Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Alton EWFW

PROVIDER: S-EPMC4673100 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Alton Eric W F W EWFW Armstrong David K DK Ashby Deborah D Bayfield Katie J KJ Bilton Diana D Bloomfield Emily V EV Boyd A Christopher AC Brand June J Buchan Ruaridh R Calcedo Roberto R Carvelli Paula P Chan Mario M Cheng Seng H SH Collie D David S DDS Cunningham Steve S Davidson Heather E HE Davies Gwyneth G Davies Jane C JC Davies Lee A LA Dewar Maria H MH Doherty Ann A Donovan Jackie J Dwyer Natalie S NS Elgmati Hala I HI Featherstone Rosanna F RF Gavino Jemyr J Gea-Sorli Sabrina S Geddes Duncan M DM Gibson James S R JSR Gill Deborah R DR Greening Andrew P AP Griesenbach Uta U Hansell David M DM Harman Katharine K Higgins Tracy E TE Hodges Samantha L SL Hyde Stephen C SC Hyndman Laura L Innes J Alastair JA Jacob Joseph J Jones Nancy N Keogh Brian F BF Limberis Maria P MP Lloyd-Evans Paul P Maclean Alan W AW Manvell Michelle C MC McCormick Dominique D McGovern Michael M McLachlan Gerry G Meng Cuixiang C Montero M Angeles MA Milligan Hazel H Moyce Laura J LJ Murray Gordon D GD Nicholson Andrew G AG Osadolor Tina T Parra-Leiton Javier J Porteous David J DJ Pringle Ian A IA Punch Emma K EK Pytel Kamila M KM Quittner Alexandra L AL Rivellini Gina G Saunders Clare J CJ Scheule Ronald K RK Sheard Sarah S Simmonds Nicholas J NJ Smith Keith K Smith Stephen N SN Soussi Najwa N Soussi Samia S Spearing Emma J EJ Stevenson Barbara J BJ Sumner-Jones Stephanie G SG Turkkila Minna M Ureta Rosa P RP Waller Michael D MD Wasowicz Marguerite Y MY Wilson James M JM Wolstenholme-Hogg Paul P

The Lancet. Respiratory medicine 20150703 9

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 26149841

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Dataset Information

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

Background

Methods

Findings

Interpretation

Funding

Publications

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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