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Rationale: Clinical trials have shown that use of elexacaftor/tezacaftor/ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition, and quality of life in people with cystic fibrosis (CF). Little is known about the impact of ETI on ventilation inhomogeneity and lung structure. Objectives: RECOVER is a real-world study designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (lung clearance index; LCI2.5) and FEV1. Secondary endpoints included spirometry-controlled chest computed tomography (CT) scores. Methods: The study was conducted in seven sites in Ireland and the United Kingdom. Participants ages 12 years and older who were homozygous for the F508del mutation (F508del/F508del) or heterozygous for F508del and a minimum-function mutation (F508del/MF) were recruited before starting ETI and were followed up over 12 months. LCI2.5 was measured using nitrogen multiple breath washout (MBW) at baseline and at 6 and 12 months. Spirometry was performed as per the criteria of the American Thoracic Society and the European Respiratory Society. Spirometry-controlled chest CT scans were performed at baseline and at 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R), and sweat chloride. Measurements and Main Results: One hundred seventeen people with CF ages 12 and older were recruited to the study. Significant improvements were seen in LCI scores (-2.5; 95% confidence interval [CI], -3.0, -2.0) and in the percents predicted for FEV1 (8.9; 95% CI, 7.0, 10.9), FVC (6.6; 95% CI, 4.9, 8.3), and forced expiratory flow between 25% and 75% of expired volume (12.4; 95% CI, 7.8, 17.0). Overall PRAGMA-CF scores reflecting airway disease improved significantly (-3.46; 95% CI, -5.23, -1.69). Scores for trapped air, mucus plugging, and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (-43.1; 95% CI, -47.4, -38.9) and F508del/MF (-42.8; 95% CI, -48.5, -37.2) groups. Scores on the Respiratory Domain of the CFQ-R improved by 14.2 points (95% CI, 11.3, 17.2). At 1 year, sweat chloride levels were significantly lower for the F508del/F508del group compared with scores for the F508del/MF group (33.93 vs. 53.36, P < 0.001). Conclusions: ETI is associated with substantial improvements in LCI2.5, spirometry, and PRAGMA-CF CT scores in people with CF ages 12 years and older. ETI led to improved nutrition and quality of life. People in the F508del/F508del group had significantly lower sweat chloride on ETI treatment compared with the F508del/MF group. Clinical trial registered with www.clinicaltrials.gov (NCT04602468).
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Fibrosis Quística , Humanos , Aminofenoles/uso terapéutico , Benzodioxoles/uso terapéutico , Agonistas de los Canales de Cloruro/uso terapéutico , Cloruros/análisis , Fibrosis Quística/diagnóstico por imagen , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/uso terapéutico , Pulmón , Mutación , Calidad de Vida , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Data from clinical trials of lumacaftor-ivacaftor (LUM-IVA) demonstrate improvements in lung clearance index (LCI) but not in FEV1 in children with Cystic Fibrosis (CF) aged 6-11 years and homozygous for the Phe508del mutation. It is not known whether LUM/IVA use in children can impact the progression of structural lung disease. We sought to determine the real-world impact of LUM/IVA on lung structure and function in children aged 6-11 years. 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 ppFEV1, nutritional indices and exacerbations requiring hospitalisation. 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 (AlumenA ratio) were abnormal at baseline and worsened over the course of the study. In 28 participants, the mean annual change from baseline LCI2.5 (-0.055 (-0.61 to 0.50), p = 0.85) measurements over two years were not significant. Improvements from baseline in weight (0.10 (0.06 to 0.15, p < 0.0001), height (0.05 (0.02 to 0.09), p = 0.002) and BMI (0.09 (0.03 to 0.15) p = 0.005) z-scores were seen with LUM/IVA treatment. The mean annual change from baseline ppFEV1 (-2.45 (-4.44 to 2.54), p = 0.66) measurements over two years were not significant. CONCLUSION: 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.
