The clinical impact of Lumacaftor-Ivacaftor on structural lung disease and lung function in children aged 6-11 with cystic fibrosis in a real-world setting.
Children
Lung clearance index
PRAGMA CF scores
Real-world studies
Journal
Respiratory research
ISSN: 1465-993X
Titre abrégé: Respir Res
Pays: England
ID NLM: 101090633
Informations de publication
Date de publication:
11 Aug 2023
11 Aug 2023
Historique:
received:
13
02
2023
accepted:
21
07
2023
medline:
14
8
2023
pubmed:
12
8
2023
entrez:
11
8
2023
Statut:
epublish
Résumé
Data from clinical trials of lumacaftor-ivacaftor (LUM-IVA) demonstrate improvements in lung clearance index (LCI) but not in FEV This real-world observational cohort study was conducted across four paediatric sites in Ireland over 24-months using spirometry-controlled CT scores and LCI as primary outcome measures. Children commencing LUM-/IVA as part of routine care were included. CT scans were manually scored with the PRAGMA CF scoring system and analysed using the automated bronchus-artery (BA) method. Secondary outcome measures included rate of change of ppFEV Seventy-one participants were recruited to the study, 31 of whom had spirometry-controlled CT performed at baseline, and after one year and two years of LUM/IVA treatment. At two years there was a reduction from baseline in trapped air scores (0.13 to 0.07, p = 0.016), but an increase from baseline in the % bronchiectasis score (0.84 to 1.23, p = 0.007). There was no change in overall % disease score (2.78 to 2.25, p = 0.138). Airway lumen to pulmonary artery ratios (A In a real-world setting, the use of LUM/IVA over two years in children with CF aged 6-11 resulted in improvements in air trapping on CT but worsening in bronchiectasis scores. Our results suggest that LUM/IVA use in this age group improves air trapping but does not prevent progression of bronchiectasis over two years of treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Data from clinical trials of lumacaftor-ivacaftor (LUM-IVA) demonstrate improvements in lung clearance index (LCI) but not in FEV
METHODS
METHODS
This real-world observational cohort study was conducted across four paediatric sites in Ireland over 24-months using spirometry-controlled CT scores and LCI as primary outcome measures. Children commencing LUM-/IVA as part of routine care were included. CT scans were manually scored with the PRAGMA CF scoring system and analysed using the automated bronchus-artery (BA) method. Secondary outcome measures included rate of change of ppFEV
RESULTS
RESULTS
Seventy-one participants were recruited to the study, 31 of whom had spirometry-controlled CT performed at baseline, and after one year and two years of LUM/IVA treatment. At two years there was a reduction from baseline in trapped air scores (0.13 to 0.07, p = 0.016), but an increase from baseline in the % bronchiectasis score (0.84 to 1.23, p = 0.007). There was no change in overall % disease score (2.78 to 2.25, p = 0.138). Airway lumen to pulmonary artery ratios (A
CONCLUSION
CONCLUSIONS
In a real-world setting, the use of LUM/IVA over two years in children with CF aged 6-11 resulted in improvements in air trapping on CT but worsening in bronchiectasis scores. Our results suggest that LUM/IVA use in this age group improves air trapping but does not prevent progression of bronchiectasis over two years of treatment.
Identifiants
pubmed: 37568199
doi: 10.1186/s12931-023-02497-0
pii: 10.1186/s12931-023-02497-0
pmc: PMC10416528
doi:
Substances chimiques
ivacaftor
1Y740ILL1Z
lumacaftor
EGP8L81APK
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
Aminopyridines
0
Drug Combinations
0
Types de publication
Observational Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
199Subventions
Organisme : Vertex Pharmaceuticals
ID : IIS-2017-106550
Organisme : National Children's Research Centre
ID : Innovation grant
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Elborn JS. Cystic fibrosis. Lancet. 2016;388(10059):2519–31.
doi: 10.1016/S0140-6736(16)00576-6
pubmed: 27140670
Davis SD, et al. Computed tomography reflects lower airway inflammation and tracks changes in early cystic fibrosis. Am J Respir Crit Care Med. 2007;175(9):943–50.
doi: 10.1164/rccm.200603-343OC
pubmed: 17303797
Mott LS, et al. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax. 2012;67(6):509–16.
doi: 10.1136/thoraxjnl-2011-200912
pubmed: 22201161
de Jong PA, et al. Progressive damage on high resolution computed tomography despite stable lung function in cystic fibrosis. Eur Respir J. 2004;23(1):93–7.
doi: 10.1183/09031936.03.00006603
pubmed: 14738238
Wijker NE et al. Early markers of cystic fibrosis structural lung disease: follow-up of the ACFBAL cohort. Eur Respir J, 2020. 55(4).
Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 2015;16(1):45–56.
doi: 10.1038/nrg3849
pubmed: 25404111
Wainwright CE, et al. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220–31.
doi: 10.1056/NEJMoa1409547
pubmed: 25981758
pmcid: 4764353
Burgel PR, et al. Real-life safety and effectiveness of Lumacaftor-Ivacaftor in patients with cystic fibrosis. Am J Respir Crit Care Med. 2020;201(2):188–97.
doi: 10.1164/rccm.201906-1227OC
pubmed: 31601120
van Straten M, et al. Guidance for computed tomography (CT) imaging of the lungs for patients with cystic fibrosis (CF) in research studies. J Cyst Fibros. 2020;19(2):176–83.
doi: 10.1016/j.jcf.2019.09.001
pubmed: 31537430
Loeve M, et al. Cystic fibrosis: are volumetric ultra-low-dose expiratory CT scans sufficient for monitoring related lung disease? Radiology. 2009;253(1):223–9.
doi: 10.1148/radiol.2532090306
pubmed: 19710003
Robinson TE. Computed tomography scanning techniques for the evaluation of cystic fibrosis lung disease. Proc Am Thorac Soc. 2007;4(4):310–5.
doi: 10.1513/pats.200612-184HT
pubmed: 17652492
Kongstad T, et al. Association between spirometry controlled chest CT scores using computer-animated biofeedback and clinical markers of lung disease in children with cystic fibrosis. Eur Clin Respir J. 2017;4(1):1318027.
doi: 10.1080/20018525.2017.1318027
pubmed: 28649308
pmcid: 5475300
Tiddens H, et al. Chest computed tomography outcomes in a randomized clinical trial in cystic fibrosis: Lessons learned from the first ataluren phase 3 study. PLoS ONE. 2020;15(11):e0240898.
doi: 10.1371/journal.pone.0240898
pubmed: 33141825
pmcid: 7608929
Tiddens H, et al. The effect of inhaled hypertonic saline on lung structure in children aged 3–6 years with cystic fibrosis (SHIP-CT): a multicentre, randomised, double-blind, controlled trial. Lancet Respir Med; 2022.
Kuo W, et al. Diagnosis of bronchiectasis and airway wall thickening in children with cystic fibrosis: objective airway-artery quantification. Eur Radiol. 2017;27(11):4680–9.
doi: 10.1007/s00330-017-4819-7
pubmed: 28523349
pmcid: 5635089
Kuo W, et al. Objective airway artery dimensions compared to CT scoring methods assessing structural cystic fibrosis lung disease. J Cyst Fibros. 2017;16(1):116–23.
doi: 10.1016/j.jcf.2016.05.015
pubmed: 27343002
Kuo W, et al. Quantitative assessment of airway dimensions in young children with cystic fibrosis lung disease using chest computed tomography. Pediatr Pulmonol. 2017;52(11):1414–23.
doi: 10.1002/ppul.23787
pubmed: 28881106
Gustafsson PM, et al. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax. 2008;63(2):129–34.
doi: 10.1136/thx.2007.077784
pubmed: 17675316
Subbarao P, et al. Multiple-breath washout as a lung function test in cystic fibrosis. A cystic Fibrosis Foundation Workshop Report. Ann Am Thorac Soc. 2015;12(6):932–9.
doi: 10.1513/AnnalsATS.201501-021FR
pubmed: 26075554
pmcid: 5466249
Ratjen F, et al. 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 Respir Med. 2017;5(7):557–67.
doi: 10.1016/S2213-2600(17)30215-1
pubmed: 28606620
Chilvers MA, et al. 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. Lancet Respir Med. 2021;9(7):721–32.
doi: 10.1016/S2213-2600(20)30517-8
pubmed: 33516285
Sandvik RM, et al. Prospective longitudinal association between repeated multiple breath washout measurements and computed tomography scores in children with cystic fibrosis. J Cyst Fibros. 2021;20(4):632–40.
doi: 10.1016/j.jcf.2020.09.010
pubmed: 33028501
Salamon E, et al. Spirometer guided chest imaging in children: it is worth the effort! Pediatr Pulmonol. 2017;52(1):48–56.
doi: 10.1002/ppul.23490
pubmed: 27273821
Rosenow T, et al. PRAGMA-CF. a quantitative structural lung Disease Computed Tomography Outcome in Young children with cystic fibrosis. Am J Respir Crit Care Med. 2015;191(10):1158–65.
doi: 10.1164/rccm.201501-0061OC
pubmed: 25756857
Robinson PD, et al. Consensus statement for inert gas washout measurement using multiple- and single- breath tests. Eur Respir J. 2013;41(3):507–22.
doi: 10.1183/09031936.00069712
pubmed: 23397305
Saunders C, et al. Integrating the multiple breath washout test into international multicentre trials. J Cyst Fibros. 2020;19(4):602–7.
