323 results found
Alton EW, Boyd AC, Davies JC, et al., 2020, Gene therapy for respiratory diseases; progress and a changing context., Hum Gene Ther
The UK Respiratory Gene Therapy Consortium (GTC) The GTC was formed in 2001 from three groups at the Universities of Edinburgh and Oxford and Imperial College, London to explore gene therapy as a therapeutic option for people with cystic fibrosis (CF)1. The gene responsible for CF, Cystic Fibrosis Transmembrane conductance Regulator (CFTR), was identified in 19892 and over 2000 mutations are now known3, typically classified into six groups4. Whilst considerable progress has been made with this mutation-agnostic approach, gene therapy is not yet a clinical reality. In parallel, mutation-specific, small molecule CFTR modulator therapy has now demonstrated substantial clinical efficacy5. Here, we briefly summarise the opinions of the GTC on navigating this evolving terrain, as well as noting some opportunities for gene therapy in other respiratory diseases.
Saunders C, jensen R, Robinson PD, et al., 2020, Integrating the multiple breath washout test into international multicentre trials, Journal of Cystic Fibrosis, Vol: 19, Pages: 602-607, ISSN: 1569-1993
BackgroundThe lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials.MethodsHere we describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial.ResultsThree regional (North America (NA), Europe (EU), Australia (AUS)) central over-reading centres (CORC) were established to provide a collaborative platform for MBW training, certification and quality control of data.One hundred and thirty-two naïve operators from 53 sites across NA, EU and AUS were successfully trained and certified to perform MBW testing. Incorporation of a re-screening opportunity in the study protocol resulted a final screening feasibility rate of 93%, success remained high throughout the study resulting in an overall feasibility of MBW study data of 88.1% (1107/1257). MBW test acceptability was similar between geographical regions: NA (88%), EU (89%) and AUS (89%).ConclusionWith this approach we achieved high MBW test feasibility and sustained collection of good quality data, demonstrating the utility of LCI as an effective primary endpoint in the first international phase III clinical trial to report LCI as the primary outcome.
Kyrilli S, Henry T, Wilschanski M, et al., 2020, Insights into the variability of nasal potential difference, a biomarker of CFTR activity, Journal of Cystic Fibrosis, Vol: 19, Pages: 620-626, ISSN: 1569-1993
BACKGROUND: Nasal potential difference (NPD) is used to evaluate CFTR function in vivo. We aimed to evaluate the intrasubject and intersubject variability of NPD measurements. METHODS: We reviewed NPD tracings of 116 patients with CF enrolled in the placebo arm of a multicenter study. Patients carried at least one nonsense mutation and underwent repeated NPD tests every 16 weeks. NPD parameters included basal potential difference (basal PD), inhibition of sodium absorption by amiloride (Δ Amiloride), chloride (Cl-) transport in response to a Cl--free solution (Δ Low Cl-), isoproterenol (Δ Isoproterenol), the sum of Δ Low Cl- and Δ Isoproterenol (Δ Low Cl--Isoproterenol) and ATP (Δ ATP). RESULTS: Basal PD and Δ Amiloride displayed the highest variabilities, mainly stemming from intercenter and intrasubject effect. Δ Low Cl-, Δ Isoproterenol and Δ Low Cl--Isoproterenol demonstrated a large intrasubject variability but a smaller intersubject variability. The intrasubject measurement variability for Δ Low Cl--Isoproterenol, was within ± 7.2 mV with 95% probability. It was greater in patients reporting ongoing pulmonary exacerbations. CONCLUSIONS: The large intercenter variability of basal PD and Δ Amiloride highlights the operator-dependent aspect of these measurements. A difference greater than 7.2 mV in Δ Low Cl--Isoproterenol in a given patient on CFTR modulator can be attributed, with 95% probability, to a treatment effect rather than to the variability inherent in the measurement.