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Bronquiectasia , Fibrosis Quística , Humanos , Niño , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Aminopiridinas/uso terapéutico , Pulmón/diagnóstico por imagen , Combinación de Medicamentos , MutaciónRESUMEN
BACKGROUND: This research estimates the broader socioeconomic impacts of reducing pre-hospital delay times across Australia in patients with heart attack symptoms. METHODS: A cost benefit analysis (CBA) was undertaken to demonstrate the costs and benefits of a public awareness/education campaign to reduce pre-hospital delay time from 5.2hours (Base Case) to 4.1hours (Scenario 1) and 2.0hours (Scenario 2). All assumptions underlying the CBA are supported by academic literature. Financial impacts considered include campaign/public education costs, direct inpatient costs and long-term health care costs. Socioeconomic impacts considered include burden of disease, productivity losses, informal care costs and net deadweight loss. RESULTS: The campaign is expected to generate an additional net benefit of $41.2-139.1 million in comparison to the Base Case, resulting in a benefit cost ratio (BCR) of 3.23-5.06. Disability Adjusted Life Years (DALYs) reduced by 6,046-7,575 years. CONCLUSION: This research illustrates that an investment in public awareness/education campaign can generate considerable benefits, more than offsetting the costs associated with the campaign and keeping people living longer such as ongoing health care costs. However, significant effort, supplementary strategies and sustained investment will be required to ensure the impact and benefit is sustained over the long term.
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Costo de Enfermedad , Análisis Costo-Beneficio , Costos de la Atención en Salud , Hospitalización/economía , Infarto del Miocardio/economía , Australia , Femenino , Humanos , Masculino , Infarto del Miocardio/terapiaRESUMEN
RATIONALE: Lung clearance index (LCI) is a more sensitive measure of lung function than spirometry in cystic fibrosis (CF) and correlates well with abnormalities in high-resolution computed tomography (HRCT) scanning. We hypothesized LCI would be equally sensitive to lung disease in primary ciliary dyskinesia (PCD). OBJECTIVES: To test the relationships between LCI, spirometry, and HRCT in PCD and to compare them to the established relationships in CF. METHODS: Cross-sectional study of 127 patients with CF and 33 patients with PCD, all of whom had spirometry and LCI, of which a subset of 21 of each had HRCT performed. HRCT was scored for individual features and these features compared with physiological parameters. MEASUREMENTS AND MAIN RESULTS: Unlike in CF, and contrary to our hypothesis, there was no correlation between spirometry and LCI in PCD and no correlation between HRCT features and LCI or spirometry in PCD. CONCLUSIONS: We show for the first time that HRCT, spirometry, and LCI have different relationships in different airway diseases and that LCI does not appear to be a sensitive test of airway disease in advanced PCD. We hypothesize that this results from dissimilarities between the components of large and small airway disease in CF and PCD. These differences may in part lead to the different prognosis in these two neutrophilic airway diseases.
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Síndrome de Kartagener/fisiopatología , Pulmón/fisiopatología , Pruebas de Función Respiratoria/métodos , Estudios Transversales , Fibrosis Quística/diagnóstico por imagen , Fibrosis Quística/fisiopatología , Volumen Espiratorio Forzado , Humanos , Síndrome de Kartagener/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Sensibilidad y Especificidad , Espirometría , Tomografía Computarizada por Rayos XRESUMEN
Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients. There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.
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BACKGROUND: Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures. AIM: To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy. METHODS: A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers. RESULTS: Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31). DISCUSSION: We identify the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with our study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.
