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

Kevin W Southern, Jared Murphy, Ian P Sinha, Sarah J Nevitt, Kevin W Southern, Jared Murphy, Ian P Sinha, Sarah J Nevitt

Abstract

Background: Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators.

Objectives: To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del).

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020.

Selection criteria: Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations.

Data collection and analysis: Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data.

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.

Trial registration: ClinicalTrials.gov NCT01225211 NCT00865904 NCT03029455 NCT03224351 NCT01746784 NCT03093714 NCT03227471 NCT00004428 NCT01931839 NCT02514473 NCT00590538 NCT01807923 NCT01807949 NCT00016744 NCT01897233 NCT00742092 NCT00945347 NCT01899105 NCT03447262 NCT03525574 NCT03537651 NCT03601637 NCT03633526 NCT03691779 NCT04043806 NCT04058366 NCT04105972 NCT04183790 NCT04235140 NCT04362761 NCT04537793 NCT04545515 NCT02392234 NCT03045523 NCT03559062.

Conflict of interest statement

Professor Kevin Southern declares no potential conflict of interest.

Dr Ian Sinha is in receipt of a NIHR HTA grant for paediatric asthma and is a member of the NICE asthma committee; however, neither of these are related to cystic fibrosis or this review and thus do not constitute a potential conflict of interest.

Dr Sarah J Nevitt declares no potential conflict of interest.

Dr Jared Murphy declares no potential conflict of interest.

