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Efficacy and Safety of CFTR Corrector and Potentiator Combination Therapy in Patients with Cystic Fibrosis for the F508del-CFTR Homozygous Mutation: A Systematic Review and Meta-analysis



Cystic fibrosis (CF) is a progressive, genetic disease that causes persistent lung infections and limits the ability to breathe over time. The combination of a cystic fibrosis transmembrane conductance regulator (CFTR) corrector and potentiator has provided a benefit by decreasing sweat chloride concentration in CF for the F508del-CFTR homozygous mutation, but it remains controversial in lung function, nutritional status, clinical score and safety.


The authors performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of combination therapy on lung function, nutritional status, clinical score and safety in CF for the F508del-CFTR homozygous mutation. Web of Science, Cochrane Central Register of Controlled Trials, Medline, and Embase were searched. The registered PROSPERO number was CRD42018085875.


Five RCTs, including a total of 1637 participants with the F508del-CFTR homozygous mutation who accepted CFTR corrector and potentiator combination therapy along with basic treatment were enrolled in this analysis. Primary analysis revealed that combination therapy improved the percent of predicted FEV1 (ppFEV1) (MD 2.38, 1.62–3.15, P < 0.00001), Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score (MD 2.59, 0.96–4.22, P = 0.002) and body-mass index (BMI) (MD 0.21, 0.03–0.39, P = 0.02). In the secondary analysis, combination therapy had no impact on the number of participants reporting adverse events (OR 0.88, 0.58–1.33, P = 0.53), but increased the proportion of discontinued treatments due to adverse events (OR 2.71, 1.3–5.63, P = 0.008).


CFTR corrector and potentiator combination therapy effectively improves lung function, nutritional status and clinical score in CF patients with the F508del-CFTR homozygous mutation, and has an acceptable safety profile.

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  1. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1891–904.

    Article  Google Scholar 

  2. Döring G, Ratjen F. Immunology of cystic fibrosis. In: Hodson ME, Geddes D, Bush A, editors. Cystic fibrosis. London, England: Arnold Hammer; 2007. p. 69–80.

  3. Berger HA, Anderson MP, Gregory RJ, Thompson S, Howard PW, Maurer RA, et al. Identification and regulation of the cystic fibrosis trans-membrane conductance regulator-generated chloride channel. J Clin Invest. 1991;88:1422–31.

    CAS  Article  Google Scholar 

  4. Choi JY, Muallem D, Kiselyov K, Lee MG, Thomas PJ, Muallem S. Aberrant CFTR-dependent HCO3-transport in mutations associated with cystic fibrosis. Nature. 2001;410:94–7.

    CAS  Article  Google Scholar 

  5. Derichs N. Targeting a genetic defect: cystic fibrosis trans-membrane conductance regulator modulators in cystic fibrosis. Eur Respir Rev. 2013;22:58–65.

    Article  Google Scholar 

  6. Clinical and Functional Translation of CFTR (CFTR2). Accessed 15 Feb 2018.

  7. Lukacs GL, Mohamed A, Kartner N, Chang XB, Riordan JR, Grinstein S. Conformational maturation of CFTR but not its mutant counterpart (delta F508) occurs in the endoplasmic reticulum and requires ATP. EMBO J. 1994;13:6076–86.

    CAS  Article  Google Scholar 

  8. Van GF, Straley KS, Cao D, Gonzalez J, Hadida S, Hazlewood A, et al. Rescue of DeltaF508-CFTR trafcking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol. 2006;290:L1117–30.

    Article  Google Scholar 

  9. Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, et al. Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature. 1991;354:526–8.

    CAS  Article  Google Scholar 

  10. US Food and Drug Administration. FDA Approves New Treatment for Cystic Fibrosis. Silver Spring, MD: US Food and Drug Administration, 2015. Accessed 15 Feb 2018.

  11. ORKAMBI (lumacaftor/ivacaftor). European Public Assessment Report Product Information. Vertex Pharmaceuticals Inc. London, UK, July 2016. Accessed 15 Feb 2018.

  12. Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373:220–31.

    CAS  Article  Google Scholar 

  13. Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014;2:527–38.

    CAS  Article  Google Scholar 

  14. Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017;5:557–67.

    CAS  Article  Google Scholar 

  15. Donaldson SH, Pilewski JM, Griese M, Cooke J, Viswanathan L, Tullis E, et al. Tezacaftor/ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Respir Crit Care Med. 2018;197 (2):2, 214–24.

  16. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–34.