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Antibacterianos/administración & dosificación , Fibrosis Quística/tratamiento farmacológico , Volumen Espiratorio Forzado/fisiología , Enfermedades Pulmonares/tratamiento farmacológico , Pulmón/fisiopatología , Tomografía Computarizada por Rayos X , Adolescente , Adulto , Antibacterianos/uso terapéutico , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Niño , Fibrosis Quística/diagnóstico , Fibrosis Quística/fisiopatología , Femenino , Humanos , Inyecciones Intravenosas , Interleucina-6/sangre , Complejo de Antígeno L1 de Leucocito/sangre , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/fisiopatología , Masculino , Recurrencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Recently, a cross-talk error with commercial multiple breath nitrogen washout (MBWN2 ) software was discovered, which produced an absolute over-reading of N2 of approximately 1%, i.e., 2% N2 read as 3%. This caused an extended tail to the washout, and over-estimated lung clearance index (LCI2.5 ) values. Subsequently an updated and corrected software version has been released. Within the field there have been discussions on how to correct legacy data, whether to migrate or completely "rerun" raw data A-files from the old software into the new corrected software. To our knowledge, no research has been published assessing whether either method is equivalent to directly collecting data in the new corrected software. We prospectively recruited 19 participants, 10 adult healthy controls and 9 people with cystic fibrosis (CF). MBWN2 was performed using the Exhalyzer® D first on the old 3.1.6 software and next, directly on corrected 3.3.1 software. Multiple breath washout (MBW) data directly collected in 3.3.1 was significantly different from both migrated and rerun data. A total of 7 of the 19 participants (37%; 4 CF) had a relative difference in LCI2.5 > 10% for both migrated and rerun data compared to 3.3.1 collected data. Our findings have implications for the Global Lung Initiative MBW project, which is accepting a combination of directly collected, A-file reruns and migrated data to establish normative values. Further, caution must be used in clinical practice when comparing corrected legacy data versus 3.3.1 collected data for clinical interpretation. We recommend that a new baseline is collected directly on 3.3.1. before clinical interpretation and decisions are determined when comparing consecutive MBW tests.
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Fibrosis Quística , Nitrógeno , Adulto , Humanos , Pruebas Respiratorias/métodos , Pruebas de Función Respiratoria/métodos , PulmónRESUMEN
This study explored the use of computed cardiopulmonography (CCP) to assess lung function in early-stage cystic fibrosis (CF). CCP has two components. The first is a particularly accurate technique for measuring gas exchange. The second is a computational cardiopulmonary model where patient-specific parameters can be estimated from the measurements of gas exchange. Twenty-five participants (14 healthy controls, 11 early-stage CF) were studied with CCP. They were also studied with a standard clinical protocol to measure the lung clearance index (LCI2.5). Ventilation inhomogeneity, as quantified through CCP parameter σlnCl, was significantly greater (P < 0.005) in CF than in controls, and anatomical deadspace relative to predicted functional residual capacity (DS/FRCpred) was significantly more variable (P < 0.002). Participant-specific parameters were used with the CCP model to calculate idealized values for LCI2.5 (iLCI2.5) where extrapulmonary influences on the LCI2.5, such as breathing pattern, had all been standardized. Both LCI2.5 and iLCI2.5 distinguished clearly between CF and control participants. LCI2.5 values were mostly higher than iLCI2.5 values in a manner dependent on the participant's respiratory rate (r = 0.46, P < 0.05). The within-participant reproducibility for iLCI2.5 appeared better than for LCI2.5, but this did not reach statistical significance (F ratio = 2.2, P = 0.056). Both a sensitivity analysis on iLCI2.5 and a regression analysis on LCI2.5 revealed that these depended primarily on an interactive term between CCP parameters of the form σlnCL*(DS/FRC). In conclusion, the LCI2.5 (or iLCI2.5) probably reflects an amalgam of different underlying lung changes in early-stage CF that would require a multiparameter approach, such as potentially CCP, to resolve.NEW & NOTEWORTHY Computed cardiopulmonography is a new technique comprising a highly accurate sensor for measuring respiratory gas exchange coupled with a cardiopulmonary model that is used to identify a set of patient-specific characteristics of the lung. Here, we show that this technique can improve on a standard clinical approach for lung function testing in cystic fibrosis. Most particularly, an approach incorporating multiple model parameters can potentially separate different aspects of pathological change in this disease.
