Growth in Prepubertal Children With Cystic Fibrosis Treated With Ivacaftor

Abstract

BACKGROUND AND OBJECTIVES Cystic fibrosis (CF) is known for its impact on the lung and pancreas of affected individuals; however, impaired growth is also a common complication. We hypothesized that targeting the biological defect in the CF transmembrane conductance regulator (CFTR) protein may impact growth outcomes. METHODS In this post hoc analysis, we assessed linear growth and weight in 83 children (aged 6–11) enrolled in 2 clinical trials, the longitudinal-observation GOAL study and the placebo-controlled ENVISION study, to evaluate the effects of ivacaftor, a CFTR potentiator. We calculated height and weight z scores and height and weight growth velocities (GVs). RESULTS In ivacaftor-treated children in GOAL, height and weight z scores increased significantly from baseline to 6 months (increases of 0.1 [P < .05] and 0.26 [P < .0001], respectively); height GV increased significantly from 3 to 6 months (2.10 cm/y increase [P < .01]). In ivacaftor-treated children in ENVISION, height and weight z scores increased significantly from baseline to 48 weeks (increases of 0.17 [P < .001] and 0.35 [P < .001], respectively). Height and weight GVs from baseline to 48 weeks were also significantly higher with ivacaftor than with placebo (differences of 1.08 cm/y [P < .05] and 3.11 kg/y [P < .001], respectively). CONCLUSIONS Ivacaftor treatment in prepubescent children may help to address short stature and altered GV in children with CF; results from these analyses support the existence of an intrinsic defect in the growth of children with CF that may be ameliorated by CFTR modulation.

Reduced bone length, growth plate thickness, bone content, and IGF-I as a model for poor growth in the CFTR-deficient rat

“…The 2015 CFF Annual Data Report implies that reduced growth is CFTR mutation class dependent—subsequently CFTR activity—and is not necessarily related to weight [ 1 ]. Most recently, children with the G551D CFTR genotype demonstrated improved height z-scores and weight z-scores, as well as height and weight growth velocities, when treated with ivacaftor, a CFTR potentiator, which strongly suggests a CFTR dependence to these findings [ 19 ].…”

Cystic fibrosis year in review 2017

“…Ivacaftor was evaluated for expanded CFTR mutations in small series . Effects of ivacaftor treatment in the GOAL (G551D observation Study) and ENVISION studies included increases in height, weight, and growth velocities, suggesting that ivacaftor use in prepubertal children may reduce short stature and altered growth velocity . Other effects of ivacaftor included reduction in reflux symptoms as assessed by questionnaires completed in 12 patients with the G551D mutation before and after ivacaftor treatment .…”

GH-IGF-1 Axis in Children with Cystic Fibrosis

“…2,6,7 The exact mechanisms of this effect are not known, although it is generally thought to be caused by concomitant severe disease complications due to the inflammation itself, as well as prolonged use of glucocorticoids and suboptimal nutrition. [8][9][10] Moreover, an important correlation has been found between poor growth and reduced long-term lung function in children with CF. 11 The growth hormone insulin-like growth factor (GH-IGF) axis is the most important endocrine axis involved in linear growth in children and adolescents.…”

“…In fact, IGF-I signaling is mediated by CFTR, and consequently CFTR dysfunction may impact linear growth, adding to indirect effects due to malnutrition. 10,11 Furthermore, IGF-I plays an important role in inflammation and, in turn, is related to lung function and nutritional status in CF.…”