Publications
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Derichs N, Taylor-Cousar JL, Davies JC, et al., 2021, Riociguat for the treatment of Phe508del homozygous adults with cystic fibrosis, JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 1018-1025, ISSN: 1569-1993
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- Citations: 3
Dobra R, Elborn JS, Madge S, et al., 2021, Guiding the rational design of patient-centred drug trials in Cystic Fibrosis: A Delphi study, JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 986-993, ISSN: 1569-1993
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- Citations: 3
Dobra R, Davies G, Pike K, et al., 2021, Optimising equity of access: how should we allocate slots to the most competitive trials in Cystic Fibrosis (CF)?, Journal of Cystic Fibrosis, Vol: 20, Pages: 978-985, ISSN: 1569-1993
Background:Trial participation can allow people with CF early access to CFTR modulator therapies, with high potential for clinical benefit. Therefore, the number of people wishing to participate can substantially exceed the number of slots available. We aimed to understand how the CF community thinks slots to competitive trials should be allocated across the UK and whether this should be driven by clinical need, patients’ engagement/adherence or be random. For the latter, we explored site-level versus registry-based, national randomisation processes.Methods:We developed an online survey, recruiting UK-based stakeholders through social media, newsletters and personal contacts. Closed questions were analysed for frequencies and percentages of responses. Free-text questions were analysed using thematic analysis.Results:We received 203 eligible responses. Overall, 75% of stakeholders favoured allocation of slots to individual sites based on patient population size, although pharma favoured allocation based on previous metrics. Currently, few centres have defined strategies for allocating slots locally. At face-value, stakeholders believe all eligible participants should have an equal chance of getting a slot. However, further questioning reveals preference for prioritisation strategies, primarily perceived treatment adherence, although healthcare professionals were less likely to favour this strategy than other stakeholder groups. The majority of stakeholders would prefer to allocate slots and participate in trials locally but 80% said if necessary, they would engage in a system of national allocation.Conclusions:Fair allocation to highly competitive trials does not appear to have a universally acceptable solution. Therefore, transparency and empathy remain critical to negotiate this uncertain territory.
Johnson H, Piggin M, McKibben S, et al., 2021, Insight Report: Respiratory medicine research prioritisation online survey
Insight report summarising the findings from an online survey aiming to help shape respiratory medicine research priorities in North West London.
Moiseenko A, Pineault K, Sergijenko A, et al., 2021, Functional characterisation of an engineered next generation lentivirus vector for the treatment of cystic fibrosis, ESGCT Collaborative Virtual Congress, Publisher: MARY ANN LIEBERT, INC, Pages: A39-A39, ISSN: 1043-0342
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- Citations: 1
O'Toole GA, Crabbe A, Kummerli R, et al., 2021, Model Systems to Study the Chronic, Polymicrobial Infections in Cystic Fibrosis: Current Approaches and Exploring Future Directions, MBIO, Vol: 12, ISSN: 2150-7511
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- Citations: 17
Hine C, Desai M, Davies J, et al., 2021, Systematic review of lung clearance index (LCI) in non-cystic fibrosis (CF), non-primary ciliary dyskinesia (PCD) bronchiectasis (Bx), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Barben J, Castellani C, Munck A, et al., 2021, Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID), JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 810-819, ISSN: 1569-1993
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- Citations: 47
Chilvers MA, Davies J, Milla C, et al., 2021, Long-term safety and efficacy of lumacaftor/ivacaftor therapy in children aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label extension study, The Lancet Respiratory Medicine, Vol: 9, Pages: 721-732, ISSN: 2213-2600
Background: The safety and efficacy of 24 weeks of lumacaftor/ivacaftor combination therapy in children aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously demonstrated in two phase 3 studies. Here, we report long-term safety and efficacy data in children who rolled over from these two parent studies into a 96-week lumacaftor/ivacaftor open-label extension study (NCT02544451).Methods: The primary endpoint was safety. Secondary endpoints included change from baseline in lung clearance index 2∙5% (LCI2·5), sweat chloride concentration, body mass index, and Cystic Fibrosis Questionnaire–Revised respiratory domain score.Findings: Of 239 children who enrolled in the study and received at least one dose of lumacaftor/ivacaftor, 215 completed 96 weeks of treatment. Most children had adverse events (AEs) that were mild or moderate in severity, and there was a low rate of AEs leading to treatment discontinuation. The most frequently reported AEs were common manifestations or complications of cystic fibrosis or were consistent with the known safety profile of lumacaftor/ivacaftor in older children and adults. No new safety concerns were identified with extended lumacaftor/ivacaftor treatment. Children treated with placebo in the parent study and who began lumacaftor/ivacaftor in this extension study had improvements in efficacy endpoints consistent with those observed in the parent studies. Improvements observed in lumacaftor/ivacaftor-treated children in the parent studies were generally maintained in the extension study. Interpretation: Lumacaftor/ivacaftor therapy in children homozygous for F508del-CFTR who initiated treatment at ages 6–11 years was generally safe and well tolerated, and efficacy was sustained for up to 120 weeks in this open-label extension study. These data support the long-term use of lumacaftor/ivacaftor to treat children aged ≥6 years homozygous for the F508del-CFTR mutation.
