CFDB - Cystic Fibrosis DataBase

Cochrane Database of Systematic Reviews - Cochrane Review

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del)

Study design (if review, criteria of inclusion for studies)

RCTs of parallel design. Excl: quasi-randomised studies; cross-over studies.

List of included studies (19)

Boyle 2014; Clancy 2012; Donaldson 2014; Donaldson 2017; Donaldson 2018; McCarty 2002; PROGRESS 2017; Ratjen 2017; Rubenstein 1998; Taylor-Cousar 2017; TRAFFIC 2015; TRANSPORT 2015; Zeitlin 2002;

Participants

Children or adults with CF, as confirmed either by the presence of two disease-causing mutations, or by a combination of positive sweat test and recognised clinical features of CF. Participants should have at least one class II mutation.

Interventions

CFTR correctors (drugs which aims to increase the amount of CFTR expressed at the epithelial cell apical membrane, by reducing or preventing degradation of CFTR by normal intracellular mechanisms) compared with either placebo or another intervention.

Outcome measures

Primary outcomes 1. Survival 2. Quality of life (QoL) measured using validated quantitative scales or scores 3. Physiological measures of lung function: FEV1, FVC. Secondary outcomes 1. Adverse effects 2. Hospitalisation 3. School or work attendance 4. Extra courses of antibiotics 5. Sweat chloride 6. Radiological measures 7. Acquisition of respiratory pathogens 8. Eradication of respiratory pathogens 9. Nutrition and growth (weight, BMI, height)

Main results

We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor‐ivacaftor studies provided additional 96‐week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual‐therapy RCTs (1840 participants) (lumacaftor‐ivacaftor or tezacaftor‐ivacaftor) and five triple‐therapy RCTs (775 participants) (elexacaftor‐tezacaftor‐ivacaftor or VX‐659‐tezacaftor‐ivacaftor); below we report only the data from elexacaftor‐tezacaftor‐ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non‐standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically‐relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo‐controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate‐ to high‐quality evidence). QoL scores (respiratory domain) favoured both lumacaftor‐ivacaftor and tezacaftor‐ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high‐quality evidence). A similar effect was observed for twice‐daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low‐quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice‐daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate‐quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV1) % predicted improved with combination therapies compared to placebo by: 5.21% with once‐daily lumacaftor‐ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high‐quality evidence); 2.40% with twice‐daily lumacaftor‐ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low‐quality evidence); and 6.80% with tezacaftor‐ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate‐quality evidence). More pwCF reported early transient breathlessness with lumacaftor‐ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high‐quality evidence). Over 120 weeks (initial study period and follow‐up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice‐daily 400 mg lumacaftor‐ivacaftor (80 participants; high‐quality evidence). The tezacaftor‐ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate‐quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor‐ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high‐quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor‐tezacaftor‐ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV1 (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor‐tezacaftor‐ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV1 (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor‐ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor‐tezacaftor‐ivacaftor and placebo or control (moderate‐quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol‐defined pulmonary exacerbation with elexacaftor‐tezacaftor‐ivacaftor over 24 weeks (moderate‐quality evidence).

Authors' conclusions

There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor‐ivacaftor, tezacaftor‐ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor‐ivacaftor was associated with an increase in early transient shortness of breath and longer‐term increases in blood pressure (not observed for tezacaftor‐ivacaftor). Tezacaftor‐ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor‐ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer‐term adult data when considering lumacaftor‐ivacaftor. There is high‐quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor‐tezacaftor‐ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.

Related topics

Keywords: Child; Adult; Adolescent; Aminophenols; CFTR Modulators; Genetic Predisposition to Disease; pharmacological_intervention; VX-770; ivacaftor;