De Boeck K, Lee T, Amaral M, et al., 2020, Cystic fibrosis drug trial design in the era of CFTR modulators associated with substantial clinical benefit: stakeholders' consensus view., J Cyst Fibros
CFTR modulators associated with substantial clinical benefit are expected to rapidly improve the baseline condition of people with cystic fibrosis (PWCF) as well as decrease the rate of lung function decline, the occurrence of pulmonary exacerbations and likely even other disease complications. These changes in clinical status of PWCF introduced by clinically effective modulator therapy will have major repercussions on modalities of future CF drug development. As part of its 'Strategic Plan to speed up Access to new Drugs', the European Cystic Fibrosis Society (ECFS) convened a meeting in Brussels on November 27th 2019 with relevant stakeholders (CF researchers and clinicians, patient organization and pharmaceutical company representatives, regulators, health technology assessors; see Acknowledgments for list of attendees) to discuss the future of clinical trials in cystic fibrosis (CF) in the context of HEMT entering the clinical arena. The following is the conclusion of the presentations and discussions. It is hoped that these concepts will be considered in future regulatory guidelines and may provide rationale and support for alternative trial designs.
Mayer-Hamblett N, van Koningsbruggen-Rietschel S, Nichols DP, et al., 2020, Building global development strategies for cf therapeutics during a transitional cftr modulator era., J Cyst Fibros
As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.
Morris-Rosendahl DJ, Edwards M, McDonnell MJ, et al., 2020, Whole-gene sequencing of CFTR reveals a high prevalence of the intronic variant c.3874-4522A>G in cystic fibrosis., American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1438-1441, ISSN: 1073-449X
Isaac SM, Jensen R, Anagnostopoulou P, et al., 2020, Evaluation of a multiple breath nitrogen washout system in children, PEDIATRIC PULMONOLOGY, Vol: 55, Pages: 2108-2114, ISSN: 8755-6863
Short C, Saunders C, Davies JC, 2020, Horses for courses: Learning from functional tests of pulmonary health?, PEDIATRIC PULMONOLOGY, Vol: 55, Pages: 1855-1858, ISSN: 8755-6863
Bentley S, Davies JC, Carr SB, et al., 2020, Combination antifungal therapy for Scedosporium species in cystic fibrosis, PEDIATRIC PULMONOLOGY, Vol: 55, Pages: 1993-1995, ISSN: 8755-6863
Nichols AL, Davies JC, Jones D, et al., 2020, Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor, Paediatric Respiratory Reviews, ISSN: 1526-0542
Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1-5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.
Bayfield KJ, Alton E, Irving S, et al., 2020, “Nitrogen offset in N2 multiple washout method”. Katie J. Bayfield, Eric Alton, Samantha Irving, Andrew Bush, Jane C. Davies. ERJ Open Res 2019; 6: 00043-2020, ERJ Open Research, Vol: 6, Pages: 1-1, ISSN: 2312-0541
This article was originally published with the sentence “Thank you for the opportunity to respond to the correspondence by J.G. Nielsen from Innovision about our recent paper”. The authors have since been made aware that J.G. Nielsen sold Innovision ApS (Glamsbjerg, Denmark) prior to the submission of his correspondence and, at the time of writing, has no financial interests in any business relating to lung clearance index technologies. This sentence has now been changed to “Thank you for the opportunity to respond to the correspondence by J.G. Nielsen about our recent paper” in the article itself.
Turnbull A, Hughes D, Davies J, 2020, Selective sampling of the lower airway in children with CF: what are we missing?, American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 747-748, ISSN: 1073-449X
Langawi MA, Byrnes C, Davies JC, et al., 2020, ‘Go for it, dream big, work hard and persist’: A message to the next generation of CF leaders in recognition of International Women's Day 2020, Journal of Cystic Fibrosis, Vol: 19, Pages: 184-193, ISSN: 1569-1993
The focus for International Women's Day 2020 is gender equity:'We can actively choose to challenge stereotypes, fight bias, broaden perceptions, improve situations and celebrate women's achievements. Collectively, each one of us can help create a gender equal world.' We have come together as an international group of women holding senior positions within CF to raise awareness. There is growing recognition of gender imbalance within our sector in senior leadership, grant and publication success. Several institutions, such as National Institutes of Health, have missions to tackle this. The issues raised by our panellists were wide-ranging: decisions around starting a family, impact on career progression; experiences of bias in appointments or promotions; selfbelief. We hope that raising these issues will encourage future leaders in CF to step up, to build teams based on fairness, equity and diversity, and to catalyse steps towards this goal in their institutions and society more widely.