Shteinberg M, Haq IJ, Polineni D, et al., 2021, Cystic fibrosis, LANCET, Vol: 397, Pages: 2195-2211, ISSN: 0140-6736
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- Citations: 209
MacSweeney R, Reddy K, Davies J, et al., 2021, Trans-epithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome, Thorax, Vol: 76, Pages: 1099-1107, ISSN: 0040-6376
Background: Impaired alveolar fluid clearance, determined in part by alveolar sodium transport, is associated with acute respiratory distress syndrome (ARDS). Nasal sodium transport may reflect alveolar transport. The primary objective of this prospective, observational study was to determine if reduced nasal sodium transport, as measured by nasal potential difference (NPD), was predictive of the development of and outcome from ARDS.Methods: NPD was measured in 15 healthy controls and in 88 patients: 40 mechanically ventilated patients defined as ‘at-risk’ for ARDS, 61 mechanically ventilated patients with ARDS (13 who were previously included in the ‘at-risk’ group) and 8 ARDS survivors on the ward.Results: In at-risk subjects, maximum NPD (mNPD) was greater in those who developed ARDS (difference –8.4 mV; 95% CI –13.8 to –3.7; p=0.005) and increased mNPD predicted the development of ARDS before its onset (area under the curve (AUC) 0.75; 95% CI 0.59 to 0.89). In the ARDS group, mNPD was not significantly different for survivors and non-survivors (p=0.076), and mNPD was a modest predictor of death (AUC 0.60; 95% CI 0.45 to 0.75). mNPD was greater in subjects with ARDS (−30.8 mV) than in at-risk subjects (−24.2 mV) and controls (−19.9 mV) (p<0.001). NPD values were not significantly different for survivors and controls (p=0.18).Conclusions: Increased NPD predicts the development of ARDS in at-risk subjects but does not predict mortality. NPD increases before ARDS develops, is greater during ARDS, but is not significantly different for controls and survivors. These results may reflect the upregulated sodium transport necessary for alveolar fluid clearance in ARDS. NPD may be useful as a biomarker of endogenous mechanisms to stimulate sodium transport. Larger studies are now needed to confirm these associations and predictive performance.
Hughes DA, Price H, Rosenthal M, et al., 2021, Pseudomonas aeruginosa in the cystic fibrosis airway: does it deserve its reputation as a predatory 'Bully'?, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 1027-1030, ISSN: 1073-449X
Sepahzad A, Morris-Rosendahl D, Davies J, 2021, Cystic fibrosis lung disease modifiers and their relevance in the new era of precision medicine, Genes, Vol: 12, ISSN: 2073-4425
Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.
Sabnis A, Haggard K, Kloeckner A, et al., 2021, Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane, eLife, Vol: 10, Pages: 1-26, ISSN: 2050-084X
Colistin is an antibiotic of last resort, but has poor efficacy and resistance is a growing problem. Whilst it is well established that colistin disrupts the bacterial outer membrane (OM) by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in Escherichia coli is due to modified LPS at the cytoplasmic rather than OM. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane (CM). We then exploited this information to devise a new therapeutic approach. Using the LPS transport inhibitor murepavadin, we were able to cause LPS accumulation in the CM of Pseudomonas aeruginosa, which resulted in increased susceptibility to colistin in vitro and improved treatment efficacy in vivo. These findings reveal new insight into the mechanism by which colistin kills bacteria, providing the foundations for novel approaches to enhance therapeutic outcomes.
