Background

Cystic fibrosis is a common life‐shortening genetic disorder in the Caucasian population (less common in other ethnic groups) caused by the mutation of a single gene that codes for the production of the cystic fibrosis transmembrane conductance regulator protein. This protein coordinates the transport of salt (and bicarbonate) across cell surfaces and the mutation most notably affects the airways. In the lungs of people with cystic fibrosis, defective protein results in a dehydrated surface liquid and compromised mucociliary clearance. The resulting thick mucus makes the airway prone to chronic infection and inflammation, which consequently damages the structure of the airways, eventually leading to respiratory failure. Additionally, abnormalities in the cystic fibrosis transmembrane conductance regulator protein lead to other systemic complications including malnutrition, diabetes and subfertility.

Five classes of mutation have been described, depending on the impact of the mutation on the processing of the cystic fibrosis transmembrane conductance regulator protein in the cell. In class I mutations, the presence of premature termination codons prevents the production of any functional protein resulting in a severe cystic fibrosis phenotype. Advances in the understanding of the molecular genetics of cystic fibrosis has led to the development of novel mutation‐specific therapies. Therapies targeting class I mutations (premature termination codons) aim to mask the abnormal gene sequence and enable the normal cellular mechanism to read through the mutation, potentially restoring the production of the cystic fibrosis transmembrane conductance regulator protein. This could in turn make salt transport in the cells function more normally and may decrease the chronic infection and inflammation that characterises lung disease in people with cystic fibrosis.

Objectives

To evaluate the benefits and harms of ataluren and similar compounds on clinically important outcomes in people with cystic fibrosis with class I mutations (premature termination codons).

Search methods

We searched the Cochrane Cystic Fibrosis Trials Register which is compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles. Last search of Group's register: 24 October 2016.

We searched clinical trial registries maintained by the European Medicines Agency, the US National Institutes of Health and the WHO. Last search of clinical trials registries: 28 November 2016.

Selection criteria

Randomised controlled trials of parallel design comparing ataluren and similar compounds (specific therapies for class I mutations) with placebo in people with cystic fibrosis who have at least one class I mutation. Cross‐over trials were reviewed individually to evaluate whether data from the first treatment arm could be included. We excluded trials that combined therapies for premature termination codon class I mutations with other mutation‐specific therapies.

Data collection and analysis

The authors independently assessed the risk of bias and extracted data from the included trial; they contacted trial authors for additional data.

Main results

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.

Authors' conclusions

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.