Imperial College London

ProfessorJaneDavies

Faculty of MedicineNational Heart & Lung Institute

Professor of Paediatric Respirology & Experimental Medicine
 
 
 
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Contact

 

+44 (0)20 7594 7973j.c.davies

 
 
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Assistant

 

Mrs Gina Rivellini +44 (0)20 7594 7986

 
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Location

 

171Emmanuel Kaye BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

346 results found

Davies JC, Wainwright CE, Sawicki GS, Higgins MN, Campbell D, Harris C, Panorchan P, Haseltine E, Tian S, Rosenfeld Met 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., Am J Respir Crit Care Med, Vol: 203, Pages: 585-593

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months.Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations.Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B.Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved.Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.Clinical trial registered with clinicaltrials.gov (NCT02725567).

Journal article

Davies J, Dobra R, Boeri M, Elborn S, Kee F, Madge Set 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, ISSN: 0007-1447

Journal article

Dave K, Dobra R, Scott S, Saunders C, Matthews J, Simmonds NJ, Davies JCet al., 2021, Entering the era of highly effective modulator therapies, PEDIATRIC PULMONOLOGY, Vol: 56, Pages: S79-S89, ISSN: 8755-6863

Journal article

Coates M, Alton E, Rapeport W, Davies J, Ito Ket al., 2021, Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway, PLoS One, ISSN: 1932-6203

Journal article

Davies JC, Sermet-Gaudelus I, Naehrlich L, Harris RS, Campbell D, Ahluwalia N, Short C, Haseltine E, Panorchan P, Saunders C, Owen CA, Wainwright CE, VX16-661-115 Investigator Groupet 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 F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation., J Cyst Fibros, Vol: 20, Pages: 68-77

BACKGROUND: The CFTR modulator tezacaftor/ivacaftor was efficacious and generally safe and well tolerated in Phase 3 studies in participants ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous with a residual function-CFTR mutation (F/F or F/RF respectively). We evaluated tezacaftor/ivacaftor's efficacy and safety over 8 weeks in participants 6 through 11 years of age with these mutations. METHODS: Participants were randomized 4:1 to tezacaftor/ivacaftor or a blinding group (placebo for F/F, ivacaftor for F/RF). The primary endpoint was within-group change from baseline in the lung clearance index 2·5 (LCI2·5) through Week 8. Secondary endpoints were change from baseline in sweat chloride (SwCl), cystic fibrosis questionnaire-revised (CFQ-R) respiratory domain score, and safety. RESULTS: Sixty-seven participants received at least one study drug dose. Of those, 54 received tezacaftor/ivacaftor (F/F, 42; F/RF, 12), 10 placebo, and 3 ivacaftor; 66 completed the study. The within-group change in LCI2·5 was significantly reduced (improved) by -0·51 (95% CI: -0·74, -0·29). SwCl concentration decreased (improved) by -12·3 mmol/L and CFQ-R respiratory domain score increased (improved, nonsignificantly) by 2·3 points. There were no serious adverse events (AEs) or AEs leading to tezacaftor/ivacaftor discontinuation or interruption. The most common AEs (≥10%) in participants receiving tezacaftor/ivacaftor were cough, headache, and productive cough. CONCLUSIONS: Tezacaftor/ivacaftor improved lung function (assessed using LCI) and CFTR function (measured by SwCl concentration) in participants 6 through 11 years of age with F/F or F/RF genotypes. Tezacaftor/ivacaftor was safe and well tolerated; no new safety concerns were identified.

Journal article

Hughes DA, Price H, Rosenthal M, Davies JCet al., 2020, Pseudomonas aeruginosa in the CF airway: does it deserve its reputation as a predatory 'Bully'?, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Journal article

Barben J, Castellani C, Munck A, Davies JC, de Winter-de Groot KM, Gartner S, Kashirskaya N, Linnane B, Mayell SJ, McColley S, Ooi CY, Proesmans M, Ren CL, Salinas D, Sands D, Sermet-Gaudelus I, Sommerburg O, Southern KW, European CF Society Neonatal Screening Working Group ECFS NSWGet al., 2020, Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID)., J Cyst Fibros

