PMID- 33331662
OWN - NLM
STAT- MEDLINE
DCOM- 20210115
LR  - 20231201
IS  - 1469-493X (Electronic)
IS  - 1361-6137 (Linking)
VI  - 12
IP  - 12
DP  - 2020 Dec 17
TI  - Corrector therapies (with or without potentiators) for people with cystic 
      fibrosis with class II CFTR gene variants (most commonly F508del).
PG  - CD010966
LID - 10.1002/14651858.CD010966.pub3 [doi]
LID - CD010966
AB  - 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 
      (FEV(1)) % 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 
      FEV(1) (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 FEV(1) (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.
CI  - Copyright (c) 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
FAU - Southern, Kevin W
AU  - Southern KW
AD  - Department of Women's and Children's Health, University of Liverpool, Liverpool, 
      UK.
FAU - Murphy, Jared
AU  - Murphy J
AD  - Department of Women's and Children's Health, University of Liverpool, Liverpool, 
      UK.
FAU - Sinha, Ian P
AU  - Sinha IP
AD  - Department of Women's and Children's Health, University of Liverpool, Liverpool, 
      UK.
FAU - Nevitt, Sarah J
AU  - Nevitt SJ
AD  - Department of Biostatistics, University of Liverpool, Liverpool, UK.
LA  - eng
SI  - ClinicalTrials.gov/NCT01225211
SI  - ClinicalTrials.gov/NCT00865904
SI  - ClinicalTrials.gov/NCT03029455
SI  - ClinicalTrials.gov/NCT03224351
SI  - ClinicalTrials.gov/NCT01746784
SI  - ClinicalTrials.gov/NCT03093714
SI  - ClinicalTrials.gov/NCT03227471
SI  - ClinicalTrials.gov/NCT00004428
SI  - ClinicalTrials.gov/NCT01931839
SI  - ClinicalTrials.gov/NCT02514473
SI  - ClinicalTrials.gov/NCT00590538
SI  - ClinicalTrials.gov/NCT01807923
SI  - ClinicalTrials.gov/NCT01807949
SI  - ClinicalTrials.gov/NCT00016744
SI  - ClinicalTrials.gov/NCT01897233
SI  - ClinicalTrials.gov/NCT00742092
SI  - ClinicalTrials.gov/NCT00945347
SI  - ClinicalTrials.gov/NCT01899105
SI  - ClinicalTrials.gov/NCT03447262
SI  - ClinicalTrials.gov/NCT03525574
SI  - ClinicalTrials.gov/NCT03537651
SI  - ClinicalTrials.gov/NCT03601637
SI  - ClinicalTrials.gov/NCT03633526
SI  - ClinicalTrials.gov/NCT03691779
SI  - ClinicalTrials.gov/NCT04043806
SI  - ClinicalTrials.gov/NCT04058366
SI  - ClinicalTrials.gov/NCT04105972
SI  - ClinicalTrials.gov/NCT04183790
SI  - ClinicalTrials.gov/NCT04235140
SI  - ClinicalTrials.gov/NCT04362761
SI  - ClinicalTrials.gov/NCT04537793
SI  - ClinicalTrials.gov/NCT04545515
SI  - ClinicalTrials.gov/NCT02392234
SI  - ClinicalTrials.gov/NCT03045523
SI  - ClinicalTrials.gov/NCT03559062
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
PT  - Systematic Review
DEP - 20201217
PL  - England
TA  - Cochrane Database Syst Rev
JT  - The Cochrane database of systematic reviews
JID - 100909747
RN  - 0 (Aminophenols)
RN  - 0 (Aminopyridines)
RN  - 0 (Benzodioxoles)
RN  - 0 (Drug Combinations)
RN  - 0 (Indoles)
RN  - 0 (Phenylbutyrates)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridines)
RN  - 0 (Quinolines)
RN  - 0 (Quinolones)
RN  - 0 (elexacaftor, ivacaftor, tezacaftor drug combination)
RN  - 0 (lumacaftor, ivacaftor drug combination)
RN  - 0 (tezacaftor, ivacaftor drug combination)
RN  - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
SB  - IM
UOF - Cochrane Database Syst Rev. 2018 Aug 02;8:CD010966. PMID: 30070364
UIN - Cochrane Database Syst Rev. 2023 Nov 20;11:CD010966. PMID: 37983082
MH  - Adult
MH  - Aminophenols/therapeutic use
MH  - Aminopyridines/therapeutic use
MH  - Benzodioxoles/therapeutic use
MH  - Bias
MH  - Child
MH  - Cystic Fibrosis/*drug therapy/*genetics
MH  - Cystic Fibrosis Transmembrane Conductance Regulator/*drug effects/*genetics
MH  - Drug Combinations
MH  - Humans
MH  - Indoles/therapeutic use
MH  - *Mutation
MH  - Phenylbutyrates/therapeutic use
MH  - Pyrazoles/therapeutic use
MH  - Pyridines/therapeutic use
MH  - Quality of Life
MH  - Quinolines/therapeutic use
MH  - Quinolones/therapeutic use
MH  - Randomized Controlled Trials as Topic
PMC - PMC8094390
COIS- 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.
EDAT- 2020/12/18 06:00
MHDA- 2021/01/16 06:00
PMCR- 2021/12/17
CRDT- 2020/12/17 08:43
PHST- 2020/12/17 08:43 [entrez]
PHST- 2020/12/18 06:00 [pubmed]
PHST- 2021/01/16 06:00 [medline]
PHST- 2021/12/17 00:00 [pmc-release]
AID - CD010966.pub3 [pii]
AID - 10.1002/14651858.CD010966.pub3 [doi]
PST - epublish
SO  - Cochrane Database Syst Rev. 2020 Dec 17;12(12):CD010966. doi: 
      10.1002/14651858.CD010966.pub3.