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figures

1
1
PRISMA study flow diagram
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2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1. Analysis
1.1. Analysis
Comparison 1: Lumacaftor versus placebo, Outcome 1: FEV1 % predicted (absolute change from baseline)
1.2. Analysis
1.2. Analysis
Comparison 1: Lumacaftor versus placebo, Outcome 2: Adverse effects: 100 mg and 200 mg lumacaftor groups (combined data) versus placebo at up to 1 month
1.3. Analysis
1.3. Analysis
Comparison 1: Lumacaftor versus placebo, Outcome 3: Adverse effects: 200 mg lumacaftor group versus placebo at up to 1 month
1.4. Analysis
1.4. Analysis
Comparison 1: Lumacaftor versus placebo, Outcome 4: Adverse effects requiring study drug discontinuation at up to 1 month
1.5. Analysis
1.5. Analysis
Comparison 1: Lumacaftor versus placebo, Outcome 5: Sweat chloride concentration (change from baseline at up to 1 month) [mmol/L]
1.6. Analysis
1.6. Analysis
Comparison 1: Lumacaftor versus placebo, Outcome 6: Sweat chloride concentration (change from baseline)
2.1. Analysis
2.1. Analysis
Comparison 2: Cavosonstat (N91115) (200 mg twice daily) versus placebo, Outcome 1: CFQR respiratory domain: absolute change from baseline
2.2. Analysis
2.2. Analysis
Comparison 2: Cavosonstat (N91115) (200 mg twice daily) versus placebo, Outcome 2: CFQR eating domain: absolute change from baseline
2.3. Analysis
2.3. Analysis
Comparison 2: Cavosonstat (N91115) (200 mg twice daily) versus placebo, Outcome 3: Adverse events occurring in > 10% of participants at up to 1 month
2.4. Analysis
2.4. Analysis
Comparison 2: Cavosonstat (N91115) (200 mg twice daily) versus placebo, Outcome 4: Sweat chloride
3.1. Analysis
3.1. Analysis
Comparison 3: N6022 versus placebo, Outcome 1: FEV1 % predicted (relative change from baseline at up to 1 month)
3.2. Analysis
3.2. Analysis
Comparison 3: N6022 versus placebo, Outcome 2: Treatment‐emergent adverse events (mild) at up to 1 month
3.3. Analysis
3.3. Analysis
Comparison 3: N6022 versus placebo, Outcome 3: Treatment‐emergent adverse events (moderate) at up to 1 month
3.4. Analysis
3.4. Analysis
Comparison 3: N6022 versus placebo, Outcome 4: Treatment‐emergent adverse events (serious or severe) at up to 1 month
4.1. Analysis
4.1. Analysis
Comparison 4: FDL169 (400 mg three times daily) versus placebo, Outcome 1: Mean change in CFQ‐R respiratory domain
4.2. Analysis
4.2. Analysis
Comparison 4: FDL169 (400 mg three times daily) versus placebo, Outcome 2: FEV1 % predicted absolute change (% points)
4.3. Analysis
4.3. Analysis
Comparison 4: FDL169 (400 mg three times daily) versus placebo, Outcome 3: Adverse events at up to 1 month
4.4. Analysis
4.4. Analysis
Comparison 4: FDL169 (400 mg three times daily) versus placebo, Outcome 4: Sweat chloride change from baseline [mmol/L]
5.1. Analysis
5.1. Analysis
Comparison 5: FDL169 (600 mg three times daily) versus placebo, Outcome 1: Mean change in CFQ‐R respiratory domain
5.2. Analysis
5.2. Analysis
Comparison 5: FDL169 (600 mg three times daily) versus placebo, Outcome 2: FEV1 % predicted absolute change (% points)
5.3. Analysis
5.3. Analysis
Comparison 5: FDL169 (600 mg three times daily) versus placebo, Outcome 3: Adverse events at up to 1 month
5.4. Analysis
5.4. Analysis
Comparison 5: FDL169 (600 mg three times daily) versus placebo, Outcome 4: Sweat chloride change from baseline [mmol/L]
6.1. Analysis
6.1. Analysis
Comparison 6: FDL169 (800 mg three times daily) versus placebo, Outcome 1: Mean change in CFQ‐R respiratory domain
6.2. Analysis
6.2. Analysis
Comparison 6: FDL169 (800 mg three times daily) versus placebo, Outcome 2: FEV1 % predicted absolute change (% points)
6.3. Analysis
6.3. Analysis
Comparison 6: FDL169 (800 mg three times daily) versus placebo, Outcome 3: Adverse events at up to 1 month
6.4. Analysis
6.4. Analysis
Comparison 6: FDL169 (800 mg three times daily) versus placebo, Outcome 4: Sweat chloride change from baseline [mmol/L]
7.1. Analysis
7.1. Analysis
Comparison 7: CPX versus placebo, Outcome 1: Adverse events occurring in more than 3% of participants in all treatment groups (combined data) versus placebo at up to 1 month
8.1. Analysis
8.1. Analysis
Comparison 8: 4PBA versus placebo, Outcome 1: Adverse events at up to 1 month
8.2. Analysis
8.2. Analysis
Comparison 8: 4PBA versus placebo, Outcome 2: Participants requiring study drug termination or a reduced dosage at up to 1 month
9.1. Analysis
9.1. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 1: Quality of life ‐ Euro Quality of Life Scale (EuroQol) 5‐Dimension‐3 Level (EQ‐5D‐3L) Index Score (absolute change from baseline)
9.2. Analysis
9.2. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 2: Quality of life ‐ CFQ‐R respiratory domain (absolute change from baseline)
9.3. Analysis
9.3. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 3: Quality of life ‐ EQ‐5D‐3L VAS Score (absolute change from baseline)
9.4. Analysis