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Fibrosis Quística , Humanos , Reproducibilidad de los Resultados , Pruebas de Función Respiratoria/métodos , Pulmón , RespiraciónRESUMEN
This is an exciting time for research and novel drug development in cystic fibrosis. However, rarely has the adage, "Children are not just little adults" been more relevant. This article is divided into two main sections. In the first, we explore why it is important to involve children in research. We discuss the potential benefits of understanding a disease and its treatment in children, and we highlight that children have the same legal and ethical right to evidence-based therapy as adults. Additionally, we discuss why extrapolation from adults may be inappropriate, for example, medication pharmacokinetics may be different in children, and there may be unpredictable adverse effects. In the second part, we discuss how to involve children and their families in research. We outline the importance and the complexities of selecting appropriate outcome measures, and we discuss the role co-design may have in improving the involvement of children. We highlight the importance of appropriate staffing and resourcing, and we outline some of the common challenges and possible solutions, including practical tips on obtaining consent/assent in children and adolescents. We conclude that it is unethical to simply rely on extrapolation from adult studies because research in young children is challenging and that research should be seen as a normal part of the paediatric therapeutic journey.
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BACKGROUND: Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI2.5). METHODS: We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCIShX). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores. RESULTS: HC/ CF group differences were larger with LCIShX than LCI2.5 (P<0.001). Within the CF group UVLU was highly variable and when abnormal it did not correlate with corresponding LCI2.5. Signal showed little variability during clinical stability (n = 11 CF; 2 visits; median inter-test variability 2.6% LCIShX, 2.5% LCI2.5). PEx signal was significantly greater for LCIShX both for onset and resolution. Both MBW parameters correlated significantly with total lung CT scores and hyperinflation but only LCIShX correlated with mucus plugging. CONCLUSIONS: UVLU captured within the LCIShX varies between individuals; the lack of relationship with LCI2.5 demonstrates that new, additional information is being captured. LCIShX repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status.
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Pruebas Respiratorias/métodos , Fibrosis Quística/fisiopatología , Pruebas de Función Respiratoria/métodos , Adolescente , Adulto , Niño , Preescolar , Fibrosis Quística/diagnóstico por imagen , Femenino , Humanos , Masculino , Proyectos Piloto , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study. METHODS: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index2.5 (LCI2.5), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI). RESULTS: One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQR respiratory domain score, and BMI observed from parent study baseline to Week 96. CONCLUSIONS: Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.
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Agonistas de los Canales de Cloruro , Fibrosis Quística , Aminofenoles , Benzodioxoles , Niño , Agonistas de los Canales de Cloruro/uso terapéutico , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Progresión de la Enfermedad , Homocigoto , Humanos , Indoles , Mutación , QuinolonasRESUMEN
Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer-term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual-agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA-based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizations, registries, and people with CF is something we are all rightly proud of, but innovative trial design and implementation will be needed if we are to continue to build on this progress and further develop drugs for people with CF.
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Aminofenoles/uso terapéutico , Agonistas de los Canales de Cloruro/uso terapéutico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/efectos de los fármacos , Fibrosis Quística/tratamiento farmacológico , Quinolonas/uso terapéutico , Aminofenoles/administración & dosificación , Aminofenoles/farmacología , Aminopiridinas/administración & dosificación , Benzodioxoles/administración & dosificación , Niño , Agonistas de los Canales de Cloruro/administración & dosificación , Agonistas de los Canales de Cloruro/farmacología , Ensayos Clínicos como Asunto , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/fisiología , Quimioterapia Combinada , Humanos , Indoles/administración & dosificación , Mutación , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Pirrolidinas/administración & dosificación , Quinolonas/administración & dosificación , Quinolonas/farmacologíaRESUMEN
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.
