Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial

Eric W F W Alton, David K Armstrong, Deborah Ashby, Katie J Bayfield, Diana Bilton, Emily V Bloomfield, A Christopher Boyd, June Brand, Ruaridh Buchan, Roberto Calcedo, Paula Carvelli, Mario Chan, Seng H Cheng, D David S Collie, Steve Cunningham, Heather E Davidson, Gwyneth Davies, Jane C Davies, Lee A Davies, Maria H DewarAnn Doherty, Jackie Donovan, Natalie S Dwyer, Hala I Elgmati, Rosanna F Featherstone, Jemyr Gavino, Sabrina Gea-sorli, Duncan M Geddes, James S R Gibson, Deborah R Gill, Andrew P Greening, Uta Griesenbach, David M Hansell, Katharine Harman, Tracy E Higgins, Samantha L Hodges, Stephen C Hyde, Laura Hyndman, J Alastair Innes, Joseph Jacob, Nancy Jones, Brian F Keogh, Maria P Limberis, Paul Lloyd-evans, Alan W Maclean, Michelle C Manvell, Dominique McCormick, Michael McGovern, Gerry McLachlan, Cuixiang Meng, M Angeles Montero, Hazel Milligan, Laura J Moyce, Gordon D Murray, Andrew G Nicholson, Tina Osadolor, Javier Parra-leiton, David J Porteous, Ian A Pringle, Emma K Punch, Kamila M Pytel, Alexandra L Quittner, Gina Rivellini, Clare J Saunders, Ronald K Scheule, Sarah Sheard, Nicholas J Simmonds, Keith Smith, Stephen N Smith, Najwa Soussi, Samia Soussi, Emma J Spearing, Barbara J Stevenson, Stephanie G Sumner-jones, Minna Turkkila, Rosa P Ureta, Michael D Waller, Marguerite Y Wasowicz, James M Wilson, Paul Wolstenholme-hogg

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

BACKGROUND: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis.

METHODS: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with, number NCT01621867.

FINDINGS: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1-7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups.

INTERPRETATION: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials.

FUNDING: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

Original languageEnglish
Pages (from-to)684-691
JournalThe Lancet Respiratory Medicine
Issue number9
Early online date3 Jul 2015
Publication statusPublished - Sept 2015


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