Advertisement

Digestive Diseases and Sciences

, Volume 61, Issue 1, pp 198–207 | Cite as

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

  • Drucy Borowitz
  • Barry Lubarsky
  • Michael Wilschanski
  • Anne Munck
  • Daniel Gelfond
  • Frank Bodewes
  • Sarah Jane Schwarzenberg
Original Article

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.

Keywords

Weight gain Growth Cystic fibrosis transmembrane conductance regulator Potentiator Bicarbonate Kalydeco 

Notes

Grant Support

This study was sponsored by Vertex Pharmaceuticals Incorporated.

Compliance with Ethical Standards

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.

References

  1. 1.
    O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1891–1904.PubMedCrossRefGoogle Scholar
  2. 2.
    Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992–2001.PubMedCrossRefGoogle Scholar
  3. 3.
    Cystic Fibrosis Registry of Ireland 2012 Annual Report. Dublin, Ireland: Cystic Fibrosis Registry of Ireland; 2014.Google Scholar
  4. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 10.
    Sproul A, Huang N. Growth patterns in children with cystic fibrosis. J Pediatr. 1964;65:664–676.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 18.
    Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet. 2008;372:415–417.PubMedCrossRefGoogle Scholar
  19. 19.
    Clarke LL, Harline MC. Dual role of CFTR in cAMP-stimulated. Am J Physiol. 1998;274:G718–G726.PubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 21.
    Smith JJ, Welsh MJ. cAMP stimulates bicarbonate secretion across normal, but not cystic fibrosis airway epithelia. J Clin Invest. 1992;89:1148–1153.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Li L, Somerset S. Digestive system dysfunction in cystic fibrosis: challenges for nutrition therapy. Dig Liver Dis. 2014;46:865–874.PubMedCrossRefGoogle Scholar
  23. 23.
    Weber AM, Roy CC. Intraduodenal events in cystic fibrosis. J Pediatr Gastroenterol Nutr. 1984;3:S113–S119.PubMedCrossRefGoogle Scholar
  24. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 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. 26.
    Lai Y, Gallo RL. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 2009;30:131–141.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Durie PR, Forstner GG. Pathophysiology of the exocrine pancreas in cystic fibrosis. J R Soc Med. 1989;82:2–10.PubMedPubMedCentralGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 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.Google Scholar
  33. 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.PubMedGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 35.
    De Lisle RC, Borowitz D. The cystic fibrosis intestine. Cold Spring Harb Perspect Med. 2013;3:a009753.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 37.
    Murphy JL, Wootton SA. Nutritional management in cystic fibrosis—an alternative perspective in gastrointestinal function. Disabil Rehabil. 1998;20:226–234.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Drucy Borowitz
    • 1
  • Barry Lubarsky
    • 2
  • Michael Wilschanski
    • 3
  • Anne Munck
    • 4
  • Daniel Gelfond
    • 5
  • Frank Bodewes
    • 6
  • Sarah Jane Schwarzenberg
    • 7
  1. 1.Department of PediatricsUniversity at Buffalo, State University of New York, Women and Children’s Hospital of BuffaloBuffaloUSA
  2. 2.Department of Medical AffairsVertex Pharmaceuticals IncorporatedBostonUSA
  3. 3.Department of PediatricsHadassah University HospitalJerusalemIsrael
  4. 4.Assistance publique-Hôpitaux de Paris, Hôpital Robert Debré, Paediatric Gastroenterology and Respiratory DepartmentCF CenterParisFrance
  5. 5.Department of Pediatrics, Gastroenterology/Nutrition (SMD)University of RochesterRochesterUSA
  6. 6.Department of PediatricsBeatrix Children’s HospitalGroningenThe Netherlands
  7. 7.Division of Pediatric GastroenterologyUniversity of MinnesotaMinneapolisUSA

Personalised recommendations