Does Monotherapy With Correctors Have Clinical Benefit in Cystic Fibrosis?

Insufficient evidence exists to demonstrate that monotherapy with correctors has clinically important effects in individuals with cystic fibrosis (CF) who have 2 copies of the F508del mutation, according to an analysis published in the Cochrane Database of Systematic Reviews.

Researchers conducted a search of the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, as well as a literature search of reference lists of relevant articles and online trial registries. The most recent search was conducted on February 24, 2018. They sought to assess the effects of CF transmembrane conductance regulator (CFTR) correctors on clinically important outcomes, both benefits and harms, in children and adults with CF and class II CFTR mutations (most commonly F508del).

Parallel-design randomized controlled trials (RCTs) that compared CFTR correctors with placebo in individuals with CF and class II mutations were selected for analysis. RCTs that compared CFTR correctors combined with CFTR potentiators were also compared with placebo. In these trials, 2 researchers independently extracted data and evaluated the risk for bias and the quality of the evidence using the GRADE criteria.

A total of 13 RCTs (2215 participants total), each lasting between 1 day and 24 weeks, were included in the analysis. At 96 weeks, additional safety data from an extension study of 2 lumacaftor-ivacaftor trials with a total of 1029 participants were available. The investigators evaluated monotherapy (4PBA, CPX, lumacaftor, or cavosonstat) in 7 of the RCTs (317 participants) and combination therapy (lumacaftor-ivacaftor or tezacaftor-ivacaftor) in 6 of the RCTs (1898 participants).

The risk for bias varied across the trials. Some of the findings were based on single RCTs and were thus too small to demonstrate significant effects. In 5 of the RCTs, the results were not generalizable to all individuals with CF because of the age limits of the recruited populations (eg, children only or adults only) or a nonstandard design of switching from monotherapy to combination therapy.

In the monotherapy vs placebo studies, no deaths were reported, and no clinically relevant improvements in quality of life (QoL) were demonstrated in any RCT. Moreover, no placebo-controlled studies of monotherapy revealed a difference in mild, moderate, or severe adverse effects. In the combination therapy vs placebo studies, no deaths were reported in any RCT. In addition, QoL scores (respiratory domain) showed advantages of combination therapy compared with placebo at all time points.

The investigators concluded that the quality of the evidence of the outcomes measured in this analysis varied from low to high, thus rendering interpretation of the study results difficult in many instances. Because the design of the studies was generally poorly reported, it was difficult to render clear judgments with respect to potential bias; however, there were fewer concerns in this regard in the 6 larger, more recent trials.

Reference

Southern KW, Patel S, Sinha IP, Nevitt SJ. Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis. Cochrane Database Syst Rev. 2018;8:CD010966.