Martin I, Kenna D, Morales S, et al., 2021, Variability in bacteriophage and antibiotic sensitivity in serial Pseudomonas aeruginosa isolates from cystic fibrosis airway cultures over 12 months, Mircoorganisms, Vol: 9, ISSN: 2076-2607
Antibiotic treatment for Pseudomonas aeruginosa (Pa) in cystic fibrosis is limited in efficacy and may lead to multi-drug resistance (MDR). Alternatives such as bacteriophages are being explored but well designed, and controlled trials are crucial. The rational selection of patients with bacteriophage susceptible infections is required for both safety and efficacy monitoring. We questioned whether bacteriophage susceptibility profiles were constant or variable over time, variability having been reported with antibiotics. Serial Pa isolates (n = 102) from 24 chronically infected cystic fibrosis (CF) patients over one year were investigated with plaque and antibiotic disc diffusion assays. Variable number tandem repeat (VNTR) analysis identified those patients with >1 isolate. A median (range) of 4 (3–6) isolates/patient were studied. Twenty-one (87.5%) individuals had a single VNTR type; three (12.5%) had two VNTR types at different times. Seventy-five percent of isolates were sensitive to bacteriophage at ≥ 1 concentration; 50% of isolates were antibiotic multidrug resistant. Serial isolates, even when representing a single VNTR type, varied in sensitivity to both bacteriophages and antibiotics. The rates of sensitivity to bacteriophage supports the development of this therapy; however, the variability in response has implications for the selection of patients in future trials which must be on the basis of current, not past, isolate testing.
Zemanick ET, Taylor-Cousar JL, Davies J, et al., 2021, A Phase 3 open-label study of ELX/TEZ/IVA in children 6 through 11 years of age with CF and at least one F508del allele., American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 1522-1532, ISSN: 1073-449X
RATIONALE: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients aged 12 years and older with cystic fibrosis and at least one F508del-CFTR allele, but has not been evaluated in children <12 years of age. OBJECTIVES: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes. METHODS: In this 24-week open-label Phase 3 study, children (N=66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours) while children weighing ≥30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most common reported adverse events (AEs) included cough, headache, and pyrexia; in most of the children who had AEs, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the ppFEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period compared to the pre-treatment baseline. CONCLUSIONS: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT03691779 This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No D
Davies J, Dobra R, Boeri M, et al., 2021, Protocol: A discrete choice experiment (DCE) to quantify the influence of trial features on the decision to participate in Cystic Fibrosis (CF) clinical trials, British medical journal, Vol: 11, Pages: 1-7, ISSN: 0007-1447
Introduction Engaging people with cystic fibrosis (CF) in clinical trials is critical to improving outcomes for this fatal disease. Following extensive exploration of engagement in CF trials we believe six key concepts require a quantitative understanding of their influence in the current CF trials landscape including how controversial issues like placebos, washouts, stipend provision and location of trial visits are viewed by the CF community and how these might be modified depending on the type of medicine being investigated and the mechanism of access to the drug on trial completion.Methods and analysis We have designed and will administer an online discrete choice experiment to elicit and quantify preferences of people with CF for these trials’ attributes and estimate the relative importance of an attribute when choosing to participate in a trial. The cross-sectional data generated will be explored using conditional multinomial logit model. Mixed logit models such as the random-parameters logit and a latent class models will be used to explore preference heterogeneity. To determine the relative importance of an attribute, the difference between the attribute level with the highest preference weight and the level with the lowest preference weight will be calculated.Ethics and dissemination Imperial College London Joint Research Compliance Office has granted ethical approval for this study. Patient consent will be sought following full explanation. No identifying information will be collected. Dissemination will be via international conferences, peer-review publication and patient accessible forums. Major CF trials networks have agreed to incorporate our findings into their review process, meaning our results can realistically influence and optimise CF trial delivery.PROSPERO registration number CRD42020184886.
