Fila Libor, Grandcourtova Alzbeta, Bilkova Alena, Drevinek Pavel
Department of Pneumology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.
Department of Medical Microbiology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.
Front Pharmacol. 2023 Jun 2;14:1178009. doi: 10.3389/fphar.2023.1178009. eCollection 2023.
Seminal clinical trials with the triple combination of elexacaftor-tezacaftor-ivacaftor (ETI) demonstrated clinical efficacy in people with cystic fibrosis (pwCF) who carry at least one F508del mutation. However, due to exclusion criteria of these clinical trials, the effect of ETI was not studied in a substantial number of pwCF. Thus, we ran a single center trial to evaluate a clinical efficacy of ETI treatment in adult pwCF who were ineligible for enrollment in registration studies. PwCF on ETI with prior lumacaftor-ivacaftor therapy, severe airway obstruction, well-preserved lung function, or with airway infection with pathogens at risk of more rapid decline in lung function formed the study group, while all the others on ETI formed the control group. Lung function, nutritional status and sweat chloride concentration were assessed before and after initialization of ETI therapy over a 6-month period. Approximately a half of the ETI-treated pwCF at the adult Prague CF center (49 of 96) were assigned to the study group. Their mean changes in body mass index ( + 1.04 kg/m) and in sweat chloride concentration (-48.4 mmol/L) were similar to the control group ( + 1.02 kg/m; -49.7 mmol/L), while the mean change in percent predicted forced expiratory volume in 1 s (ppFEV; + 10.3 points) was significantly lower than in the control group ( + 15.8 points) ( = 0.0015). In the subgroup analysis, pwCF with severe airway obstruction (ppFEV <40) and pwCF with well-preserved lung function (ppFEV >90) showed a less potential for improvement in lung function during the ETI treatment than controls (median change in ppFEV + 4.9 points and + 9.5 points, respectively). PwCF not eligible for inclusion in clinical trials demonstrated improvement in lung function and nutritional status following the initiation of treatment with the ETI combination. Moderate increase in ppFEV was observed in those with severe airway obstruction or well-preserved lung function.
依列卡福妥-替扎卡福妥-依伐卡福妥（ETI）三联疗法的开创性临床试验证明，对于携带至少一个F508del突变的囊性纤维化患者（pwCF）具有临床疗效。然而，由于这些临床试验的排除标准，大量pwCF未被纳入研究ETI的疗效。因此，我们开展了一项单中心试验，以评估ETI治疗对不符合注册研究入组条件的成年pwCF的临床疗效。接受过鲁马卡福妥-依伐卡福妥治疗、有严重气道阻塞、肺功能良好或有肺部感染且感染病原体有肺功能快速下降风险的ETI治疗的pwCF组成研究组，而其他所有接受ETI治疗的pwCF组成对照组。在ETI治疗开始后的6个月内，评估肺功能、营养状况和汗液氯化物浓度。在布拉格成人CF中心接受ETI治疗的pwCF中，约一半（96例中的49例）被分配到研究组。他们的体重指数平均变化（+1.04kg/m）和汗液氯化物浓度平均变化（-48.4mmol/L）与对照组相似（+1.02kg/m；-49.7mmol/L），而1秒用力呼气容积预测值百分比（ppFEV）的平均变化（+10.3个百分点）显著低于对照组（+15.8个百分点）（P=0.0015）。在亚组分析中，有严重气道阻塞（ppFEV<40）的pwCF和肺功能良好（ppFEV>90）的pwCF在ETI治疗期间肺功能改善的潜力低于对照组（ppFEV的中位变化分别为+4.9个百分点和+9.5个百分点）。不符合临床试验入组条件的pwCF在开始ETI联合治疗后肺功能和营养状况有所改善。在有严重气道阻塞或肺功能良好的患者中观察到ppFEV有适度增加。