    Article  Google Scholar 

  17. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions version 5.3.0. Oxford: the Cochrane collaboration, 2014. Updated March 2014. Accessed 15 Feb 2018.

  18. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–6.

    Article  Google Scholar 

  19. Hubert D, Chiron R, Camara B, Grenet D, Prévotat A, Bassinet L, et al. Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease. J Cyst Fibrosis. 2017;16:388–91.

    CAS  Article  Google Scholar 

  20. Michael WK, Edward FM, Richard BM, Gautham M, Simon T, David W, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5:107–18.

  21. Carlos EM, Felix R, Gautham M, Fang L, David W, Margaret R, et al. Lumacaftor/ivacaftor in patients aged 6–11 years with cystic fibrosis and homozygous for F508del-CFTR. Am J Resp Crit Care. 2017;195:7.

    Article  Google Scholar 

  22. Chilvers M, Tian S, Marigowda G, Bsharat M, Hug C, Solomon M, et al. An open-label extension (EXT) study of lumacaftor/ivacaftor (LUM/IVA) therapy in patients aged 6 to 11 years with cystic fibrosis (CF) homozygous for F508del-CFTR. J Cyst Fibrosis. 2017;16:S77.

    Article  Google Scholar 

  23. Jennings MT, Dezube R, Paranjape S, West NE, Hong G, Braun A, et al. An observational study of outcomes and tolerances in patients with cystic fibrosis initiated on lumacaftor/ivacaftor. Ann Am Thorac Soc. 2017;14:1662–6.

    Article  Google Scholar 

  24. Stallings VA, Stark L, Robinson KA, Feranchak AP, Quinton H, Clinical Practice Guidelines on Growth and Nutrition Subcommittee, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108:832–9.

  25. Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, et al. Clinical mechanism of the cystic fibrosis trans-membrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014;190:175–84.

    CAS  Article  Google Scholar 

  26. Vaisman N, Pencharz PB, Corey M, Canny GJ, Hahn E. Energy expenditure of patients with cystic fibrosis. J Pediatr. 1987;111:496–500.

    CAS  Article  Google Scholar 

  27. Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of the cystic fibrosis questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis. Chest. 2005;128:2347–54.

    Article  Google Scholar 

  28. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135:1610–8.

    Article  Google Scholar 

  29. Elborn JS, Ramsey BW, Boyle MP, Konstan MW, Huang XH, Marigowda G, et al. Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis. Lancet Respir Med. 2016;4:617–26.

    CAS  Article  Google Scholar 

  30. Marigowda Gautham, Liu Fang, Waltz David. Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy. J Cyst Fibros. 2017;16(2):246–9.

    CAS  Article  Google Scholar 

  31. Labaste A, Ohlmann C, Mainguy C, Jubin V, Perceval M, Coutier L, et al. Real-life acute lung function changes after lumacaftor/ivacaftor first administration in pediatric patients with cystic fibrosis. J Cyst Fibros. 2017;16:709–12.

    CAS  Article  Google Scholar 

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We thank all the people who participated in the primary randomized controlled trials and the teams who carried them out.


No funding or sponsorship was received for this study or publication of this article. The article-processing charges were funded by the authors.


All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authors’ Contribution

Hong-xia Wu and De-yun Cheng initiated and coordinated the study. Xiao-feng Xiong, Min Zhu, Jia Wei and Kai-quan Zhuo were responsible for the data collection and data analysis. Studies were reviewed by De-yun Cheng. Hong-xia Wu wrote the first draft of the manuscript. All the authors were involved in the interpretation of the analyses and gave input to the final manuscript.


Hong-xia Wu, Min Zhu, Xiao-feng Xiong, Jia Wei, Kai-quan Zhuo and De-yun Cheng have nothing to disclose.

Compliance with Ethics Guidelines

The protocols of all enrolled RCTs were reviewed and approved by ethics committees. Informed consents were obtained from all individual participants included in enrolled RCTs.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Correspondence to De-yun Cheng.

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Wu, Hx., Zhu, M., Xiong, Xf. et al. Efficacy and Safety of CFTR Corrector and Potentiator Combination Therapy in Patients with Cystic Fibrosis for the F508del-CFTR Homozygous Mutation: A Systematic Review and Meta-analysis. Adv Ther 36, 451–461 (2019).

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  • Cystic fibrosis
  • Cystic fibrosis transmembrane conductance regulator
  • Ivacaftor
  • Lumacaftor
  • Tezacaftor