Davies J, Bayfield K, Alton E, et al., 2020, Letter to the ERJ OPEN reply 24th January 2020
Soren O, Rineh A, Silva DG, et al., 2020, Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 75, Pages: 117-125, ISSN: 0305-7453
Bell SC, Mall MA, Gutierrez H, et al., 2020, The future of cystic fibrosis care: a global perspective, The Lancet Respiratory Medicine, Vol: 8, Pages: 65-124, ISSN: 2213-2600
Turnbull A, Pyle C, Patel D, et al., 2020, Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis, Journal of Cystic Fibrosis, Vol: 19, Pages: 40-48, ISSN: 1569-1993
BackgroundProline–glycine–proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms.MethodsBroncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed.ResultsWhilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase.ConclusionsA striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.
Davies J, Alton E, Simbo A, et al., 2019, Training dogs to differentiate Pseudomonas aeruginosa from other cystic fibrosis bacterial pathogens: not to be sniffed at?, European Respiratory Journal, Vol: 54, ISSN: 0903-1936
Southern KW, Barben J, Gartner S, et al., 2019, Inconclusive diagnosis after a positive newborn bloodspot screening result for cystic fibrosis; clarification of the harmonised international definition, JOURNAL OF CYSTIC FIBROSIS, Vol: 18, Pages: 778-780, ISSN: 1569-1993
Rosenfeld M, Cunningham S, Harris WT, et al., 2019, An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB)., Journal of Cystic Fibrosis, Vol: 18, Pages: 838-843, ISSN: 1569-1993
BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.
Bayfield KJ, Horsley A, Alton E, et al., 2019, Simultaneous sulfur hexafluoride and nitrogen multiple-breath washout (MBW) to examine inherent differences in MBW outcomes, ERJ Open Research, Vol: 5, ISSN: 2312-0541
Multiple-breath washout (MBW) can be performed with different gases (sulfur hexafluoride (SF6-) and nitrogen (N2)) and different devices, all of which give discrepant results. This study aimed to confirm previously reported differences and explore factors influencing discrepant results; equipment factors or the physical properties of gases used. Methods: Healthy controls (HCs) and participants with cystic fibrosis (CF) completed MBW trials on two commercially available devices (Exhalyzer D (N2) and Innocor (SF6)). Simultaneous washout of both gases at the same time on the commercial equipment and simultaneous washouts using a respiratory mass spectrometer (RMS) were completed in subsets. Primary outcomes were lung clearance index (LCI), breath number and time required to washout. Results: Breath number was higher with N2 washout than SF6 in both HCs and patients with CF, whether washouts were completed individually or simultaneously. The difference was greater in more advanced disease, largely caused by differences in the final part of the washout. Results from commercial devices were similar to those obtained with the RMS. Conclusions: N2 MBW results were higher than SF6 MBW, with some of the largest differences reported to date being observed. The biggest impact was at the end of the washout and this was even the case when gases were washed out simultaneously. N2 and SF6 MBW results are inherently different and should be considered as independent measurements.