Over the past two decades there has been considerable progress with the evaluation and management of infants with an inconclusive diagnosis following Newborn Screening (NBS) for cystic Fibrosis (CF). In addition, we have an increasing amount of evidence on which to base guidance on the management of these infants and, importantly, we have a consistent designation being used across the globe of CRMS/CFSPID. There is still work to be undertaken and research questions to answer, but these infants now receive more consistent and appropriate care pathways than previously. It is clear that the majority of these infants remain healthy, do not convert to a diagnosis of CF in childhood, and advice on management should reflect this. However, it is also clear that some will convert to a CF diagnosis and monitoring of these infants should facilitate their early recognition. Those infants that do not convert to a CF diagnosis have some potential of developing a CFTR-RD later in life. At present, it is not possible to quantify this risk, but families need to be provided with clear information of what to look out for. This paper contains a number of changes from previous guidance in light of developing evidence, but the major change is the recommendation of a detailed assessment of the child with CRMS/CFSPID in the sixth year of age, including respiratory function assessment and imaging. With these data, the CF team can discuss future care arrangements with the family and come to a shared decision on the best way forward, which may include discharge to primary care with appropriate information. Information is key for these families, and we recommend consideration of a further appointment when the individual is a young adult to directly communicate the implications of the CRMS/CFSPID designation.

Journal article

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

Journal article

Nissenbaum C, Davies G, Horsley A, Davies JCet 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.

Journal article

Davies J, Chilvers MA, Milla C, Tian S, Han Z, Cornell AG, Owen CA, Ratjen Fet al., 2020, 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, 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.

Journal article

Farrant KV, Spiga L, Davies JC, Williams Het al., 2020, Response of Pseudomonas aeruginosa to the innate immune system-derived oxidants hypochlorous acid and hypothiocyanous acid, Journal of Bacteriology, 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.

Journal article

Kerem E, Cohen-Cymberknoh M, Tsabari R, Wilschanski M, Reiter J, Shoseyov D, Gileles-Hillel A, Pugatsch T, Davies JC, Short C, Saunders C, DeSouza C, Sullivan JC, Doyle JR, Chandarana K, Kinnman Net 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, 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

Journal article

O'Neill K, Ferguson K, Cosgrove D, Tunney MM, De Soyza A, Carroll M, Chalmers JD, Gatheral T, Hill AT, Hurst JR, Johnson C, Loebinger MR, Angyalosi G, Haworth CS, Jensen R, Ratjen F, Saunders C, Short C, Davies J, Elborn JS, Bradley JMet 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.

Journal article

Stanford G, Davies JC, Usmani O, Banya W, Charman S, Jones M, Simmonds NJ, Bilton Det 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.

Journal article

Gardner L, Pinto LA, Davies JC, Semple Tet al., 2020, THE USE OF THORACIC CT TO DETERMINE BONE MINERAL DENSITY IN ADULTS AND CHILDREN WITH CYSTIC FIBROSIS, Publisher: WILEY, Pages: S87-S87, ISSN: 8755-6863

Conference paper

van Koningsbruggen-Rietschel S, Davies J, Pressler T, Fischer R, MacGregor G, Donaldson SH, Smerud K, Meland N, Mortensen J, Fosbøl MØ, Downey DG, Myrset AH, Flaten H, Rye PDet al., 2020, Inhaled dry powder alginate oligosaccharide (OligoG) in cystic fibrosis: A randomized, double-blind, placebo-controlled cross-over Phase 2b study, European Respiratory Journal, Vol: 6, ISSN: 0903-1936

Background: OligoG is a low molecular-weight alginate oligosaccharide that improves the viscoelastic properties of CF mucus and disrupts biofilms, thereby potentiating the activity of antimicrobial agents. The efficacy of inhaled OligoG was evaluated in adult patients with cystic fibrosis (CF). Methods: A randomized, double-blind, placebo-controlled multi-centre cross-over study was used to demonstrate safety and efficacy of inhaled dry powder OligoG. Subjects were randomly allocated to receive OligoG 1050mg per day (10 capsules TID) or matching placebo for 28-days, with 28-day washout periods following each treatment period. The primary endpoint was absolute change in percent predicted FEV1 at the end of 28-day treatment. The ITT population (N=65) was defined as randomised to treatment with at least one administration of study medication and post-dosing evaluation.Results:Ninety adult subjects were screened and 65 randomized. Statistically significant improvement in FEV1 was not observed in the ITT population. Adverse events (AEs) included nasopharyngitis, cough and pulmonary exacerbation. The number and proportions of patients with AEs and SAEs were similar between OligoG and placebo group.Conclusions: Inhalation of OligoG-DPI over 28-days was safe in adult CF subjects. Statistically significant improvement of FEV1 was not reached. The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo. Post-hoc exploratory analyses showed subgroup results which indicate that further studies of OligoG in this patient population are justified.

