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

UK Cystic Fibrosis Gene Therapy Consortium

Research output: Contribution to journalArticle

182 Citations (Scopus)

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 (1. 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.

Original languageEnglish (US)
Article number180
Pages (from-to)684-691
Number of pages8
JournalThe Lancet Respiratory Medicine
Volume3
Issue number9
DOIs
StatePublished - Sep 1 2015

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Cystic Fibrosis
Genetic Therapy
Placebos
Forced Expiratory Volume
Random Allocation
Liposomes
Lung
Genes
National Institutes of Health (U.S.)
Program Evaluation
Therapeutics
Biomedical Research
Plasmids
Mutation
DNA
Research
Population

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis : A randomised, double-blind, placebo-controlled, phase 2b trial. / UK Cystic Fibrosis Gene Therapy Consortium.

In: The Lancet Respiratory Medicine, Vol. 3, No. 9, 180, 01.09.2015, p. 684-691.

Research output: Contribution to journalArticle

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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 (1. 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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T1 - Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis

T2 - A randomised, double-blind, placebo-controlled, phase 2b trial

AU - UK Cystic Fibrosis Gene Therapy Consortium

AU - Alton, Eric W F W

AU - Armstrong, David K.

AU - Ashby, Deborah

AU - Bayfield, Katie J.

AU - Bilton, Diana

AU - Bloomfield, Emily V.

AU - Boyd, A. Christopher

AU - Brand, June

AU - Buchan, Ruaridh

AU - Calcedo, Roberto

AU - Carvelli, Paula

AU - Chan, Mario

AU - Cheng, Seng H.

AU - Collie, D. David S

AU - Cunningham, Steve

AU - Davidson, Heather E.

AU - Davies, Gwyneth

AU - Davies, Jane C.

AU - Davies, Lee A.

AU - Dewar, Maria H.

AU - Doherty, Ann

AU - Donovan, Jackie

AU - Dwyer, Natalie S.

AU - Elgmati, Hala I.

AU - Featherstone, Rosanna F.

AU - Gavino, Jemyr

AU - Gea-Sorli, Sabrina

AU - Geddes, Duncan M.

AU - Gibson, James S R

AU - Gill, Deborah R.

AU - Greening, Andrew P.

AU - Griesenbach, Uta

AU - Hansell, David M.

AU - Harman, Katharine

AU - Higgins, Tracy E.

AU - Hodges, Samantha L.

AU - Hyde, Stephen C.

AU - Hyndman, Laura

AU - Innes, J. Alastair

AU - Jacob, Joseph

AU - Jones, Nancy

AU - Keogh, Brian F.

AU - Limberis, Maria P.

AU - Lloyd-Evans, Paul

AU - Maclean, Alan W.

AU - Manvell, Michelle C.

AU - McCormick, Dominique

AU - McGovern, Michael

AU - McLachlan, Gerry

AU - Quittner, Alexandra

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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 (1. 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.

AB - 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 (1. 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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