| Autor: |
Stahl M; Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine and.; German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin, Berlin, Germany., Roehmel J; Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine and.; German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin, Berlin, Germany., Eichinger M; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.; Department of Diagnostic and Interventional Radiology and.; Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany., Doellinger F; Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Naehrlich L; Department of Pediatrics, Justus Liebig University Giessen, Giessen, Germany.; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany., Kopp MV; Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland.; Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany., Dittrich AM; Department for Pediatric Pulmonology, Allergology, and Neonatology, and.; BREATH, German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany., Sommerburg O; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.; Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, Heidelberg University Hospital, Heidelberg, Germany., Ray P; Vertex Pharmaceuticals Incorporated, Boston, Massachusetts; and., Maniktala A; Vertex Pharmaceuticals Incorporated, Boston, Massachusetts; and.; ICON plc, Global Strategic Solutions, Raleigh, North Carolina., Xu T; Vertex Pharmaceuticals Incorporated, Boston, Massachusetts; and., Conner S; Vertex Pharmaceuticals Incorporated, Boston, Massachusetts; and., Joshi A; Vertex Pharmaceuticals Incorporated, Boston, Massachusetts; and., Mascia M; Vertex Pharmaceuticals Incorporated, Boston, Massachusetts; and., Wielpütz MO; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.; Department of Diagnostic and Interventional Radiology and.; Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany., Mall MA; Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine and.; German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin, Berlin, Germany. |
| Abstrakt: |
Rationale: Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age. Objectives: To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2-5 years. Methods: This phase 2 trial had two parts: part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2-5 years (previously reported) was followed by a 48-week open-label treatment period in which all children received LUM/IVA (part 2; reported here). Endpoints assessed in part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at Week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z -scores at Week 96; lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (LCI 2.5 ) through Week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at Week 96; sweat chloride, amount of immunoreactive trypsinogen, fecal elastase-1 concentration, and fecal calprotectin through Week 96; and number of pulmonary exacerbations, time to first pulmonary exacerbation, and number of CF-related hospitalizations. Results: Forty-nine children received one or more doses of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group), with a mean exposure of 47.1 (standard deviation [SD], 5.2) weeks. The mean absolute change in MRI global score (negative value indicates improvement) from baseline at Week 96 was -2.7 (SD, 7.0; 95% confidence interval [CI], -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD, 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI 2.5 , sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment because of adverse events (distal intestinal obstruction syndrome [ n = 1] and alanine aminotransferase increase [ n = 1]). Conclusions: These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age. Clinical trial registered with ClinicalTrials.gov (NCT03625466). |