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Aminofenoles/administración & dosificación , Benzodioxoles/administración & dosificación , Agonistas de los Canales de Cloruro/administración & dosificación , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Indoles/administración & dosificación , Mutación , Quinolonas/administración & dosificación , Aminofenoles/efectos adversos , Benzodioxoles/efectos adversos , Niño , Agonistas de los Canales de Cloruro/efectos adversos , Fibrosis Quística/fisiopatología , Combinación de Medicamentos , Femenino , Heterocigoto , Homocigoto , Humanos , Indoles/efectos adversos , Masculino , Quinolonas/efectos adversos , Resultado del TratamientoRESUMEN
Rationale: Ivacaftor's clinical effects in the residual function mutations 3849 + 10kb CâT and D1152H warrant further characterization.Objectives: To evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with 3849 + 10kb CâT or D1152H residual function mutations and to 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 versus 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 of 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 CâT or D1152H mutation, ivacaftor treatment improved clinical endpoints compared with 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 (NCT03068312).
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Fibrosis Quística , Aminofenoles/uso terapéutico , Teorema de Bayes , Estudios Cruzados , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Volumen Espiratorio Forzado , Humanos , Mutación , QuinolonasRESUMEN
BACKGROUND: Riociguat is a first-in-class soluble guanylate cyclase stimulator for which preclinical data suggested improvements in cystic fibrosis transmembrane conductance regulator (CFTR) function. METHODS: This international, multicenter, two-part, Phase II study of riociguat enrolled adults with cystic fibrosis (CF) homozygous for Phe508del CFTR. Part 1 was a 28-day, randomized, double-blind, placebo-controlled study in participants not receiving CFTR modulator therapy. Twenty-one participants were randomized 1:2 to placebo or oral riociguat (0.5 mg three times daily [tid] for 14 days, increased to 1.0 mg tid for the subsequent 14 days). The primary and secondary efficacy endpoints were change in sweat chloride concentration and percent predicted forced expiratory volume in 1 second (ppFEV1), respectively, from baseline to Day 14 and Day 28 with riociguat compared with placebo. RESULTS: Riociguat did not alter CFTR activity (change in sweat chloride) or lung function (change in ppFEV1) at doses up to 1.0 mg tid after 28 days. The most common drug-related adverse event (AE) was headache occurring in three participants (21%); serious AEs occurred in one participant receiving riociguat (7%) and one participant receiving placebo (14%). This safety profile was consistent with the underlying disease and the known safety of riociguat for its approved indications. CONCLUSIONS: The Rio-CF study was terminated due to lack of efficacy and the changing landscape of CF therapeutic development. The current studyâ , within its limits of a small sample size, did not provide evidence that riociguat could be a valid treatment option for CF. CLINICAL TRIAL REGISTRATION NUMBER: NCT02170025.
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Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Activadores de Enzimas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Método Doble Ciego , Femenino , Homocigoto , Humanos , MasculinoAsunto(s)
Asma/fisiopatología , Pruebas Respiratorias/métodos , Fibrosis Quística/fisiopatología , Síndrome de Kartagener/fisiopatología , Ventilación Pulmonar/fisiología , Administración Intravenosa , Adolescente , Antibacterianos/uso terapéutico , Asma/tratamiento farmacológico , Niño , Fibrosis Quística/tratamiento farmacológico , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inyecciones Intramusculares , Masculino , Estudios Retrospectivos , Triamcinolona/uso terapéuticoRESUMEN
BACKGROUND: The 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. METHODS: Here 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. RESULTS: Three 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%). CONCLUSION: With 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.