Davies JC, Wainwright CE, Sawicki GS, et al., 2021, Ivacaftor in Infants Aged 4 to <12 Months with Cystic Fibrosis and a Gating Mutation Results of a Two-Part Phase 3 Clinical Trial, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 203, Pages: 585-593, ISSN: 1073-449X
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- Citations: 53
Davies J, Dobra R, Huband K, et al., 2021, Strengthening clinical trial pharmacovigilance: simple interventions improve communication over serious adverse events, Journal of Clinical Trials
Coates M, Alton E, Rapeport W, et al., 2021, Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway, PLoS One, Vol: 16, ISSN: 1932-6203
Pseudomonas aeruginosa (Pa) infection is a major cause of airway inflammation in immunocompromised and cystic fibrosis (CF) patients. Mitogen-activated protein (MAP) and tyrosine kinases are integral to inflammatory responses and are therefore potential targets for novel anti-inflammatory therapies. We have determined the involvement of specific kinases in Pa-induced inflammation. The effects of kinase inhibitors against p38MAPK, MEK 1/2, JNK 1/2, Syk or c-Src, a combination of a p38MAPK with Syk inhibitor, or a novel narrow spectrum kinase inhibitor (NSKI), were evaluated against the release of the proinflammatory cytokine/chemokine, IL-6 and CXCL8 from BEAS-2B and CFBE41o- epithelial cells by Pa. Effects of a Syk inhibitor against phosphorylation of the MAPKs were also evaluated. IL-6 and CXCL8 release by Pa were significantly inhibited by p38MAPK and Syk inhibitors (p<0.05). Phosphorylation of HSP27, but not ERK or JNK, was significantly inhibited by Syk kinase inhibition. A combination of p38MAPK and Syk inhibitors showed synergy against IL-6 and CXCL8 induction and an NSKI completely inhibited IL-6 and CXCL8 at low concentrations. Pa-induced inflammation is dependent on p38MAPK primarily, and Syk partially, which is upstream of p38MAPK. The NSKI suggests that inhibiting specific combinations of kinases is a potent potential therapy for Pa-induced inflammation.
Rosenfeld M, Wainwright C, Sawicki GS, et al., 2021, IVACAFTOR IN 4-TO <6-MONTH-OLD INFANTS WITH CYSTIC FIBROSIS AND A GATING MUTATION: RESULTS OF A 2-PART, SINGLE-ARM, PHASE 3 STUDY, Winter Meeting of the British-Thoracic-Society (BTS), Publisher: BMJ PUBLISHING GROUP, Pages: A39-A39, ISSN: 0040-6376
Dave K, Dobra R, Scott S, et al., 2021, Entering the era of highly effective modulator therapies, PEDIATRIC PULMONOLOGY, Vol: 56, Pages: S79-S89, ISSN: 8755-6863
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- Citations: 16
Gardner LE, Pinto LA, Davies JC, et al., 2021, THE USE OF THORACIC CT TO DETERMINE BONE MINERAL DENSITY IN ADULTS AND CHILDREN WITH CYSTIC FIBROSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A158-A158, ISSN: 0040-6376
Farrant KV, Spiga L, Davies JC, et al., 2021, Response of Pseudomonas aeruginosa to the innate immune system-derived oxidants hypochlorous acid and hypothiocyanous acid, Journal of Bacteriology, Vol: 203, ISSN: 0021-9193
Pseudomonas aeruginosa is a significant nosocomial pathogen and associated with lung infections in cystic fibrosis (CF). Once established, P. aeruginosa infections persist and are rarely eradicated despite host immune cells producing antimicrobial oxidants, including hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). There is limited knowledge as to how P. aeruginosa senses, responds to, and protects itself against HOCl and HOSCN, and the contribution of such responses to its success as a CF pathogen. To investigate the P. aeruginosa response to these oxidants we screened 707 transposon mutants, with mutations in regulatory genes, for altered growth following HOCl exposure. We identified regulators of antibiotic resistance, methionine biosynthesis and catabolite repression, and PA14_07340, the homologue of the Escherichia coli HOCl-sensor RclR (30% identical), that are required for protection against HOCl. We have shown that RclR (PA14_07340) protects specifically against HOCl and HOSCN stress, and responds to both oxidants by upregulating expression of a putative peroxiredoxin, rclX (PA14_07355). Transcriptional analysis revealed that while there was specificity in the response to HOCl (231 genes upregulated) and HOSCN (105 genes upregulated) there was considerable overlap, with 74 genes upregulated by both oxidants. These included genes encoding the type III secretion system, sulphur and taurine transport, and the MexEF-OprN efflux pump. RclR coordinates part of the response to both oxidants, including upregulation of pyocyanin biosynthesis genes, and in the presence of HOSCN, downregulation of chaperone genes. These data indicate that the P. aeruginosa response to HOCl and HOSCN is multifaceted, with RclR playing an essential role.