9.4. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 4: FEV1 % predicted (relative change from baseline)
9.5. Analysis
9.5. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 5: FEV1 % predicted (absolute change from baseline)
9.6. Analysis
9.6. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 6: Adverse events by end of study (at 6 months)
9.7. Analysis
9.7. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 7: Time to first pulmonary exacerbation
9.8. Analysis
9.8. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 8: Rate of exacerbations
9.9. Analysis
9.9. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 9: Weight (kg) (absolute change from baseline)
9.10. Analysis
9.10. Analysis
Comparison 9: Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 10: BMI (absolute change from baseline)
10.1. Analysis
10.1. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 1: Quality of life ‐ Euro Quality of Life Scale (EuroQol) 5‐Dimension‐3 Level (EQ‐5D‐3L) Index Score (absolute change from baseline)
10.2. Analysis
10.2. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 2: Quality of life ‐ CFQ‐R respiratory domain (absolute change from baseline)
10.3. Analysis
10.3. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 3: Quality of life ‐ EQ‐5D‐3L VAS Score (absolute change from baseline)
10.4. Analysis
10.4. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 4: FEV1 % predicted (relative change from baseline)
10.5. Analysis
10.5. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 5: FEV1 % predicted (absolute change from baseline)
10.6. Analysis
10.6. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 6: Adverse events by end of study (at 6 months)
10.7. Analysis
10.7. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 7: Time to first pulmonary exacerbation
10.8. Analysis
10.8. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 8: Rate of exacerbations
10.9. Analysis
10.9. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 9: Weight (kg) (absolute change from baseline)
10.10. Analysis
10.10. Analysis
Comparison 10: Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 10: BMI (absolute change from baseline)
11.1. Analysis
11.1. Analysis
Comparison 11: Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 1: Quality of life ‐ Euro Quality of Life Scale (EuroQol) 5‐Dimension‐3 Level (EQ‐5D‐3L) Index Score (absolute change from baseline)
11.2. Analysis
11.2. Analysis
Comparison 11: Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 2: Quality of life ‐ CFQ‐R respiratory domain (absolute change from baseline)
11.3. Analysis
11.3. Analysis
Comparison 11: Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 3: Quality of life ‐ EQ‐5D‐3L VAS Score (absolute change from baseline)
11.4. Analysis
11.4. Analysis
Comparison 11: Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 4: FEV1 % predicted (relative change from baseline)
11.5. Analysis
11.5. Analysis
Comparison 11: Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 5: FEV1 % predicted (absolute change from baseline)
11.6. Analysis
11.6. Analysis
Comparison 11: Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 6: Adverse events by end of study (at 6 months)
11.7. Analysis
11.7. Analysis
Comparison 11: Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 7: Weight (kg) (absolute change from baseline)
11.8. Analysis
11.8. Analysis
Comparison 11: Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 8: BMI (absolute change from baseline)
12.1. Analysis
12.1. Analysis
Comparison 12: Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (150 mg twice daily) for days 15 to 21 versus placebo, Outcome 1: FEV1 % predicted (absolute change from baseline)
12.2. Analysis
12.2. Analysis
Comparison 12: Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (150 mg twice daily) for days 15 to 21 versus placebo, Outcome 2: Adverse events occurring in 10% or more participants (from days 15 ‐ 21)
12.3. Analysis
12.3. Analysis
Comparison 12: Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (150 mg twice daily) for days 15 to 21 versus placebo, Outcome 3: Sweat chloride concentration (mmol/L) (change from baseline)
13.1. Analysis
13.1. Analysis
Comparison 13: Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (250 mg twice daily) for days 15 to 21 versus placebo, Outcome 1: FEV1 % predicted (absolute change from baseline)
13.2. Analysis
13.2. Analysis
Comparison 13: Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (250 mg twice daily) for days 15 to 21 versus placebo, Outcome 2: Adverse events occurring in 10% or more participants (from days 15 ‐ 21)
13.3. Analysis
13.3. Analysis
Comparison 13: Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (250 mg twice daily) for days 15 to 21 versus placebo, Outcome 3: Sweat chloride concentration (mmol/L) (change from baseline)
14.1. Analysis
14.1. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 1: Quality of life ‐ CFQ‐R respiratory domain (absolute change from baseline)
14.2. Analysis