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Pruebas Respiratorias/métodos , Fibrosis Quística , Depuración Mucociliar/efectos de los fármacos , Evaluación de Resultado en la Atención de Salud/métodos , Pruebas de Función Respiratoria , Desarrollo de Personal , Certificación , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/fisiopatología , Recolección de Datos/normas , Estudios de Factibilidad , Femenino , Humanos , Cooperación Internacional , Masculino , Control de Calidad , Estándares de Referencia , Pruebas de Función Respiratoria/métodos , Pruebas de Función Respiratoria/normas , Desarrollo de Personal/métodos , Desarrollo de Personal/normasRESUMEN
INTRODUCTION: The multiple breath nitrogen washout (MBW) test offers a sensitive measure of airway function. In this study we aim to (a) assess the validity of the EasyOne Pro LAB (MBWndd ) in an in vitro lung model, (b) assess the feasibility, repeatability, and reproducibility of MBWndd and (c) compare outcomes with the Exhalyzer D (MBWEM ) and body plethysmography. METHODS: In vitro, functional residual capacity (FRC) measurements were assessed using a lung model under quasi-physiological conditions and compared to measured FRC. In vivo plethysmography and MBW were performed in a prospective study of children at two visits (n = 45 healthy; n = 41 cystic fibrosis [CF]). Bland-Altman plots were used to compare agreement between FRC and lung clearance index (LCI) measurements. RESULTS: In vitro FRCndd measurements were repeatable but lung volumes were underestimated (mean relative difference -5.4% (limits of agreement [LA] -9.6%; -1.1%), 95% confidence interval (CI) -6.27; -4.45). In vivo, compared to plethysmography, FRCndd was consistently lower (-19.3% [-40.5; 1.9], 95% CI [-23.9; -14.7]), and showed a volume dependency. LCIndd values were also higher in children with smaller lung volumes. The within-test coefficient of variation of the FRCndd and LCIndd were 4.9% in health, and 5.6% and 6.9% in CF respectively. LCIndd was reproducible between-visits (mean relative difference [LA] -3.7% [-14.8, -7.5; 95% CI -6.6; -0.73] in health [n = 17] and 0.34% [-13.2, 22.8; 95% CI -5.0; 5.69] in CF [n = 23]). When calculated using the same algorithm, LCIndd was similar to LCIEM in health. CONCLUSIONS: MBWndd measurements are feasible, repeatable, and reproducible, however, MBW-derived outcomes are not interchangeable with MBWEM .
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Pruebas Respiratorias , Fibrosis Quística/fisiopatología , Nitrógeno/análisis , Adolescente , Niño , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Pletismografía Total , Reproducibilidad de los Resultados , Pruebas de Función RespiratoriaRESUMEN
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 lung clearance index (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. Of 22 sites, 18 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p<0.001). By the end of the study recruitment, 15 of 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 of 589 (79%) tests met the quality criteria following central over-reading, compared with 137 of 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 naïve sites and patients with worse lung function may have contributed to the lower success rate in the i-BEST-1 study.
RESUMEN
RATIONALE: After recent standardization of forced expiratory maneuvers for both infants and preschool children, longitudinal measurements are now possible from birth. OBJECTIVES: The aim of this study was to investigate the evolution of lung function during the first 6 years of life after a clinical diagnosis of cystic fibrosis (CF) in infancy in children with CF and in healthy control subjects. METHODS: The raised volume technique was used during infancy and incentive spirometry during the preschool years. MEASUREMENTS AND MAIN RESULTS: Forty-eight children with CF and 33 healthy control subjects had up to seven (median, 3) measurements. Over these early years, the diagnosis of CF itself accounted for a significant mean reduction of 7.5% (95% confidence interval, 0.9 - 13.6%) in FEV(0.75) and 15.1% (95% confidence interval, 3.6 - 25.3%) in FEF(25-75). Wheeze on auscultation, recent cough, and Pseudomonas aeruginosa (PsA) infection (even if apparently effectively treated) were all independently associated with further reductions in lung function. Premorbid lung function did not predict infection with PsA. CONCLUSIONS: This is the first study to describe physiologic measurements from infancy through the preschool years in subjects with CF and healthy control subjects, the understanding of which is critical for future intervention trials. Airflow obstruction in uncomplicated CF persists through the preschool years despite treatment, with PsA acquisition being associated with further deterioration in lung function, even when apparently eradicated. This suggests that new therapies are needed to treat the airflow obstruction of uncomplicated CF, and rigorous strategies to prevent PsA acquisition.