Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in 6- to 11-Year-Olds with Cystic Fibrosis: An Observational Study

Abstract Rationale Elexacaftor/tezacaftor/ivacaftor (ETI) provided substantial health benefits to children with cystic fibrosis (CF) in clinical trials; there is less information about its effectiveness in a “real world” setting. Objectives The aim of the PROMISE (A Prospective Study to Evaluate Biological and Clinical Effects of Significantly Corrected CFTR Function) Pediatric substudy is to determine the long-term (four years) impact of clinically prescribed ETI among children 6–11 years of age at enrollment. The primary outcome measure is the lung clearance index at a 2.5% (LCI2.5). Methods The PROMISE Pediatric substudy enrolled children with CF 6 to 12 years of age starting ETI. Outcomes measured at baseline (before ETI) and 1, 3, 6, and 12 months after ETI initiation included LCI2.5, percentage predicted forced expiratory volume in 1 second, Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain symptom score, height, weight, oropharyngeal cultures, and culture and deoxyribonucleic acid–based analysis of sputum microbiology (when sputum was available). Sweat chloride was assessed at baseline and at 1 and 6 months. Results One hundred twenty-five participants were enrolled at 20 U.S. CF centers. Lung function improvement after ETI initiation was rapid and sustained through 12 months, with a mean decrease in LCI2.5 of −0.79 (95% confidence interval CI, −1.04 to 0.55) and a mean increase in percentage predicted forced expiratory volume in 1 second of 5.6% (95% CI, 3.4% to 7.7%). Respiratory symptoms also diminished significantly (mean change in CFQ-R respiratory domain symptom score, 4.1 95% CI, 1.94 to 6.24). Sweat chloride decreased significantly at 6 months (mean change, −47.2 mmol/L 95% CI, −51.99 to −43.8 mmol/L). Weight, body mass index, and height z-scores were not different from baseline at 12 months. Staphylococcus aureus prevalence in oropharyngeal or sputum cultures did not change, but its density in sputum cultures decreased a mean of 1.47 log10 colony-forming units/g (95% CI, −2.37 to −0.58 colony-forming units/g) at 12 months. Conclusions Initiation of ETI in a real-world setting was associated with clinically significant improvements in lung function and symptoms and decreased S. aureus sputum density at one year; lung function improvements were smaller than those reported in clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT 04038047).