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
Cystic 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 po...
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| Format: | Journal article |
| Jezik: | English |
| Izdano: |
NIHR Journals Library
2016
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| _version_ | 1826262063204270080 |
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| author | Alton, EWFW Armstrong, DK Ashby, D Bayfield, KJ Bilton, D Bloomfield, EV Boyd, AC Brand, J Buchan, R Calcedo, R Carvelli, P Chan, M Cheng, SH Collie, DS Cunningham, S Davidson, HE Davies, G Davies, JC Davies, LA Dewar, MH Doherty, A Donovan, J Dwyer, NS Elgmati, HI Featherstone, RF Gavino, J Gea-Sorli, S Geddes, DM Gibson, JSR Gill, DR Greening, AP Griesenbach, U Hansell, DM Harman, K Higgins, TE Hodges, SL Hyde, SC Hyndman, L Innes, JA Jacob, J Jones, N Keogh, BF Limberis, MP Lloyd-Evans, P Maclean, AW Manvell, MC McCormick, D McGovern, M McLachlan, G Meng, C Montero, MA Milligan, H Moyce, LJ Murray, GD Nicholson, AG Osadolor, T Parra-Leiton, J Porteous, DJ Pringle, IA Punch, EK Pytel, KM Quittner, AL Rivellini, G Saunders, CJ Scheule, RK Sheard, S Simmonds, NJ Smith, K Smith, SN Soussi, N Soussi, S Spearing, EJ Stevenson, BJ Sumner-Jones, SG Turkkila, M Ureta, RP Waller, MD Wasowicz, MY Wilson, JM Wolstenholme-Hogg, P UK Cystic Fibrosis Gene Therapy Consortium |
| author_facet | Alton, EWFW Armstrong, DK Ashby, D Bayfield, KJ Bilton, D Bloomfield, EV Boyd, AC Brand, J Buchan, R Calcedo, R Carvelli, P Chan, M Cheng, SH Collie, DS Cunningham, S Davidson, HE Davies, G Davies, JC Davies, LA Dewar, MH Doherty, A Donovan, J Dwyer, NS Elgmati, HI Featherstone, RF Gavino, J Gea-Sorli, S Geddes, DM Gibson, JSR Gill, DR Greening, AP Griesenbach, U Hansell, DM Harman, K Higgins, TE Hodges, SL Hyde, SC Hyndman, L Innes, JA Jacob, J Jones, N Keogh, BF Limberis, MP Lloyd-Evans, P Maclean, AW Manvell, MC McCormick, D McGovern, M McLachlan, G Meng, C Montero, MA Milligan, H Moyce, LJ Murray, GD Nicholson, AG Osadolor, T Parra-Leiton, J Porteous, DJ Pringle, IA Punch, EK Pytel, KM Quittner, AL Rivellini, G Saunders, CJ Scheule, RK Sheard, S Simmonds, NJ Smith, K Smith, SN Soussi, N Soussi, S Spearing, EJ Stevenson, BJ Sumner-Jones, SG Turkkila, M Ureta, RP Waller, MD Wasowicz, MY Wilson, JM Wolstenholme-Hogg, P UK Cystic Fibrosis Gene Therapy Consortium |
| author_sort | Alton, EWFW |
| collection | OXFORD |
| description | Cystic 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-mediated CFTR gene therapy formulation through preclinical and clinical development.To determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF.This was a randomised, double-blind, placebo-controlled Phase IIb trial of the CFTR gene–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.Data were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database.Patients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination of CFTR mutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised).Subjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year.The primary end point was the relative change in percentage predicted FEV1 over 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.There 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 or CFTR mutation class. Subjects with a more severe baseline FEV1 had a FEV1 TE 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.Monthly 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.Although encouraging, the improvement in FEV1 was modest and was not accompanied by detectable improvement in patients’ quality of life.Future 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.ClinicalTrials.gov NCT01621867.This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership. |
| first_indexed | 2024-03-06T19:30:26Z |
| format | Journal article |
| id | oxford-uuid:1d452da7-a1b1-4d93-ae93-e22c76576751 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:30:26Z |
| publishDate | 2016 |
| publisher | NIHR Journals Library |
| record_format | dspace |
| spelling | oxford-uuid:1d452da7-a1b1-4d93-ae93-e22c765767512022-03-26T11:10:03ZA randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1d452da7-a1b1-4d93-ae93-e22c76576751EnglishSymplectic Elements at OxfordNIHR Journals Library2016Alton, EWFWArmstrong, DKAshby, DBayfield, KJBilton, DBloomfield, EVBoyd, ACBrand, JBuchan, RCalcedo, RCarvelli, PChan, MCheng, SHCollie, DSCunningham, SDavidson, HEDavies, GDavies, JCDavies, LADewar, MHDoherty, ADonovan, JDwyer, NSElgmati, HIFeatherstone, RFGavino, JGea-Sorli, SGeddes, DMGibson, JSRGill, DRGreening, APGriesenbach, UHansell, DMHarman, KHiggins, TEHodges, SLHyde, SCHyndman, LInnes, JAJacob, JJones, NKeogh, BFLimberis, MPLloyd-Evans, PMaclean, AWManvell, MCMcCormick, DMcGovern, MMcLachlan, GMeng, CMontero, MAMilligan, HMoyce, LJMurray, GDNicholson, AGOsadolor, TParra-Leiton, JPorteous, DJPringle, IAPunch, EKPytel, KMQuittner, ALRivellini, GSaunders, CJScheule, RKSheard, SSimmonds, NJSmith, KSmith, SNSoussi, NSoussi, SSpearing, EJStevenson, BJSumner-Jones, SGTurkkila, MUreta, RPWaller, MDWasowicz, MYWilson, JMWolstenholme-Hogg, PUK Cystic Fibrosis Gene Therapy ConsortiumCystic 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-mediated CFTR gene therapy formulation through preclinical and clinical development.To determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF.This was a randomised, double-blind, placebo-controlled Phase IIb trial of the CFTR gene–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.Data were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database.Patients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination of CFTR mutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised).Subjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year.The primary end point was the relative change in percentage predicted FEV1 over 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.There 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 or CFTR mutation class. Subjects with a more severe baseline FEV1 had a FEV1 TE 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.Monthly 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.Although encouraging, the improvement in FEV1 was modest and was not accompanied by detectable improvement in patients’ quality of life.Future 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.ClinicalTrials.gov NCT01621867.This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership. |
