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

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.

Recent findings in the use of reflectance oximetry: a critical review.

PURPOSE OF REVIEW: Pulse oximetry is ubiquitous but detailed understanding of the technology is poor. This is illustrated by publications addressing knowledge of pulse oximetry and those warning against the use of transmission pulse oximeter sensors in a reflectance manner, unintended by the manufacturers, owing to the potential for iatrogenic problems. Reflectance oximetry sensors are distinct and their application rather specific. Users must adhere to the manufacturer's guidelines to be assured of approximating the claimed accuracy and other specifications. Moreover, a thorough understanding of the device's shortcomings will optimize performance and avoid misuse. Cautious skepticism is appropriate with use of any technology but particularly with indirect measures of vital signs. RECENT FINDINGS: The studies of reflectance sensors described here illustrate a diversity of successful applications and opportunities for further research. The genesis of applications for some sensors, for example fetal sensors, has proven helpful in other clinical settings where low mean arterial pressure and need for accurate monitoring of a SpO2 of less than 80% is poorly provided by transmittance sensors. Reflectance sensors are more prone to placement over contaminating sources (for example arteries and pigmentation), but their more sophisticated design can provide greater versatility than transillumination methods. SUMMARY: This invited review highlights recent developments and applications of reflectance oximetry with an emphasis on the potential clinical and research advantages.