Skip to main content

Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor

Abstract

Background

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gating mutation G551D prevents sufficient ion transport due to reduced channel-open probability. Ivacaftor, an oral CFTR potentiator, increases the channel-open probability.

Aim

To further analyze improvements in weight and body mass index (BMI) in two studies of ivacaftor in patients aged ≥6 years with CF and the G551D mutation.

Methods

Patients were randomized 1:1 to ivacaftor 150 mg or placebo every 12 h for 48 weeks. Primary end point (lung function) was reported previously. Other outcomes included weight and height measurements and CF Questionnaire-Revised (CFQ-R).

Results

Studies included 213 patients (aged ≤ 20 years, n = 105; aged > 20 years, n = 108). In patients ≤20 years, adjusted mean change from baseline to week 48 in body weight was 4.9 versus 2.2 kg (ivacaftor vs. placebo, p = 0.0008). At week 48, change from baseline in mean weight-for-age z-score was 0.29 versus −0.06 (p < 0.0001); change in mean BMI-for-age z-score was 0.26 versus −0.13 (p < 0.0001). In patients >20 years, adjusted mean change from baseline to week 48 in body weight was 2.7 versus −0.2 kg (p = 0.0003). Mean BMI change at week 48 was 0.9 versus −0.1 kg/m2 (p = 0.0003). There was no linear correlation evident between changes in body weight and improvements in lung function or sweat chloride. Significant CFQ-R improvements were seen in perception of eating, body image, and sense of ability to gain weight.

Conclusions

Nutritional status improved following treatment with ivacaftor for 48 weeks.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1891–1904.

    PubMed  Article  Google Scholar 

  2. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992–2001.

    PubMed  CAS  Article  Google Scholar 

  3. Cystic Fibrosis Registry of Ireland 2012 Annual Report. Dublin, Ireland: Cystic Fibrosis Registry of Ireland; 2014.

  4. Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA. 2009;106:18825–18830.

    PubMed  PubMed Central  Article  Google Scholar 

  5. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187:1219–1225.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  6. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663–1672.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  7. Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H. 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;108:832–839.

    PubMed  Article  Google Scholar 

  8. Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life for children with cystic fibrosis. J Pediatr Psychol. 2003;28:535–545.

    PubMed  Article  Google Scholar 

  9. 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;128:2347–2354.

    PubMed  Article  Google Scholar 

  10. Sproul A, Huang N. Growth patterns in children with cystic fibrosis. J Pediatr. 1964;65:664–676.

    PubMed  CAS  Article  Google Scholar 

  11. Yen EH, Quinton H, Borowitz D. Better nutritional status in early childhood is associated with improved clinical outcomes and survival in patients with cystic fibrosis. J Pediatr. 2013;162:530–535.

    PubMed  Article  Google Scholar 

  12. McKone EF, Borowitz D, Drevinek P, et al. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med. 2014;2:902–910.

    PubMed  CAS  Article  Google Scholar 

  13. Hayes D Jr, McCoy KS, Sheikh SI. Improvement of sinus disease in cystic fibrosis with ivacaftor therapy. Am J Respir Crit Care Med. 2014;190:468.

    PubMed  Article  Google Scholar 

  14. Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014;190:175–184.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  15. Magoffin A, Allen JR, McCauley J, et al. Longitudinal analysis of resting energy expenditure in patients with cystic fibrosis. J Pediatr. 2008;152:703–708.

    PubMed  Article  Google Scholar 

  16. Tomezsko JL, Stallings VA, Kawchak DA, Goin JE, Diamond G, Scanlin TF. Energy expenditure and genotype of children with cystic fibrosis. Pediatr Res. 1994;35:451–460.

    PubMed  CAS  Article  Google Scholar 

  17. Kalnins D, Pencharz PB, Grasemann H, Solomon M. Energy expenditure and nutritional status in pediatric patients before and after lung transplantation. J Pediatr. 2013;163:1500–1502.

    PubMed  Article  Google Scholar 

  18. Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet. 2008;372:415–417.

    PubMed  CAS  Article  Google Scholar 

  19. Clarke LL, Harline MC. Dual role of CFTR in cAMP-stimulated. Am J Physiol. 1998;274:G718–G726.

    PubMed  CAS  Google Scholar 

  20. Ishiguro H, Yamamoto A, Nakakuki M, et al. Physiology and pathophysiology of bicarbonate secretion by pancreatic duct epithelium. Nagoya J Med Sci. 2012;74:1–18.

    PubMed  CAS  Google Scholar 

  21. Smith JJ, Welsh MJ. cAMP stimulates bicarbonate secretion across normal, but not cystic fibrosis airway epithelia. J Clin Invest. 1992;89:1148–1153.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  22. Li L, Somerset S. Digestive system dysfunction in cystic fibrosis: challenges for nutrition therapy. Dig Liver Dis. 2014;46:865–874.

