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Clinical Trial
. 2017 Apr 1;195(7):912-920.
doi: 10.1164/rccm.201608-1754OC.

Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR

Carlos E Milla  1 , Felix Ratjen  2 , Gautham Marigowda  3 , Fang Liu  3 , David Waltz  3 , Margaret Rosenfeld  4   5 ; VX13-809-011 Part B Investigator Group *
Affiliations
Clinical Trial

Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR

Carlos E Milla et al. Am J Respir Crit Care Med. .

Abstract

Rationale: Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients.

Objectives: In this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis who were homozygous for F508del-CFTR.

Methods: Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications.

Measurements and main results: Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV1 were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], -0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P < 0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (-0.88; 95% CI, -1.40 to -0.37; P = 0.0018).

Conclusions: Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT01897233).

Keywords: cystic fibrosis transmembrane conductance regulator protein; ivacaftor; lumacaftor; lung clearance index; sweat test.

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Figures

Figure 1.
Figure 1.
Patient disposition and trial profile. *One subject not homozygous for F508del-CFTR was enrolled; this subject was discontinued from treatment after Day 18 and then from the study. IVA = ivacaftor; LUM = lumacaftor; q12h = every 12 h.
Figure 2.
Figure 2.
Absolute change from baseline in percent predicted FEV1. Raw summary statistics (unadjusted for mixed-effects models for repeated measures covariates) are shown for absolute change from baseline at study visits and Week 26 follow-up visit. CI = confidence interval.
Figure 3.
Figure 3.
Absolute change from baseline in sweat chloride. Raw summary statistics (unadjusted for mixed-effects models for repeated measures covariates) are shown for absolute change from baseline at study visits and Week 26 follow-up visit. Decrease in sweat chloride indicates improvement. CI = confidence interval.
Figure 4.
Figure 4.
Absolute change from baseline in (A) BMI and (B) BMI z scores. Raw summary statistics (unadjusted for mixed-effects models for repeated measures covariates) are shown for absolute change from baseline at study visits and Week 26 follow-up visit. BMI = body mass index; CI = confidence interval.
Figure 5.
Figure 5.
Absolute change from baseline in CFQ-R respiratory domain scores. Raw summary statistics (unadjusted for mixed-effects models for repeated measures covariates) are shown for absolute change from baseline at study visits and Week 26 follow-up visit. Increase in CFQ-R score indicates improvement. CFQ-R = Cystic Fibrosis Questionnaire-Revised; CI = confidence interval.
Figure 6.
Figure 6.
Absolute change from baseline in LCI2.5. Raw summary statistics (unadjusted for mixed-effects models for repeated measures covariates) are shown for absolute change from baseline at study visits and Week 26 follow-up visit. Decrease in LCI2.5 indicates improvement. CI = confidence interval; LCI2.5 = lung clearance index (lung volume turnover required to reach 2.5% of starting N2 concentration).
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References

    1. Clinical and Functional Translation of CFTR (CFTR2)[accessed 2016 July 6]. Available from: http://cftr2.org/index.php
    1. European Cystic Fibrosis Society. Karup, Denmark: European Cystic Fibrosis Society; 2016. ECFSPR Patient Registry: 2013 annual report (version 2)
    1. Cystic Fibrosis Canada. Toronto, ON, Canada: Cystic Fibrosis Canada; 2015. Canadian Cystic Fibrosis Registry: 2013 annual report.
    1. Cystic Fibrosis Foundation. Bethesda, MD: Cystic Fibrosis Foundation; 2015. Cystic Fibrosis Foundation Patient Registry: 2014 annual data report.
    1. VanDevanter DR, Kahle JS, O’Sullivan AK, Sikirica S, Hodgkins PS. Cystic fibrosis in young children: a review of disease manifestation, progression, and response to early treatment. J Cyst Fibros. 2016;15:147–157. - PubMed

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