Flume PA, Castellani C, Davies J, 2021, JCF year in review, Journal of Cystic Fibrosis, Vol: 20, Pages: 1-2, ISSN: 1569-1993
Davies JC, Sermet-Gaudelus I, Naehrlich L, et al., 2021, A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for <i>F508del</i> or heterozygous for the <i>F508del-CFTR</i> mutation and a residual function mutation, JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 68-77, ISSN: 1569-1993
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- Citations: 27
Nissenbaum C, Davies G, Horsley A, et al., 2020, Monitoring early stage lung disease in cystic fibrosis., Current Opinion in Pulmonary Medicine, Vol: 26, Pages: 671-678, ISSN: 1070-5287
PURPOSE OF REVIEW: Early stage lung disease has long been synonymous with infancy and childhood. As diagnosis happens earlier and conventional management improves, we are seeing larger proportions of people with cystic fibrosis (CF) in adolescence and even adulthood with well preserved lung health. The availability of highly effective cystic fibrosis transmembrane conductance regulator modulator drugs for a large proportion of the CF population will impact even further. Transitioning into adult care with 'normal' lung function will become more common. However, it is crucial that we are not blasé about this phase, which sets the scene for future lung health. It is well recognized that lung function assessed by spirometry is insensitive to 'early' changes occurring in the distal, small airways. Much of our learning has come from studies in infants and young children, which have allowed assessment and optimization of alternative forms of monitoring. RECENT FINDINGS: Here, as a group of paediatric and adult CF specialists, we review the evidence base for sensitive physiological testing based on multibreath washout, lung imaging, exercise and activity monitoring, assessment of infection and quality of life measures. SUMMARY: We seek to emphasise the importance of further work in these areas, as outcome measures become widely applicable to a growing CF population.
Short C, Saunders C, Davies JC, 2020, Utility of lung clearance index in CF: What we know, what we don't know and musings on how to bridge the gap, JOURNAL OF CYSTIC FIBROSIS, Vol: 19, Pages: 852-855, ISSN: 1569-1993
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- Citations: 7
Kerem E, Cohen-Cymberknoh M, Tsabari R, et al., 2020, Ivacaftor in people with cystic fibrosis and a 3849+10kb C →T or D1152H residual function mutation., Annals of the American Thoracic Society, Vol: 18, Pages: 433-441, ISSN: 1546-3222
Rationale: Ivacaftor's clinical effects in the residual function mutations 3849+10kb C →T and D1152H warrant further characterization. Objectives: Evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with 3849+10kb C→T or D1152H residual function mutations; explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor. Methods: Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and in vitro intestinal organoid-based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function. Results: Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index2.5 with ivacaftor vs placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor's known safety profile. Dose-dependent swelling was observed in 23/25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low. Conclusions: In people with cystic fibrosis aged ≥6 years with a 3849+10kb C →T or D1152H mutation, ivacaftor treatment improved clinical endpoints vs placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations. Clinical trial registered with ClinicalTrials.gov (NCT0306831
O'Neill K, Ferguson K, Cosgrove D, et al., 2020, Multiple Breath Washout (MBW) in bronchiectasis clinical trials – Is it feasible?, European Respiratory Journal, Vol: 6, Pages: 1-10, ISSN: 0903-1936
Background: Evaluation of Multiple Breath Washout (MBW) set-up including staff training, certification and central “over-reading” for data quality control is essential to determine the feasibility of MBW in future bronchiectasis studies. Aims: To assess the outcomes of a MBW training, certification and central over-reading programme. Methods: MBW training and certification was conducted in European sites collecting LCI data in the BronchUK clinimetrics and/or i-BEST-1 studies. The blended training programme included the use of an eLearning tool and a 1-day face-to-face session. Sites submitted MBW data to trained central over-readers who determined validity and quality. Results: Thirteen training days were delivered to 56 participants from 22 sites. 18/22 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p<0.001). By the end of the study recruitment, 15/22 sites (68%) had completed certification with a mean (range) time since training of 6.2 (3-14) months. In the BronchUK clinimetrics study, 468/589 (79%) tests met45 the quality criteria following central over-reading, compared with 137/236 (58%) tests in the i-BEST-1 study. Conclusions: LCI is feasible in a bronchiectasis multicentre clinical trial setting however, consideration of site experience in terms of training as well as assessment of skill drift and the need for re-training may be important to reduce time to certification and optimise data quality. Longer times to certification, a higher percentage of naive sites and patients with worse lung function may have contributed to the lower success rate in the i-BEST-1 study.
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