Abstract: Our searches identified 28 references to eight trials; five trials were excluded (three were cross-over and one was not randomised and one did not have relevant outcomes), one cross-over trial is awaiting classification pending provision of data and one trial is ongoing. The included parallel randomised controlled trial compared ataluren to placebo for a duration of 48 weeks in 238 participants (age range 6 to 53 years) with cystic fibrosis who had at least one nonsense mutation (a type of class I mutation). The quality of evidence and risk of bias assessments for the trial were moderate overall. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented; participant blinding was less clear. Some participant data were excluded from the analysis. The trial was assessed as high risk of bias for selective outcome reporting, especially when reporting on the trial's post hoc subgroup of participants by chronic inhaled antibiotic use. The trial was sponsored by PTC Therapeutics Incorporated with grant support by the Cystic Fibrosis Foundation, the Food and Drug Administration's Office of Orphan Products Development and the National Institutes of Health (NIH). The trial reported no significant difference between treatment groups in quality of life, assessed by the Cystic Fibrosis Questionnaire-Revised respiratory domain score and no improvement in respiratory function measures (mean difference of relative change in forced expiratory volume at one second 2.97% (95% confidence interval -0.58 to 6.52)). Ataluren was associated with a significantly higher rate of episodes of renal impairment, risk ratio 17.70 (99% confidence interval 1.28 to 244.40). The trial reported no significant treatment effect for ataluren for the review's secondary outcomes: pulmonary exacerbation; computerised tomography score; weight; body mass index; and sweat chloride. No deaths were reported in the trial. A post hoc subgroup analysis of participants not receiving chronic inhaled tobramycin (n = 146) demonstrated favourable results for ataluren (n = 72) for relative change in % predicted forced expiratory volume at one second and pulmonary exacerbation rate. Participants receiving chronic inhaled tobramycin appeared to have a reduced rate of pulmonary exacerbation compared to those not receiving chronic inhaled tobramycin. This drug interaction was not anticipated and may affect the interpretation of the trial results. There is currently insufficient evidence to determine the effect of ataluren as a therapy for people with cystic fibrosis with class I mutations. Future trials should carefully assess for adverse events, notably renal impairment and consider the possibility of drug interactions. Cross-over trials should be avoided given the potential for the treatment to change the natural history of cystic fibrosis.

Plain-language summary: We found one trial (238 people took part) comparing ataluren to placebo (a dummy treatment with no active medication). The trial lasted 48 weeks and included both males and females aged six years and older. Everyone taking part had at least one copy of a nonsense mutation (a type of class I mutation that causes cystic fibrosis). In those people who took ataluren, there was no improvement in clinical outcomes such as quality of life, lung function, exacerbations (flare up of disease), sweat chloride (salt) levels or weight. The trial found that kidney damage was more common in people who took ataluren. The trial investigators then analysed the results in a way that they hadn't planned originally and looked at how ataluren or placebo affected people depending on whether they were using inhaled tobramycin on a long-term basis or not. They found that amongst those not taking inhaled tobramycin, lung function declined at a slower rate and there were fewer exacerbations in the ataluren group compared to the placebo group. We have not found enough high-quality evidence currently to determine the effect of ataluren for treating people with cystic fibrosis. We recommend that future trials are designed and reported clearly so that their results can be included in a systematic review. We judged the quality of the evidence was moderate with uncertainty due to how widely the results varied between participants. We are satisfied that everyone taking part had an equal chance of being in either group (ataluren or placebo) and that no one could work out which group the next person would be put into, so that healthier people did not receive the treatment and make the results seem better. We believe that the clinicians running the trial and those taking part in the trial did not know which treatment each person was receiving. We have some concerns on the emphasis the investigators have placed on the results of a comparison they had not planned (use of long-term inhaled tobramycin). Unfortunately, the trial did not report all their results clearly; sometimes they did not report them in a way that we could use in the review and sometimes they did not report the data at all. This affected the certainty with which we judged the overall results. The trial was sponsored by PTC Therapeutics Incorporated. The Cystic Fibrosis Foundation, the Food and Drug Administration's Office of Orphan Products Development and the National Institutes of Health (NIH) also supported the trial.