Efficacy and Safety of Triple Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Patients With Cystic Fibrosis: A Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Cystic fibrosis is a rare, recessive, progressive genetic disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Small molecules have recently been developed to treat the molecular consequences of CFTR mutations and restore CFTR protein function. However, the data on triple combination therapy (mainly from Vertex Pharmaceuticals, which is most tested in clinical trials) are limited. This meta-analysis was aimed to assess the efficacy and safety of this therapy according to different mutation genotypes and comparators.Methods: Relevant publications were identified through searching several medical databases before 31 December 2021. The primary outcomes of ppFEV1, sweat chloride concentration and Cystic Fibrosis Questionnaire-Revised (CFQ-R) score were pooled and analyzed. The secondary outcomes were adverse events in triple combination therapy.Results: Six randomized controlled trials were eligible for analysis. The total outcome of the ppFEV1 change was higher with triple combination therapy than triple placebo or active control (mean difference, MD, 13.6% and 8.74%, respectively). The pooled result of sweat chloride concentrations with triple combination therapy was lower than that of triple placebo or active control (MD, −44.13 and −39.26, respectively). The pooled estimate of the CFQ-R score was higher with triple combination therapy than triple placebo or active control (MD, 19.8% and 14.63%, respectively). No clear differences in adverse events were found between triple combination therapy and the control (placebo or active control).Conclusion: CFTR modulators in triple combination achieve better clinical results than placebo and active control, and result in comparable adverse events.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021293402, identifier PROSPERO 2021 CRD42021293402.

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis

“…Uma revisão sistemática anterior sobre a terapia tripla para pacientes com FC, também incluindo 6 estudos, encontrou resultados semelhantes. (24) No entanto, 1 dos estudos incluídos utilizou uma combinação diferente de moduladores (VX-659 em vez de elexacaftor, combinado com ivacaftor e tezacaftor), (25) Barry PJ et al (23) Heijerman HGM et al (14) Keating D et al (12) Keating D et al (12) Mall MA et al (16) Middleton PG et al (13) Sutharsan S et al (15) Total (95% CI) Heterogeneity: Tau 2 = 39.01, Chi 2 = 53.61, df = 6 (P < 0.00001); I 2 = 89% Test for overall effect: Z = 5.91 (P < 0.00001) -20 -10 0 10 20 Barry PJ et al (23) Heijerman HGM et al (14) Keating D et al (12) Keating D et al (12) Mall MA et al (16) Middleton PG et al (13) Sutharsan S et al (15) Total (95% CI) Heterogeneity: Tau 2 = 22.15, Chi 2 = 164.22, df = 6 (P < 0.00001); I 2 = 96% Test for overall effect: Z = 5.72 (P < 0.00001) -20 -10 0 10 20 Middleton PG et al (13) Sutharsan S et al (15) Total (95% CI) Heterogeneity: Chi 2 = 1.46, df = 1 (P = 0.23); I 2 = 32% Test for overall effect: Z = 11.91 (P < 0.00001) -20 -10 0 10 20 estudo de Mall et al, (16) publicado em 2022 e incluído em nosso estudo. A semelhança dos achados reforça a robustez dos dados que apoiam a efetividade clínica da terapia ETI.…”

“…A previous systematic review, also including 6 studies, about the triple therapy for CF patients found similar results. 24 However, 1 of the studies included used a different combination of modulators (VX-659 instead of elexacaftor, combined with ivacaftor and tezacaftor), 25 and because the search was limited to December of 2021, it did not include the study by Mall et al, 16 published in 2022 and included in our study. The similarity of the findings reinforces the robustness of data supporting the clinical effectiveness of ETI therapy.…”

Triterapia con moduladores de la proteína de conductancia de transmembrana en fibrosis quística

“…Hasta la fecha no hay recomendaciones respecto a la duración de la triterapia, pero probablemente no debiera ser un periodo inferior a 6 meses como lo han demostrado los estudios de eficacia y seguridad en niños y adultos 23 . Conocemos sólo un estudio realizado en adultos mayores de 20 años homocigotos para la mutación ∆F508 de la FQ que recientemente ha completado un seguimiento anual con buen perfil de eficacia y seguridad 24 .…”

α-Tocopherol Pharmacokinetics in Adults with Cystic Fibrosis: Benefits of Supplemental Vitamin C Administration

“…Several limitations to the scope of the present study in a small number of CF participants should be mentioned. Most CF patients are now on revolutionary CFTR potentiator and/or corrector therapies and these are likely to exert impacts on vitamin E pharmacokinetic via potential effects on bile and pancreatic secretions, enterocyte functions and modulations of the intensity of RT inflammatory processes [78][79][80][81][82][83][84][85]. No attempts were made in the present study to relate plasma tocopherol kinetics to either parameters of RT or systemic inflammation/oxidative stress or to acute or chronic CF exacerbations.…”