Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in 6- to 11-Year-Olds with Cystic Fibrosis: An Observational Study
Jessica E. Pittman, Sarah J. Morgan, Morgan McCreary, Phuong T. Vu, Peter Jorth, Sonya L. Heltshe, Lucas R. Hoffman, Andrea Kelly, Scott D. Sagel, Pradeep K. Singh, George M. Solomon, Margaret Rosenfeld, Félix Ratjen
Abstract
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).