    PubMed  Article  Google Scholar 

  23. Weber AM, Roy CC. Intraduodenal events in cystic fibrosis. J Pediatr Gastroenterol Nutr. 1984;3:S113–S119.

    PubMed  Article  Google Scholar 

  24. Gustafsson JK, Ermund A, Ambort D, et al. Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J Exp Med. 2012;209:1263–1272.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  25. Alaiwa A, Reznikov LR, Gansemer ND, Zabner J, Welsh MJ. pH modulates the antimicrobial activity of beta defensin-3 (BD-3) [abstract 91]. Pediatr Pulmonol. 2013;48:237.

    Google Scholar 

  26. Lai Y, Gallo RL. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 2009;30:131–141.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  27. Gelfond D, Ma C, Semler J, Borowitz D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci. 2013;58:2275–2281.

    PubMed  CAS  Article  Google Scholar 

  28. Borowitz D, Baker SS, Duffy L, et al. Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr. 2004;145:322–326.

    PubMed  CAS  Article  Google Scholar 

  29. Durie PR, Forstner GG. Pathophysiology of the exocrine pancreas in cystic fibrosis. J R Soc Med. 1989;82:2–10.

    PubMed  PubMed Central  Google Scholar 

  30. Walkowiak J, Herzig KH, Strzykala K, Przyslawski J, Krawczynski M. Fecal elastase-1 is superior to fecal chymotrypsin in the assessment of pancreatic involvement in cystic fibrosis. Pediatrics. 2002;110:e7.

    PubMed  Article  Google Scholar 

  31. Marino CR, Matovcik LM, Gorelick FS, Cohn JA. Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. J Clin Invest. 1991;88:712–716.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  32. Davies JC, Robertson S, Green Y, Rosenfeld M. An open-label study of the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2 to 5 years with CF and a CFTR gating mutation: the KIWI study [poster 200] [abstract]. Presented at the Atlanta, GA, October 9–11, 2014, Annual North American Conference of the Cystic Fibrosis Foundation. 2014.

  33. Kalivianakis M, Minich DM, Bijleveld CM, et al. Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids. Am J Clin Nutr. 1999;69:127–134.

    PubMed  CAS  Google Scholar 

  34. Wouthuyzen-Bakker M, Bodewes FA, Verkade HJ. Persistent fat malabsorption in cystic fibrosis; lessons from patients and mice. J Cyst Fibros. 2011;10:150–158.

    PubMed  CAS  Article  Google Scholar 

  35. De Lisle RC, Borowitz D. The cystic fibrosis intestine. Cold Spring Harb Perspect Med. 2013;3:a009753.

    PubMed  PubMed Central  Article  Google Scholar 

  36. van der Doef HP, Kokke FT, Beek FJ, Woestenenk JW, Froeling SP, Houwen RH. Constipation in pediatric cystic fibrosis patients: an underestimated medical condition. J Cyst Fibros. 2010;9:59–63.

    PubMed  Article  Google Scholar 

  37. Murphy JL, Wootton SA. Nutritional management in cystic fibrosis—an alternative perspective in gastrointestinal function. Disabil Rehabil. 1998;20:226–234.

    PubMed  CAS  Article  Google Scholar 

  38. Fridge JL, Conrad C, Gerson L, Castillo RO, Cox K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr. 2007;44:212–218.

    PubMed  Article  Google Scholar 

  39. Hoffman LR, Pope CE, Hayden HS, et al. Escherichia coli dysbiosis correlates with gastrointestinal dysfunction in children with cystic fibrosis. Clin Infect Dis. 2014;58:396–399.

    PubMed  PubMed Central  Article  Google Scholar 

  40. Bellin MD, Laguna T, Leschyshyn J, et al. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes. 2013;14:417–421.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  41. Hayes D Jr, McCoy KS, Sheikh SI. Resolution of cystic fibrosis-related diabetes with ivacaftor therapy. Am J Respir Crit Care Med. 2014;190:590–591.

    PubMed  Article  Google Scholar 

  42. Fogarty AW, Britton J, Clayton A, Smyth AR. Are measures of body habitus associated with mortality in cystic fibrosis? Chest. 2012;142:712–717.

    PubMed  Article  Google Scholar 

Download references

Grant Support

This study was sponsored by Vertex Pharmaceuticals Incorporated.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Drucy Borowitz.

Ethics declarations

Conflict of interest

Barry Lubarsky is an employee of Vertex Pharmaceuticals Incorporated and may own stock or stock options in the company.

Disclosures

No honoraria or other forms of payment were made for authorship of this article. Editorial assistance for this manuscript was provided by Peloton Advantage, Parsippany, NJ, and was funded by Vertex Pharmaceuticals Incorporated.

Ethical Standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. As this was a post hoc analysis, no formal patient consent is required.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Borowitz, D., Lubarsky, B., Wilschanski, M. et al. Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor. Dig Dis Sci 61, 198–207 (2016). https://doi.org/10.1007/s10620-015-3834-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-015-3834-2

Keywords

  • Weight gain
  • Growth
  • Cystic fibrosis transmembrane conductance regulator
  • Potentiator
  • Bicarbonate
  • Kalydeco