14.2. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 2: FEV1 % predicted (absolute change from baseline)
14.3. Analysis
14.3. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 3: LCI2.5 (absolute change from baseline)
14.4. Analysis
14.4. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 4: Treatment‐emergent adverse events with incidence > 10% in any treatment group (at 6 months)
14.5. Analysis
14.5. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 5: Sweat chloride concentration (absolute change from baseline)
14.6. Analysis
14.6. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 6: CT Brody score (mean change)
14.7. Analysis
14.7. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 7: CT Brody score bronchiectasis score (mean change)
14.8. Analysis
14.8. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 8: CT Brody score air trapping score (mean change)
14.9. Analysis
14.9. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 9: BMI (absolute change from baseline)
14.10. Analysis
14.10. Analysis
Comparison 14: Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 10: BMI for age z‐score (absolute change from baseline)
15.1. Analysis
15.1. Analysis
Comparison 15: Lumacaftor (200 mg once daily monotherapy for 14 days) plus ivacaftor (150 mg or 250 mg twice daily for days 15 to 21) for 21 days, Outcome 1: FEV1 % predicted (absolute change from baseline)
15.2. Analysis
15.2. Analysis
Comparison 15: Lumacaftor (200 mg once daily monotherapy for 14 days) plus ivacaftor (150 mg or 250 mg twice daily for days 15 to 21) for 21 days, Outcome 2: Adverse events occurring in 10% or more participants (from days 15 ‐ 21)
15.3. Analysis
15.3. Analysis
Comparison 15: Lumacaftor (200 mg once daily monotherapy for 14 days) plus ivacaftor (150 mg or 250 mg twice daily for days 15 to 21) for 21 days, Outcome 3: Sweat chloride concentration (mmol/L) (change from baseline)
16.1. Analysis
16.1. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 1: CFQ‐R respiratory domain (absolute change from baseline)
16.2. Analysis
16.2. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 2: CFQ‐R physical functioning domain (absolute change from baseline)
16.3. Analysis
16.3. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 3: CFQ‐R treatment burden domain (absolute change from baseline)
16.4. Analysis
16.4. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 4: CFQ‐R health perceptions domain (absolute change from baseline)
16.5. Analysis
16.5. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 5: CFQ‐R vitality domain (absolute change from baseline)
16.6. Analysis
16.6. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 6: CFQ‐R social functioning domain (absolute change from baseline)
16.7. Analysis
16.7. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 7: CFQ‐R role functioning domain (absolute change from baseline)
16.8. Analysis
16.8. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 8: CFQ‐R eating problems domain (absolute change from baseline)
16.9. Analysis
16.9. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 9: CFQ‐R emotional functioning (absolute change from baseline)
16.10. Analysis
16.10. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 10: CFQ‐R weight domain (absolute change from baseline)
16.11. Analysis
16.11. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 11: CFQ‐R digestive symptoms domain(absolute change from baseline)
16.12. Analysis
16.12. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 12: CFQ‐R body image domain (absolute change from baseline)
16.13. Analysis
16.13. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 13: FEV1 % predicted (relative change from baseline)
16.14. Analysis
16.14. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 14: FEV1 % predicted (absolute change from baseline)
16.15. Analysis
16.15. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 15: Most common adverse events (occurring in at least 10% of participants in either group)
16.16. Analysis
16.16. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 16: Time to first pulmonary exacerbation
16.17. Analysis
16.17. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 17: Sweat chloride (change from baseline)
16.18. Analysis
16.18. Analysis
Comparison 16: Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 18: BMI (change from baseline)
17.1. Analysis
17.1. Analysis
Comparison 17: VX‐659 (80 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 1: Quality of life: change in CFQ‐R respiratory domain
17.2. Analysis
17.2. Analysis
Comparison 17: VX‐659 (80 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 2: FEV1 % predicted (relative change from baseline)
17.3. Analysis
17.3. Analysis
Comparison 17: VX‐659 (80 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 3: FEV1 L (absolute change from baseline)
17.4. Analysis
17.4. Analysis
Comparison 17: VX‐659 (80 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 4: Adverse events (at 1 month)
17.5. Analysis
17.5. Analysis
