Abstract: Four randomised controlled studies met the inclusion criteria for this review, involving a total of 302 participants lasting from 29 days to 13 months; 14 studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta-analysis. One study only enrolled adult males, the remaining studies included both males and females aged 12 years and over. Risk of bias in the studies was moderate. Random sequence generation and allocation concealment was only described in the more recent study; the remaining three studies were judged to have an unclear risk of bias. All four studies documented double-blinding to the intervention, but there is some uncertainty with regards to participant blinding in one study. Some outcome data were missing from all four studies. There were no differences in either the number of respiratory exacerbations or the number of participants with an exacerbation between replacement therapy or placebo groups at any time point. Meta-analysis of most respiratory function tests showed no difference between treatment and placebo groups, but the smallest study (n = 16) reported forced vital capacity (litres) increased more in the placebo group at up to 24 hours. A further study reported a significant improvement in forced expiratory volume at one second (litres) at 30 days after participants had received their first dose of favouring the gene therapy agent, but this finding was not confirmed when combined with at second study in the meta-analysis. The more recent study (n = 140) demonstrated a small improvement in forced vital capacity (per cent predicted) at two and three months and again at 11 and 12 months for participants receiving CFTR gene replacement therapy compared to those receiving placebo. The same study reported a significant difference in the relative change in forced expiratory volume at one second (per cent predicted) at two months, three months and 12 months. One small study reported significant concerns with "influenza-like" symptoms in participants treated with CFTR gene replacement therapy; this was not reported on repeated use of the same agent in a larger recent study. There was no other evidence of positive impact on outcomes, in particular improved quality of life or reduced treatment burden. Two studies measured ion transport in the lower airways; one (n = 16) demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% confidence interval 3.77 to 9.95). The second study (n = 140) also reported significant changes toward normal values (P = 0.032); however, aggregate data were not available for analysis. In the most recent study, there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance. One study of liposome-based CFTR gene transfer therapy demonstrated some improvements in respiratory function in people with CF, but this limited evidence of efficacy does not support this treatment as a routine therapy at present. There was no evidence of efficacy for viral-mediated gene delivery. Future studies need to investigate clinically important outcome measures.

Plain-language summary: We found four studies with 302 people to include in this review. The studies lasted from 29 days to 13 months. Three of these studies included both men and women aged 12 years and over and one study only included adult men. The studies compare gene therapy to a dummy treatment (placebo) both of which are inhaled as a mist into the lungs. The studies were of different designs and used different agents. This meant we could not combine their results. Three of the studies, including the largest and most recent study, showed an improvement in some measures of lung function in people with CF given gene therapy. We did not find that any more clinically relevant outcomes such as quality of life, treatment burden or flare-up of lung disease had improved with treatment. In one study "influenza-like" symptoms were more common in people who received CFTR gene transfer agents but this was not reported when the agent was used repeatedly in a larger study. In those people who took the gene transfer agents, molecules and salt in their lower airways moved more like they do in healthy people. The limited evidence of benefit does not support this as a routine therapy at present. We recommend that future studies are designed and reported clearly so that their results can be incorporated into a systematic review. The most recent study provided detailed information on how the people were put into different treatment groups completely at random, and so we are satisfied that those taking part in the study had an equal chance of being in either group (CFTR gene transfer agent or placebo) and that no one could work out which group the next person would be put into. The other studies reported that people were put into groups at random but did not specify how, so we cannot be sure that there was an equal chance of them being in either group. We believe that the clinicians running all the studies did not know which treatment the people taking part were receiving and that in three of the studies those taking part did not know either, but we could not be sure whether the people taking part in the latest study knew which treatment they were receiving and what effect this knowledge might have on results. Unfortunately, the studies did not report all their results clearly; sometimes results were not reported in a way that we could use for the review and sometimes they were not reported at all. This reduced the certainty with which we judged the overall results.