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

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  • Eric W F W Alton
  • David K Armstrong
  • Deborah Ashby
  • Katie J Bayfield
  • Diana Bilton
  • Emily V Bloomfield
  • June Brand
  • Ruaridh Buchan
  • Roberto Calcedo
  • Paula Carvelli
  • Mario Chan
  • Seng H Cheng
  • Gwyneth Davies
  • Jane C Davies
  • Lee A Davies
  • Maria H Dewar
  • 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
  • J Alastair Innes
  • Joseph Jacob
  • Nancy Jones
  • Brian F Keogh
  • Maria P Limberis
  • Paul Lloyd-evans
  • Michelle C Manvell
  • Cuixiang Meng
  • M Angeles Montero
  • Hazel Milligan
  • Laura J Moyce
  • Andrew G Nicholson
  • Tina Osadolor
  • Javier Parra-leiton
  • 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
  • Stephen N Smith
  • Najwa Soussi
  • Samia Soussi
  • Emma J Spearing
  • Stephanie G Sumner-jones
  • Minna Turkkila
  • Rosa P Ureta
  • Michael D Waller
  • Marguerite Y Wasowicz
  • James M Wilson
  • Paul Wolstenholme-hogg

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Original languageEnglish
Pages (from-to)684-691
JournalThe Lancet Respiratory Medicine
Issue number9
Publication statusPublished - 1 Jul 2015


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 ClinicalTrials.gov, 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.

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