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Clinical Trial
. 2021 Jan;18(1):75-83.
doi: 10.1513/AnnalsATS.202002-144OC.

Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical Trial

Scott D Sagel  1 , Umer Khan  2 , Sonya L Heltshe  2   3 , John P Clancy  4   5 , Drucy Borowitz  6 , Daniel Gelfond  7 , Scott H Donaldson  8 , Antoinette Moran  9 , Felix Ratjen  10 , Jill M VanDalfsen  2 , Steven M Rowe  11
Affiliations
Clinical Trial

Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical Trial

Scott D Sagel et al. Ann Am Thorac Soc. 2021 Jan.

Abstract

Rationale: The combination of lumacaftor (LUM) and ivacaftor (IVA) is an approved CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator treatment for homozygous F508del patients with CF.Objectives: To evaluate the effectiveness of LUM/IVA in children (6 yr or more) and adults (more than 18 yr) in a postapproval setting.Methods: This longitudinal cohort study, performed at 38 centers in the U.S. CF Therapeutics Development Network, enrolled homozygous F508del patients with CF ages 6 years old and older with no prior exposure to LUM/IVA. Study assessments were performed at baseline and at 1, 3, 6, and 12 months after LUM/IVA initiation.Results: A total of 193 patients initiated LUM/IVA, and 85% completed the study through 1 year. Baseline mean percent-predicted forced expiratory volume in 1 second (ppFEV1) was 85 (standard deviation, 22.4) in this cohort. No statistically significant change in ppFEV1 was observed from baseline to any of the follow-up time points, with a mean absolute change at 12 months of -0.3 (95% confidence interval [CI], -1.8 to 1.2). Body mass index improved from baseline to 12 months (mean change, 0.8 kg/m2; P < 0.001). Sweat chloride decreased from baseline to 1 month (mean change, -18.5 mmol/L; 95% CI, -20.7 to -16.3; P < 0.001), and these reductions were sustained through the study period. There were no significant changes in hospitalization rate for pulmonary exacerbations and Pseudomonas aeruginosa infection status with treatment.Conclusions: In this real-world multicenter cohort of children and adults, LUM/IVA treatment was associated with significant improvements in growth and reductions in sweat chloride without statistically significant or clinically meaningful changes in lung function, hospitalization rates, or P. aeruginosa infection.Clinical trial registered with www.clinicaltrials.gov (NCT02477319).

Keywords: clinical effectiveness; cystic fibrosis; ivacaftor; lumacaftor; postapproval study.

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Figures

Figure 1.
Figure 1.
Consolidated Standards of Reporting Trials diagram of the study participants. IVA = ivacaftor; LUM = lumacaftor; NTM = nontuberculous mycobacteria; Resp. = respiratory.
Figure 2.
Figure 2.
Mean absolute change from baseline in clinical measures at 1, 3, 6, and 12 months after initiation of lumacaftor/ivacaftor. The bars represent the 95% confidence intervals. (A) Sweat chloride (in mmol/L). (B) ppFEV1. (C) FEV1 (in liters). (D) Body mass index (BMI) percentile (n = 125 subjects < 20 yr of age). (E) BMI (in kg/m2) (n = 68 subjects ≥ 20 yr of age). FEV1 = forced expiratory volume in 1 second; ppFEV1 = percent-predicted FEV1; SwtCl = sweat chloride.
Figure 3.
Figure 3.
Distribution of SwtCl at 6 months plotted against absolute change from baseline after initiation of lumacaftor/ivacaftor. SwtCl = sweat chloride.
Figure 4.
Figure 4.
One-month change in percent-predicted forced expiratory volume in 1 second (ppFEV1) versus 1-month change in sweat chloride (SwtCl; mmol/L). The gray dashed line represents the following model fit: 1-month change in sweat chloride, ∼ 1-month change ppFEV1 + age category. The 1-month change in SwtCl (i.e., slope estimate) corresponding to a 1% increase in ppFEV1 was +0.15 (95% confidence interval, −0.13 to 0.42) mmol/L.
Figure 5.
Figure 5.
Hospitalizations for pulmonary exacerbation and P. aeruginosa culture positivity in the 1 year before and after initiation of lumacaftor/ivacaftor (in 6-mo intervals). P values are based on paired data (i.e., data available in each 6-mo interval before and after lumacaftor/ivacaftor). IVA = ivacaftor; LUM = lumacaftor; Pa = Pseudomonas aeruginosa.
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Comment in

  • The PROSPECT Is Bright for CFTR Modulators.
    Montemayor K, Lechtzin N. Montemayor K, et al. Ann Am Thorac Soc. 2021 Jan;18(1):32-33. doi: 10.1513/AnnalsATS.202007-881ED. Ann Am Thorac Soc. 2021. PMID: 33385230 Free PMC article. No abstract available.

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