doi: 10.1016/j.jcf.2019.11.006
pubmed: 31771900
Ramsey BW, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663–72.
doi: 10.1056/NEJMoa1105185
pubmed: 22047557
pmcid: 3230303
Keating D, et al. VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med. 2018;379(17):1612–20.
doi: 10.1056/NEJMoa1807120
pubmed: 30334692
pmcid: 6289290
Ronan NJ, et al. CORK study in cystic fibrosis: sustained improvements in ultra-low-dose chest CT scores after CFTR modulation with Ivacaftor. Chest. 2018;153(2):395–403.
doi: 10.1016/j.chest.2017.10.005
pubmed: 29037527
Sheikh SI, et al. Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation. J Cyst Fibros. 2015;14(1):84–9.
doi: 10.1016/j.jcf.2014.06.011
pubmed: 25049054
Chassagnon G, et al. Long-term computed tomographic changes in cystic fibrosis patients treated with ivacaftor. Eur Respir J. 2016;48(1):249–52.
doi: 10.1183/13993003.01918-2015
pubmed: 27230445
Lauwers E, et al. The short-term effects of ORKAMBI (lumacaftor/ivacaftor) on regional and distal lung structures using functional respiratory imaging. Ther Adv Respir Dis. 2021;15:17534666211046774.
doi: 10.1177/17534666211046774
pubmed: 34541955
pmcid: 8461124
Campredon A et al. Using chest CT scan and unsupervised machine learning for predicting and evaluating response to lumacaftor-ivacaftor in people with cystic fibrosis. Eur Respir J, 2021.
Arnaud F et al. Computed tomographic changes in patients with cystic fibrosis treated by combination therapy with Lumacaftor and Ivacaftor. J Clin Med, 2021. 10(9).
Bouma NR, et al. Airway disease on chest computed tomography of preschool children with cystic fibrosis is associated with school-age bronchiectasis. Pediatr Pulmonol. 2020;55(1):141–8.
doi: 10.1002/ppul.24498
pubmed: 31496137
Svedberg M, et al. Risk factors for progression of structural lung disease in school-age children with cystic fibrosis. J Cyst Fibros. 2020;19(6):910–6.
doi: 10.1016/j.jcf.2019.10.014
pubmed: 31672554
Chen Y, et al. WS18.06 fully automated analysis of airway-artery dimensions on chest-computed tomography in preschool children with cystic fibrosis to evaluate the effect of inhaled hypertonic saline. J Cyst Fibros. 2022;21:S36–7.
doi: 10.1016/S1569-1993(22)00260-0
Muilwijk D et al. Prediction of real-world long-term outcomes of people with CF homozygous for the F508del mutation treated with CFTR modulators. J Pers Med, 2021. 11(12).
Donaldson SH et al. Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR. JCI Insight, 2018. 3(24).
Sagel SD, et al. Clinical effectiveness of Lumacaftor/Ivacaftor in patients with cystic fibrosis homozygous for F508del-CFTR. A clinical trial. Ann Am Thorac Soc. 2021;18(1):75–83.
doi: 10.1513/AnnalsATS.202002-144OC
pubmed: 32644818
pmcid: 7780982
Shaw M, et al. Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: results from the prospect study. J Cyst Fibros. 2020;19(6):931–3.
doi: 10.1016/j.jcf.2020.05.010
pubmed: 32513528
pmcid: 9125683
Bui S, et al. Long-term outcomes in Real Life of Lumacaftor-Ivacaftor treatment in adolescents with cystic fibrosis. Front Pediatr. 2021;9:744705.
doi: 10.3389/fped.2021.744705
pubmed: 34869102
pmcid: 8634876
Ejiofor LCK, et al. Patients with cystic fibrosis and advanced lung disease benefit from lumacaftor/ivacaftor treatment. Pediatr Pulmonol. 2020;55(12):3364–70.
doi: 10.1002/ppul.25059
pubmed: 32897653
Reix P et al. Real-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis. J Cyst Fibros, 2021.
Milla CE, et al. Lumacaftor/Ivacaftor in patients aged 6–11 years with cystic fibrosis and homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912–20.
doi: 10.1164/rccm.201608-1754OC
pubmed: 27805836
pmcid: 5440888
McColley SA, et al. Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV1. J Cyst Fibros. 2019;18(1):94–101.
doi: 10.1016/j.jcf.2018.07.011
pubmed: 30146268
Konstan MW, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2):107–18.
doi: 10.1016/S2213-2600(16)30427-1
pubmed: 28011037
King SJ et al. Lumacaftor/ivacaftor-associated health stabilisation in adults with severe cystic fibrosis. ERJ Open Res, 2021. 7(1).