEx were summarized from a placebo-controlled trial in 161 cystic fibrosis patients≥12years old with the G551D-CFTR mutation (NCT00909532). Short-term recovery was measured 2 to 8weeks after treatment, and long-term recovery was determined at the end-of-study, both compared with baseline measured just prior to the PEx. RESULTS: Fewer patients receiving ivacaftor experienced a PEx than patients receiving placebo (33.7% vs. 56.4%; P=0.004) and had a lower adjusted incidence rate of PEx (0.589 vs. 1.382; P<0.001). The proportion of PEx followed by full short-term recovery of percent predicted forced expiratory volume in 1s was similar (ivacaftor vs. placebo, 57.1% vs. 53.7), as was the proportion of patients having long-term recovery (46.4% vs. 47.7%). CONCLUSIONS: Ivacaftor treatment reduces the frequency of PEx but does not improve on the rate of complete lung function recovery after PEx when compared with placebo.
Smith WD, Bardin E, Cameron L, et al., 2017, Current and future therapies for Pseudomonas aeruginosa infection in patients with cystic fibrosis, FEMS Microbiology Letters, Vol: 364, ISSN: 0378-1097
Pseudomonas aeruginosa opportunistically infects the airways of patients with cystic fibrosis and causes significant morbidity and mortality. Initial infection can often be eradicated though requires prompt detection and adequate treatment. Intermittent and then chronic infection occurs in the majority of patients. Better detection of P. aeruginosa infection using biomarkers may enable more successful eradication before chronic infection is established. In chronic infection P. aeruginosa adapts to avoid immune clearance and resist antibiotics via efflux pumps, β-lactamase expression, reduced porins and switching to a biofilm lifestyle. The optimal treatment strategies for P. aeruginosa infection are still being established, and new antibiotic formulations such as liposomal amikacin, fosfomycin in combination with tobramycin and inhaled levofloxacin are being explored. Novel agents such as the alginate oligosaccharide OligoG, cysteamine, bacteriophage, nitric oxide, garlic oil and gallium may be useful as anti-pseudomonal strategies, and immunotherapy to prevent infection may have a role in the future. New treatments that target the primary defect in cystic fibrosis, recently licensed for use, have been associated with a fall in P. aeruginosa infection prevalence. Understanding the mechanisms for this could add further strategies for treating P. aeruginosa in future.
Ratjen F, Hug C, Marigowda G, et al., 2017, Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled, phase 3 trial, Lancet Respiratory Medicine, Vol: 5, Pages: 557-567, ISSN: 2213-2600
BackgroundLumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6–11 years homozygous for F508del-CFTR.MethodsIn this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index2·5 (LCI2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute
De Boeck K, Davies JC, 2017, Where are we with transformational therapies for patients with cystic fibrosis?, CURRENT OPINION IN PHARMACOLOGY, Vol: 34, Pages: 70-75, ISSN: 1471-4892
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Davies JC, 2017, Cystic Fibrosis: When the Diagnosis Is Unclear, Publisher: WILEY, Pages: S76-S77, ISSN: 8755-6863
Davies JC, 2017, Visualising early lung disease in CF: the emergence of MRI, THORAX, Vol: 72, Pages: 682-682, ISSN: 0040-6376
Harman K, Dobra R, Davies JC, 2017, Disease-modifying drug therapy in cystic fibrosis, Paediatric Respiratory Reviews, Vol: 26, Pages: 7-9, ISSN: 1526-0542
Whilst substantial progress has been made in the treatment of cystic fibrosis, the disease still carries a significant burden in terms of symptoms, requirement for treatment and early mortality. The last decade has witnessed a new era in the development of small molecule drugs targeting the CFTR protein, which for the first time may provide a truly disease-modifying approach to treatment. This article reviews progress and highlights some of the current and future challenges in CFTR modulator therapies.
Saunders C, Bayfield K, Irving S, et al., 2017, Developments in multiple breath washout testing in children with cystic fibrosis, CURRENT MEDICAL RESEARCH AND OPINION, Vol: 33, Pages: 613-620, ISSN: 0300-7995
Farrell PM, White TB, Howenstine MS, et al., 2017, Diagnosis of Cystic Fibrosis in Screened Populations, JOURNAL OF PEDIATRICS, Vol: 181, Pages: S33-+, ISSN: 0022-3476
Elborn JS, Davies J, Mall MA, et al., 2016, Current strategies for the long-term assessment, monitoring, and management of cystic fibrosis patients treated with CFTR modulator therapy, JOURNAL OF CYSTIC FIBROSIS, Vol: 16, Pages: 163-164, ISSN: 1569-1993
Coates MS, Alton EWFW, Brookes DW, et al., 2016, INCREASED RESPIRATORY SYNCYTIAL VIRUS BURDEN LEADS TO MORE RAPID CELL DEATH IN PHE508DEL BRONCHIAL EPITHELIAL CELLS, THORAX, Vol: 71, Pages: A44-A44, ISSN: 0040-6376
Davies JC, 2016, Cystic fibrosis in 2016: considerable progress, but much more to do., Lancet Respir Med, Vol: 4, Pages: 943-945
Alton EW, Beekman JM, Boyd AC, et al., 2016, Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis, Thorax, Vol: 72, Pages: 137-147, ISSN: 0040-6376
We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air-liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and 'benchmarked' against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90-100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F/HN-pseudotype
Davies JC, Robertson S, Cooke J, et al., 2016, LONG-TERM SAFETY AND EFFICACY OF IVACAFTOR IN PAEDIATRIC PATIENTS AGED 2-5 YEARS WITH CYSTIC FIBROSIS AND A CFTR GATING MUTATION, THORAX, Vol: 71, Pages: A67-A67, ISSN: 0040-6376
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