دورية أكاديمية
Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).
العنوان: | Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). |
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المؤلفون: | Heneghan M; Department of Women's and Children's Health, University of Liverpool, Liverpool, UK., Southern KW; Department of Women's and Children's Health, University of Liverpool, Liverpool, UK., Murphy J; Leighton Hospital, Crewe, UK., Sinha IP; Department of Women's and Children's Health, University of Liverpool, Liverpool, UK., Nevitt SJ; Department of Health Data Science, University of Liverpool, Liverpool, UK.; Centre for Reviews and Dissemination, University of York, York, UK. |
المصدر: | The Cochrane database of systematic reviews [Cochrane Database Syst Rev] 2023 Nov 20; Vol. 11. Cochrane AN: CD010966. Date of Electronic Publication: 2023 Nov 20. |
نوع المنشور: | Systematic Review; Journal Article; Review; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Wiley Country of Publication: England NLM ID: 100909747 Publication Model: Electronic Cited Medium: Internet ISSN: 1469-493X (Electronic) Linking ISSN: 13616137 NLM ISO Abbreviation: Cochrane Database Syst Rev Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2004- : Chichester, West Sussex, England : Wiley Original Publication: Oxford, U.K. ; Vista, CA : Update Software, |
مواضيع طبية MeSH: | Cystic Fibrosis*/drug therapy , Cystic Fibrosis*/genetics, Adult ; Child ; Humans ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Aminophenols/adverse effects ; Dyspnea/drug therapy ; Mutation |
مستخلص: | 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 is the commonest CF-causing variant (found in up to 90% of people with CF (pwCF)). The F508del variant lacks meaningful CFTR function - faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. Corrective therapy could benefit many pwCF. This review evaluates single correctors (monotherapy) and any combination of correctors (most commonly lumacaftor, tezacaftor, elexacaftor, VX-659, VX-440 or VX-152) and a potentiator (e.g. ivacaftor) (dual and triple therapies). 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 CF Trials Register (28 November 2022), reference lists of relevant articles and online trials registries (3 December 2022). 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 judged evidence certainty (GRADE); we contacted investigators for additional data. Main Results: We included 34 RCTs (4781 participants), lasting between 1 day and 48 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), 16 dual-therapy RCTs (2627 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and 11 triple-therapy RCTs (1804 participants) (elexacaftor-tezacaftor-ivacaftor/deutivacaftor; VX-659-tezacaftor-ivacaftor/deutivacaftor; VX-440-tezacaftor-ivacaftor; VX-152-tezacaftor-ivacaftor). Participants in 21 RCTs had the genotype F508del/F508del, in seven RCTs they had F508del/minimal function (MF), in one RCT F508del/gating genotypes, in one RCT either F508del/F508del genotypes or F508del/residual function genotypes, in one RCT either F508del/gating or F508del/residual function genotypes, and in three RCTs either F508del/F508del genotypes or F508del/MF genotypes. Risk of bias judgements varied across different comparisons. Results from 16 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard designs (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 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 due to their variety and few participants (all F508del/F508del). Dual therapy In a tezacaftor-ivacaftor group there was one death (deemed unrelated to the study drug). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points (moderate-certainty evidence). At six months, relative change in forced expiratory volume in one second (FEV Authors' Conclusions: There is insufficient evidence of clinically important effects from corrector monotherapy in pwCF with F508del/F508del. Additional data in this review reduced the evidence for efficacy of dual therapy; these agents can no longer be considered as standard therapy. Their use may be appropriate in exceptional circumstances (e.g. if triple therapy is not tolerated or due to age). Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar small improvements in QoL and respiratory function with lower pulmonary exacerbation rates. While the effect sizes for QoL and FEV (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.) |
التعليقات: | Update of: Cochrane Database Syst Rev. 2020 Dec 17;12:CD010966. doi: 10.1002/14651858.CD010966.pub3. (PMID: 33331662) |
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سلسلة جزيئية: | ClinicalTrials.gov NCT01225211; NCT00865904; NCT03029455; NCT03224351; NCT03559062; NCT01746784; NCT03093714; NCT03227471; NCT00004428; NCT03525444; NCT01931839; NCT02514473; NCT00590538; NCT04105972; NCT01807923; NCT01807949; NCT00016744; NCT01897233; NCT00742092; NCT00945347; NCT01899105; NCT03447262; NCT03525574; NCT03537651; NCT03601637; NCT03633526; NCT03691779; NCT04043806; NCT04058366; NCT04183790; NCT04235140; NCT04362761; NCT04537793; NCT04545515; NCT02392234; NCT03045523; NCT05033080; NCT05076149 |
المشرفين على المادة: | EGP8L81APK (lumacaftor) 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) 1Y740ILL1Z (ivacaftor) 9A4381183B (VX) 0 (Aminophenols) 0 (CFTR protein, human) |
تواريخ الأحداث: | Date Created: 20231120 Date Completed: 20231127 Latest Revision: 20240820 |
رمز التحديث: | 20240820 |
مُعرف محوري في PubMed: | PMC10659105 |
DOI: | 10.1002/14651858.CD010966.pub4 |
PMID: | 37983082 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1469-493X |
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DOI: | 10.1002/14651858.CD010966.pub4 |