Comparison 17: VX‐659 (80 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 5: Sweat chloride (change from baseline) [mmol/L]
18.1. Analysis
18.1. Analysis
Comparison 18: VX‐659 (120 mg twice daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 1: FEV1 % predicted (absolute change from baseline)
18.2. Analysis
18.2. Analysis
Comparison 18: VX‐659 (120 mg twice daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 2: Adverse events (at up to 1 month)
18.3. Analysis
18.3. Analysis
Comparison 18: VX‐659 (120 mg twice daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 3: Sweat chloride (absolute change from baseline)
19.1. Analysis
19.1. Analysis
Comparison 19: VX‐659 (240 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 1: Quality of life: change in CFQ‐R respiratory domain
19.2. Analysis
19.2. Analysis
Comparison 19: VX‐659 (240 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 2: FEV1 % predicted (relative change from baseline)
19.3. Analysis
19.3. Analysis
Comparison 19: VX‐659 (240 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 3: FEV1 L (absolute change from baseline)
19.4. Analysis
19.4. Analysis
Comparison 19: VX‐659 (240 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 4: Adverse events (at 1 month)
19.5. Analysis
19.5. Analysis
Comparison 19: VX‐659 (240 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 5: Sweat chloride (change from baseline) [mmol/L]
20.1. Analysis
20.1. Analysis
Comparison 20: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 1: Quality of life: change in CFQ‐R respiratory domain
20.2. Analysis
20.2. Analysis
Comparison 20: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 2: FEV1 % predicted (relative change from baseline)
20.3. Analysis
20.3. Analysis
Comparison 20: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 3: FEV1 L (absolute change from baseline)
20.4. Analysis
20.4. Analysis
Comparison 20: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 4: Adverse events (at 1 month)
20.5. Analysis
20.5. Analysis
Comparison 20: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 5: Sweat chloride (mmol/L) change from baseline
21.1. Analysis
21.1. Analysis
Comparison 21: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo+tez+iva [F508del homozygous], Outcome 1: Quality of life: change in CFQ‐R respiratory domain
21.2. Analysis
21.2. Analysis
Comparison 21: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo+tez+iva [F508del homozygous], Outcome 2: FEV1 % predicted (relative change from baseline)
21.3. Analysis
21.3. Analysis
Comparison 21: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo+tez+iva [F508del homozygous], Outcome 3: FEV1 L (absolute change from baseline)
21.4. Analysis
21.4. Analysis
Comparison 21: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo+tez+iva [F508del homozygous], Outcome 4: Adverse events (at 1 month)
21.5. Analysis
21.5. Analysis
Comparison 21: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo+tez+iva [F508del homozygous], Outcome 5: Sweat chloride (change from baseline) [mmol/L]
22.1. Analysis
22.1. Analysis
Comparison 22: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 1: Quality of life: change in CFQ‐R respiratory domain
22.2. Analysis
22.2. Analysis
Comparison 22: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 2: FEV1 % predicted (relative change from baseline)
22.3. Analysis
22.3. Analysis
Comparison 22: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 3: FEV1 L (absolute change from baseline)
22.4. Analysis
22.4. Analysis
Comparison 22: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 4: Adverse events (at 1 month)
22.5. Analysis
22.5. Analysis
Comparison 22: VX‐659 (400 mg once daily) plus tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 5: Sweat chloride (change from baseline) [mmol/L]
23.1. Analysis
23.1. Analysis
Comparison 23: VX‐659 400 mg tezacaftor ‐ pooled ivacaftor and VX‐561, Outcome 1: Quality of life: change in CFQ‐R respiratory domain
23.2. Analysis
23.2. Analysis
Comparison 23: VX‐659 400 mg tezacaftor ‐ pooled ivacaftor and VX‐561, Outcome 2: FEV1 % predicted (relative change from baseline)
23.3. Analysis
23.3. Analysis
Comparison 23: VX‐659 400 mg tezacaftor ‐ pooled ivacaftor and VX‐561, Outcome 3: FEV1 L (absolute change from baseline)
23.4. Analysis
23.4. Analysis
Comparison 23: VX‐659 400 mg tezacaftor ‐ pooled ivacaftor and VX‐561, Outcome 4: Adverse events (at 1 month)
23.5. Analysis
23.5. Analysis
Comparison 23: VX‐659 400 mg tezacaftor ‐ pooled ivacaftor and VX‐561, Outcome 5: Sweat chloride (change from baseline) [mmol/L]
24.1. Analysis
24.1. Analysis
Comparison 24: Elexacaftor (50 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 1: Quality of life: change in CFQ‐R respiratory domain
24.2. Analysis
24.2. Analysis
Comparison 24: Elexacaftor (50 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 2: FEV1 % predicted (relative change from baseline)
24.3. Analysis
24.3. Analysis