Waller MD, Harman K, Bayfield KJ, et al., 2019, OPPORTUNISTIC ASSESSMENT OF UPPER AND LOWER AIRWAY ELECTROPHYSIOLOGY AND LUNG FUNCTION IN CYSTIC FIBROSIS, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S163-S163, ISSN: 8755-6863
Martin AD, Davis P, Davies JC, et al., 2019, DEVELOPMENT OF A RAPID POINT-OF-CARE DIAGNOSTIC IMMUNOASSAY FOR THE DETECTION OF P. AERUGINOSA IN CYSTIC FIBROSIS PATIENTS, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S291-S292, ISSN: 8755-6863
Murphy RA, Christiansen S, Sabnis A, et al., 2019, GLATIRAMER ACETATE IS AN ANTIBIOTIC RESISTANCE BREAKER AGAINST CYSTIC FIBROSIS STRAINS OF PSEUDOMONAS AERUGINOSA VIA DISRUPTION OF THE BACTERIAL OUTER MEMBRANE, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S297-S298, ISSN: 8755-6863
Davies JC, Drevinek P, Elborn JS, et al., 2019, Speeding up access to new drugs for CF: Considerations for clinical trial design and delivery, Journal of Cystic Fibrosis, Vol: 18, Pages: 677-684, ISSN: 1569-1993
The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group was brought together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organisations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed and efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF.
Davies JC, Scott S, Dobra R, et al., 2019, Fair selection of participants in clinical trials: The challenge to push the envelope further, Journal of Cystic Fibrosis, Vol: 18, Pages: e48-e50, ISSN: 1569-1993
Amaral MD, de Boeck K, on behalf of the ECFS Strategic Planning Task Force on Speeding up access to new drugs for CF, et al., 2019, Theranostics by testing CFTR modulators in patient-derived materials: The current status and a proposal for subjects with rare CFTR mutations, Journal of Cystic Fibrosis, Vol: 18, Pages: 685-692, ISSN: 1569-1993
The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group came together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organizations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed/efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF.
Dobra R, Scott S, Davies JC, et al., 2019, Who and why; sharing our experiences of developing a standard operating procedure (SOP) to allocate screening slots for highly competitive cystic fibrosis trials, Journal of Cystic Fibrosis, Vol: 18, Pages: e45-e46, ISSN: 1569-1993
Davies JC, Van de Steen O, van Koningsbruggen-Rietschel S, et al., 2019, GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1)., Journal of Cystic Fibrosis, Vol: 18, Pages: 693-699, ISSN: 1569-1993
BACKGROUND: Investigation of novel cystic fibrosis transmembrane conductance regulator (CFTR) potentiators, such as GLPG1837, for CF patients with gating mutations is challenging as trials require patients to withhold ivacaftor, the current standard of care. This study explored the feasibility of such a study and the impact of one-week ivacaftor withdrawal. METHODS: This open-label, single-arm study aimed to enrol 32 adults ≥18 years of age with CF and at least one p.Gly551Asp (G551D) mutation. Patients received three increasing GLPG1837 dosages twice-daily for two 7-day and one 14-day period following a one-week ivacaftor washout. The primary outcome was safety; secondary outcomes were changes in sweat chloride concentration, spirometry outcomes, and pharmacokinetics. RESULTS: Twenty-six patients enrolled; 24 completed the study. Adverse events were reported by 53.8-76.9% of patients (dosage-dependent), with respiratory adverse events most common. Mean sweat chloride concentrations decreased from 97.7 mmol/L (baseline) to 68.7 mmol/L (end of GLPG1837 treatment). In ivacaftor-pre-treated patients, mean sweat chloride concentrations rose from 42.5 mmol/L at screening to 98.5 mmol/L after ivacaftor washout. Levels were decreased following GLPG1837 treatment (to 68.8 mmol/L at treatment end). Percent predicted forced expiratory volume in 1 s declined from 73.3% at screening to 68.5% after ivacaftor washout but returned to screening level at treatment end (73.1%). CONCLUSIONS: Patient willingness to participate in the study suggests that the need for a short period of ivacaftor withdrawal may not be a barrier to development of novel potentiators, such as GLPG1837. A one-week ivacaftor washout was generally well tolerated, but resulted in a decline in lung function, which was reversed with GLPG1837 treatment to pre-washout levels. Combined with the concentration-dependent decrease in sweat chloride concentration, results show that GLPG1837 increases CFTR activity in G
Davies JC, 2019, Trials and tribulations: The highs and lows of running cystic fibrosis drug studies, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 31, Pages: 25-27, ISSN: 1526-0542
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