Lung Clearance Index and High-Resolution Computed Tomography Scores in Primary Ciliary Dyskinesia

Irving, Samantha; Ives, Andrew; Davies, Gwyneth; Donovan, Jackie; Edey, Anthony; Gill, Simon; Nair, Arjun; Saunders, Clare; Wijesekera, Nevin T.; Alton, Eric W.F.W.; Hansell, David M.; Hogg, Claire; Davies, Jane; Bush, Andrew

doi:10.1164/rccm.201304-0800oc

Cited by 79 publications

(86 citation statements)

References 31 publications

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“…The presence and severity of specific CT scan features were recorded for each lobe as previously described. 81 The features studied were extent of bronchiectasis, severity of bronchiectasis, bronchial wall thickness, small and large airway mucus plugs (all scored per lobe on a range of 0-4 and the results meaned) and gas trapping (scored on a percentage basis) (features illustrated on examples in Figure 9). In addition, as a safety outcome, all subjects underwent a limited-cut inspiratory CT scan pre-dosing at the dose 4 visit; these scans were not formally scored, but were reviewed in real time by the clinical radiology team for any acute changes and the reports were provided to the DMEC.…”

Section: Lung Computed Tomography Scanningmentioning

confidence: 99%

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Alton¹,

Armstrong²,

Ashby³

et al. 2016

Efficacy Mech Eval

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BackgroundCystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene leading to abnormal airway surface ion transport, chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco®, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediatedCFTRgene therapy formulation through preclinical and clinical development.ObjectiveTo determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF.DesignThis was a randomised, double-blind, placebo-controlled Phase IIb trial of theCFTRgene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers.SettingsData were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database.ParticipantsPatients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination ofCFTRmutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised).InterventionsSubjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year.Main outcome measuresThe primary end point was the relative change in percentage predicted FEV1over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference.ResultsThere was a significant (p = 0.046) treatment effect (TE) of 3.7% [95% confidence interval (CI) 0.1% to 7.3%] in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (p = 0.031) and CT gas trapping (p = 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age orCFTRmutation class. Subjects with a more severe baseline FEV1had a FEV1TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (p = 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups.ConclusionsMonthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo.LimitationsAlthough encouraging, the improvement in FEV1was modest and was not accompanied by detectable improvement in patients’ quality of life.Future workFuture work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration.Trial registrationClinicalTrials.gov NCT01621867.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.

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Section: Lung Computed Tomography Scanningmentioning

confidence: 99%

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Alton¹,

Armstrong²,

Ashby³

et al. 2016

Efficacy Mech Eval

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“…However, only five out of 21 children with asthma had an abnormal LCIstd and, in this small group, a very small number of incorrectly characterised results [2] disproportionately skewed the data. However, it cannot be said from these data that a normal LCI0.5 excludes an abnormal LCIstd.…”

Section: To the Editormentioning

confidence: 76%

“…Lung clearance index (LCI) derived from multiple breath washout (MBW) is a sensitive, noninvasive measure of ventilation heterogeneity and is used for the assessment of cystic fibrosis (CF) [1], asthma [1] and primary ciliary dyskinesia (PCD) [2]. LCI is the number of lung turnovers (functional residual capacity (FRC)) required to washout an inhaled inert gas to 1/40 of its initial concentration: a historically set end-point of no physiological significance [3].…”

Section: To the Editormentioning

confidence: 99%

Multiple breath washouts in children can be shortened without compromising quality

et al. 2015

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“…Lung clearance index (LCI) derived from multiple breath washout is a radiation-free candidate for disease monitoring and seems to be particularly sensitive for detecting early lung disease compared to FEV1 [59]. However, correlations between LCI and HRCT have also shown opposing results, and longitudinal data are lacking [58,60].…”

Section: Lower Airway Managementmentioning

confidence: 99%

Clinical care for primary ciliary dyskinesia: current challenges and future directions

Rubbo

Lucas

2017

Eur Respir Rev

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Primary ciliary dyskinesia (PCD) is a rare genetic disease that affects the motility of cilia, leading to impaired mucociliary clearance. It is estimated that the vast majority of patients with PCD have not been diagnosed as such, providing a major obstacle to delivering appropriate care. Challenges in diagnosing PCD include lack of disease-specific symptoms and absence of a single, "gold standard", diagnostic test. Management of patients is currently not based on high-level evidence because research findings are mostly derived from small observational studies with limited follow-up period. In this review, we provide a critical overview of the available literature on clinical care for PCD patients, including recent advances. We identify barriers to PCD research and make suggestions for overcoming challenges.

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Lung Clearance Index and High-Resolution Computed Tomography Scores in Primary Ciliary Dyskinesia

Cited by 79 publications

References 31 publications

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Multiple breath washouts in children can be shortened without compromising quality

Clinical care for primary ciliary dyskinesia: current challenges and future directions

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