Comparison 24: Elexacaftor (50 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 3: FEV1 L (absolute change from baseline)
24.4. Analysis
24.4. Analysis
Comparison 24: Elexacaftor (50 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 4: Adverse events (at 1 month)
24.5. Analysis
24.5. Analysis
Comparison 24: Elexacaftor (50 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 5: Sweat chloride (change from baseline) [mmol/L]
25.1. Analysis
25.1. Analysis
Comparison 25: Elexacaftor (100 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 1: Quality of life: change in CFQ‐R respiratory sub‐domain
25.2. Analysis
25.2. Analysis
Comparison 25: Elexacaftor (100 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 2: FEV1 % predicted (relative change from baseline)
25.3. Analysis
25.3. Analysis
Comparison 25: Elexacaftor (100 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 3: FEV1 L (absolute change from baseline)
25.4. Analysis
25.4. Analysis
Comparison 25: Elexacaftor (100 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 4: Adverse events at (1 month)
25.5. Analysis
25.5. Analysis
Comparison 25: Elexacaftor (100 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus placebo [F508del/MF], Outcome 5: Sweat chloride (change from baseline) [mmol/L]
26.1. Analysis
26.1. Analysis
Comparison 26: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 1: Quality of life: change in CFQ‐R respiratory domain
26.2. Analysis
26.2. Analysis
Comparison 26: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 2: FEV1 % predicted (relative change from baseline)
26.3. Analysis
26.3. Analysis
Comparison 26: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 3: FEV1 L (absolute change from baseline)
26.4. Analysis
26.4. Analysis
Comparison 26: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 4: Adverse events (at 1 month)
26.5. Analysis
26.5. Analysis
Comparison 26: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus VX‐561 (150 mg once daily) versus placebo [F508del/MF], Outcome 5: Sweat chloride (change from baseline) [mmol/L]
27.1. Analysis
27.1. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 1: Quality of life: CFQ‐R respiratory domain (change from baseline)
27.2. Analysis
27.2. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 2: FEV1 % predicted (relative change from baseline)
27.3. Analysis
27.3. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 3: FEV1 % predicted (absolute change from baseline)
27.4. Analysis
27.4. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 4: FEV1 L (absolute change from baseline)
27.5. Analysis
27.5. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 5: Adverse events (at up to 1 month)
27.6. Analysis
27.6. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 6: Adverse events (at up to 6 months)
27.7. Analysis
27.7. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 7: Hospitalisation
27.8. Analysis
27.8. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 8: Exacerbation (need for antibiotics)
27.9. Analysis
27.9. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 9: Sweat chloride (absolute change from baseline)
27.10. Analysis
27.10. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 10: Weight (absolute change from baseline)
27.11. Analysis
27.11. Analysis
Comparison 27: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus triple placebo‐ F508del/MF, Outcome 11: BMI z score (absolute change from baseline)
28.1. Analysis
28.1. Analysis
Comparison 28: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus placebo‐tez‐iva‐ F508del/F508del, Outcome 1: Quality of life: CFQ‐R respiratory domain (change from baseline)
28.2. Analysis
28.2. Analysis
Comparison 28: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus placebo‐tez‐iva‐ F508del/F508del, Outcome 2: FEV1 % predicted (relative change from baseline)
28.3. Analysis
28.3. Analysis
Comparison 28: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus placebo‐tez‐iva‐ F508del/F508del, Outcome 3: FEV1 % predicted (absolute change from baseline)
28.4. Analysis
28.4. Analysis
Comparison 28: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus placebo‐tez‐iva‐ F508del/F508del, Outcome 4: FEV1 L (absolute change from baseline)
28.5. Analysis
28.5. Analysis
Comparison 28: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus placebo‐tez‐iva‐ F508del/F508del, Outcome 5: Adverse events (at up to 1 month)
28.6. Analysis
28.6. Analysis
Comparison 28: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus placebo‐tez‐iva‐ F508del/F508del, Outcome 6: Sweat chloride (absolute change from baseline)
28.7. Analysis
28.7. Analysis
Comparison 28: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus placebo‐tez‐iva‐ F508del/F508del, Outcome 7: Weight (change from baseline)
28.8. Analysis
28.8. Analysis
Comparison 28: Elexacaftor (200 mg once daily) tezacaftor (100 mg once daily) plus ivacaftor 150 mg twice daily versus placebo‐tez‐iva‐ F508del/F508del, Outcome 8: BMI (change from baseline)

Source: PubMed

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