Journal article

Edmondson C, Westrupp N, Wallenburg J, Brownlee K, Alton EW, Bush A, Davies JCet al., 2020, WHAT IS FEASIBLE WHEN IT COMES TO MONITORING YOUNG PEOPLE WITH CYSTIC FIBROSIS AT HOME? THE RESULTS OF THE CLIMB-CF STUDY, Publisher: WILEY, Pages: S297-S297, ISSN: 8755-6863

Conference paper

Murphy RA, Thrane S, Schelenz S, Harrison J, Vorup-Jensen T, Davies JCet al., 2020, SYNERGY WITH GLATIRAMER ACETATE REDUCES TOBRAMYCIN MINIMUM INHIBITORY CONCENTRATIONS AGAINST PSEUDOMONAS AERUGINOSA FROM CYSTIC FIBROSIS AIRWAYS, Publisher: WILEY, Pages: S154-S155, ISSN: 8755-6863

Conference paper

Rosenfeld M, Wainwright C, Sawicki GS, Higgins M, Campbell D, Harris C, Panorchan P, Tian S, Davies JCet al., 2020, 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, Publisher: WILEY, Pages: S200-S200, ISSN: 8755-6863

Conference paper

Alton EWFW, Boyd AC, Davies JC, Gill DR, Griesenbach U, Harman TE, Hyde S, McLachlan Get al., 2020, Gene Therapy for Respiratory Diseases: Progress and a Changing Context, HUMAN GENE THERAPY, Vol: 31, Pages: 911-916, ISSN: 1043-0342

Journal article

De Boeck K, Lee T, Amaral M, Drevinek P, Elborn JS, Fajac I, Kerem E, Davies JCet al., 2020, Cystic fibrosis drug trial design in the era of CFTR modulators associated with substantial clinical benefit: stakeholders' consensus view, JOURNAL OF CYSTIC FIBROSIS, Vol: 19, Pages: 688-695, ISSN: 1569-1993

Journal article

Nichols AL, Davies JC, Jones D, Carr SBet al., 2020, Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor, Paediatric Respiratory Reviews, Vol: 35, Pages: 99-102, 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.

Journal article

Mayer-Hamblett N, Van Koningsbruggen-Rietschel S, Nichols DP, VanDevanter DR, Davies JC, Lee T, Durmowicz AG, Ratjen F, Konstan MW, Pearson K, Bell SC, Clancy JP, Taylor-Cousar JL, De Boeck K, Donaldson SH, Downey DG, Flume PA, Drevinek P, Goss CH, Fajac I, Magaret AS, Quon BS, Singleton SM, VanDalfsen JM, Retsch-Bogart GZet al., 2020, Building global development strategies for cf therapeutics during a transitional cftr modulator era, JOURNAL OF CYSTIC FIBROSIS, Vol: 19, Pages: 677-687, ISSN: 1569-1993

Journal article

Kyrilli S, Henry T, Wilschanski M, Fajac I, Davies JC, Jais J-P, Sermet-Gaudelus Iet 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.

Journal article

Saunders C, jensen R, Robinson PD, Stanojevic S, Klingel M, Short C, Davies J, Ratjen Fet 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.

Journal article

Morris-Rosendahl DJ, Edwards M, McDonnell MJ, John S, Alton EWFW, Davies JC, Simmonds NJet 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

Journal article

Isaac SM, Jensen R, Anagnostopoulou P, Davies JC, Gappa M, Latzin P, Saunders C, Short C, Singer F, Stanojevic S, Zwitserloot A, Ratjen Fet al., 2020, Evaluation of a multiple breath nitrogen washout system in children, PEDIATRIC PULMONOLOGY, Vol: 55, Pages: 2108-2114, ISSN: 8755-6863

Journal article

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

Journal article

Bentley S, Davies JC, Carr SB, Balfour-Lynn IMet al., 2020, Combination antifungal therapy for Scedosporium species in cystic fibrosis, PEDIATRIC PULMONOLOGY, Vol: 55, Pages: 1993-1995, ISSN: 8755-6863

Journal article

Bayfield KJ, Alton E, Irving S, Bush A, Davies JCet 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.

Journal article

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