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;
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.
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.
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)
We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftorâivacaftor studies provided additional 96âweek safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dualâtherapy RCTs (1840 participants) (lumacaftorâivacaftor or tezacaftorâivacaftor) and five tripleâtherapy RCTs (775 participants) (elexacaftorâtezacaftorâivacaftor or VXâ659âtezacaftorâivacaftor); below we report only the data from elexacaftorâtezacaftorâivacaftor 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 nonâstandard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinicallyârelevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placeboâcontrolled 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 (moderateâ to highâquality evidence). QoL scores (respiratory domain) favoured both lumacaftorâivacaftor and tezacaftorâivacaftor 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; highâquality evidence). A similar effect was observed for twiceâdaily lumacaftor (200 mg) plus ivacaftor (250 mg), but with lowâquality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twiceâdaily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderateâquality 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 onceâdaily lumacaftorâivacaftor (95% CI 3.61% to 6.80%; 504 participants; highâquality evidence); 2.40% with twiceâdaily lumacaftorâivacaftor (95% CI 0.40% to 4.40%; 204 participants; lowâquality evidence); and 6.80% with tezacaftorâivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderateâquality evidence). More pwCF reported early transient breathlessness with lumacaftorâivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; highâquality evidence). Over 120 weeks (initial study period and followâup) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twiceâdaily 400 mg lumacaftorâivacaftor (80 participants; highâquality evidence). The tezacaftorâivacaftor 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) (moderateâquality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftorâivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (highâquality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftorâtezacaftorâivacaftor 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, elexacaftorâtezacaftorâivacaftor 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 tezacaftorâivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftorâtezacaftorâivacaftor and placebo or control (moderateâquality evidence). In 403 F508del/F508del participants, there was a longer time to protocolâdefined pulmonary exacerbation with elexacaftorâtezacaftorâivacaftor over 24 weeks (moderateâquality evidence).
There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftorâivacaftor, tezacaftorâivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftorâivacaftor was associated with an increase in early transient shortness of breath and longerâterm increases in blood pressure (not observed for tezacaftorâivacaftor). Tezacaftorâivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftorâivacaftor 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 longerâterm adult data when considering lumacaftorâivacaftor. There is highâquality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftorâtezacaftorâivacaftor) 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.