| spellingShingle | Alton, EWFW Armstrong, DK Ashby, D Bayfield, KJ Bilton, D Bloomfield, EV Boyd, AC Brand, J Buchan, R Calcedo, R Carvelli, P Chan, M Cheng, SH Collie, DS Cunningham, S Davidson, HE Davies, G Davies, JC Davies, LA Dewar, MH Doherty, A Donovan, J Dwyer, NS Elgmati, HI Featherstone, RF Gavino, J Gea-Sorli, S Geddes, DM Gibson, JSR Gill, DR Greening, AP Griesenbach, U Hansell, DM Harman, K Higgins, TE Hodges, SL Hyde, SC Hyndman, L Innes, JA Jacob, J Jones, N Keogh, BF Limberis, MP Lloyd-Evans, P Maclean, AW Manvell, MC McCormick, D McGovern, M McLachlan, G Meng, C Montero, MA Milligan, H Moyce, LJ Murray, GD Nicholson, AG Osadolor, T Parra-Leiton, J Porteous, DJ Pringle, IA Punch, EK Pytel, KM Quittner, AL Rivellini, G Saunders, CJ Scheule, RK Sheard, S Simmonds, NJ Smith, K Smith, SN Soussi, N Soussi, S Spearing, EJ Stevenson, BJ Sumner-Jones, SG Turkkila, M Ureta, RP Waller, MD Wasowicz, MY Wilson, JM Wolstenholme-Hogg, P UK Cystic Fibrosis Gene Therapy Consortium 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
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arandomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT altonewfw randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT armstrongdk randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT ashbyd randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT bayfieldkj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT biltond randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT bloomfieldev randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT boydac randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT brandj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT buchanr randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT calcedor randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT carvellip randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT chanm randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT chengsh randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT collieds randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT cunninghams randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT davidsonhe randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT daviesg randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT daviesjc randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT daviesla randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT dewarmh randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT dohertya randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT donovanj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT dwyerns randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT elgmatihi randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT featherstonerf randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT gavinoj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT geasorlis randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT geddesdm randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT gibsonjsr randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT gilldr randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT greeningap randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT griesenbachu randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT hanselldm randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT harmank randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT higginste randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT hodgessl randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT hydesc randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT hyndmanl randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT innesja randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT jacobj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT jonesn randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT keoghbf randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT limberismp randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT lloydevansp randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT macleanaw randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT manvellmc randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT mccormickd randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT mcgovernm randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT mclachlang randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT mengc randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT monteroma randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT milliganh randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT moycelj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT murraygd randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT nicholsonag randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT osadolort randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT parraleitonj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT porteousdj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT pringleia randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT punchek randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT pytelkm randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT quittneral randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT rivellinig randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT saunderscj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT scheulerk randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT sheards randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT simmondsnj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT smithk randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT smithsn randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT soussin randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT soussis randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT spearingej randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT stevensonbj randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT sumnerjonessg randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT turkkilam randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT uretarp randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT wallermd randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT wasowiczmy randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT wilsonjm randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT wolstenholmehoggp randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis AT ukcysticfibrosisgenetherapyconsortium randomiseddoubleblindplacebocontrolledtrialofrepeatednebulisationofnonviralcysticfibrosistransmembraneconductanceregulatorcftrgenetherapyinpatientswithcysticfibrosis |