Repeated application of gene therapy in cystic fibrosis patients

INTERVENTION: Administration of 5 ml pGM169/GL67A or placebo (0.9% saline) via nebuliser to the lungs every 4 weeks for 12 doses Administration of 2 ml pGM169/GL67A or placebo (0.9% saline) via nasal spray to the nose every 4 weeks for 12 doses (subgroup only) CONDITION: Cystic fibrosis ; Nutritional, Metabolic, Endocrine ; Cystic fibrosis PRIMARY OUTCOME: Relative change in percent predicted FEV1 after 12 doses SECONDARY OUTCOME: 1. Efficacy: ; 1.1. Relative change in other spirometric measures ; 1.2. Lung clearance index ; 1.3. Change in body weight; 1.4. Chest CT scan ; 1.5. Quality of Life Questionnaires ; 1.6. Exercise capacity ; 1.7. Activity monitoring ; 1.8. Serum calprotectin ; 1.9. Sputum culture ; 1.10. Sputum weight, cell counts and inflammatory markers; 1.11. Frequency of additional antibiotics for increased respiratory symptoms; 2. Clinical examination ; 3. Transcutaneous oxygen saturation ; 4. Serum inflammatory markers (CRP, white blood cell count, IL‐6); 5. Renal and hepatic function ; 6. Gas transfer ; 7. Bronchial bood flow; 8. Immune response markers (anti‐nuclear and double‐stranded DNA antibodies, CFTR‐specific T cell responses) ; 9. Endobronchial histology (subgroup only) ; 10. Gene expression outcomes (subgroups only): ; 10.1. Transgene mRNA expression in nasal and lower airway brushing samples ; 10.2. Potential difference measurements in nose and bronchi INCLUSION CRITERIA: 1. Cystic fibrosis confirmed by sweat testing or genetic analysis 2. Males and females aged 12 years and above 3. Forced expiratory volume in the 1st second (FEV1) between 50 & 90% predicted inclusive (Stanojevic reference equations) 4. Clinical stability at screening defined by: 4.1. Not on any additional antibiotics (excluding routine, long‐term treatments) for the previous 2 weeks 4.2. No increase in symptoms such as change in sputum production/colour, increased wheeze or breathlessness over the previous 2 weeks 4.3. No change in regular respiratory treatments over the previous 4 weeks 4.4. If any of these apply, entry into the study can be deferred 5. Prepared to take effective contraceptive precautions for the duration of their participation in the study and for 3 months thereafter (as stated in Gene Therapy Advisory Committee [GTAC] guidelines) 6. If taking regular rhDNase (pulmozyme), is willing and considered able by independen