Duncan M. Geddes

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.

BACKGROUND: Although many patients with severe emphysema have undergone lung-volume-reduction surgery, the benefits are uncertain. We conducted a randomized, controlled trial of the surgery in patients with emphysema. Patients with isolated bullae were excluded because such patients are known to improve after bullectomy. METHODS: Potentially eligible patients were given intensive medical treatment and completed a smoking-cessation program and a six-week outpatient rehabilitation program before random assignment to surgery or continued medical treatment. After 15 patients had been randomized, the entry criteria were modified to exclude patients with a carbon monoxide gas-transfer value less than 30 percent of the predicted value or a shuttle-walking distance of less than 150 m, because of the deaths of 5 such patients (3 treated surgically and 2 treated medically). RESULTS: Of the 174 subjects who were initially assessed, 24 were randomly assigned to continued medical treatment and 24 to surgery. At base line in both groups, the median forced expiratory volume in one second (FEV1) was 0.75 liter, and the median shuttle-walking distance was 215 m. Five patients in the surgical group (21 percent) and three patients in the medical group (12 percent) died (P=0.43). After six months, the median FEV1 had increased by 70 ml in the surgical group and decreased by 80 ml in the medical group (P=0.02). The median shuttle-walking distance increased by 50 m in the surgical group and decreased by 20 m in the medical group (P=0.02). There were similar changes on a quality-of-life scale and similar changes at 12 months of follow-up. Five of the 19 surviving patients in the surgical group had no benefit from the treatment. CONCLUSIONS: In selected patients with severe emphysema, lung-volume-reduction surgery can improve FEV1, walking distance, and quality of life. Whether it reduces mortality is uncertain.

Six patients with rapidly progressive airway obliteration in the absence of chronic bronchitis or emphysema are reported. Because this pattern of lung disease is very uncommon and five of the six patients had classical rheumatoid arthritis an association between the two diseases is suggested. The patients presented with rapidly developing breathlessness, and râles and a high-pitched mid-inspiratory squeak were heard over the lung fields. Chest radiographs showed distended lungs but were otherwise normal. Tests of lung fuction showed airflow obstruction, most marked at low lung volumes, with air trapping. The carbon monoxide gas transfer coefficient, maximum static recoil pressure and static compliance were normal. In spite of treatment with antibiotics, bronchodilators and corticosteroids, five died in respiratory failure five to 18 months after first becoming breathless. Post-mortem examination in four patients showed an obliterative bronchiolitis but no mucous gland hypertrophy or significant emphysema.