A Systematic Review (SR) and Network Meta-Analysis (NMA) of Cystic Fibrosis Transmembrane Conductance Receptor (CFTR) Modulator Therapies and Established Clinical Management (ECM) Using Percent Predicted Forced Expiratory Volume in One Second...
Author(s)
Victoria Wakefield, MBChB, Kate Ennis, MSc, Steve Edwards, BSc, MSc, DPhil, Benjamin Farrar, MA, PhD.
Technology Assessment Group, BMJ Group, London, United Kingdom.
Technology Assessment Group, BMJ Group, London, United Kingdom.
OBJECTIVES: This research aimed to assess the effectiveness of elexacafor/tezacaftor/ivacaftor (ELX/TEZ/IVA), lumacaftor/ivacaftor (LUM/IVA) and tezacaftor/ivacaftor (TEZ/IVA) compared to each other and ECM.
METHODS: An SR was conducted to identify relevant studies assessing the acute effects of CFTR modulators on ppFEV1. The following bibliographic databases were searched: MEDLINE, Embase, CENTRAL (from inception to 2023), health technology assessment body websites, conference proceedings and clinical trial registries (grey literature searched from 2018 to 2023). Bayesian NMAs were conducted in R using four chains with results based on 100,000 iterations after a “burn in” of 10,000 iterations. The NMA was conducted using fixed effect (FE) and random effects (RE), with the final model chosen based on the lowest deviance information criterion (DIC). Convergence was assessed by visually assessing the convergence of the shrink factor towards one in Brooks-Gelman-Rubin diagnostic plots.
RESULTS: Nineteen primary RCTs and seven associated open-label extension studies were included. Results of the FE NMAs were preferred either due to having a lower DIC in the homozygous F508del (F/F) genotype analysis (6.2 FE vs 8.0 RE), or due to the RE model producing implausibly wide credible intervals in the F/Gating genotype analysis. In the most common genotype (F/F), in people 12+ years, CFTR modulators were associated with a statistically significant increase in ppFEV1 compared to placebo: ELX/TEZ/IVA 10.20 (95% Credible Interval [95% CrI]: 8.25 to 12.16), LUM/IVA 2.83 (95% CrI: 1.84 to 3.81), and TEZ/IVA 4.00 (95% CrI: 3.15 to 4.85). A similar pattern of relative effectiveness was seen across all other genotypes assessed, with the smallest effect in F/RF.
CONCLUSIONS: CFTR modulators lead to acute improvements in ppFEV1 for people with CF. The magnitude of this improvement is considerably larger for ELX/TEZ/IVA. While there is a strong evidence base for the acute improvements, modelling long-term changes in ppFEV1 decline following CFTR modulator therapy remains challenging.
METHODS: An SR was conducted to identify relevant studies assessing the acute effects of CFTR modulators on ppFEV1. The following bibliographic databases were searched: MEDLINE, Embase, CENTRAL (from inception to 2023), health technology assessment body websites, conference proceedings and clinical trial registries (grey literature searched from 2018 to 2023). Bayesian NMAs were conducted in R using four chains with results based on 100,000 iterations after a “burn in” of 10,000 iterations. The NMA was conducted using fixed effect (FE) and random effects (RE), with the final model chosen based on the lowest deviance information criterion (DIC). Convergence was assessed by visually assessing the convergence of the shrink factor towards one in Brooks-Gelman-Rubin diagnostic plots.
RESULTS: Nineteen primary RCTs and seven associated open-label extension studies were included. Results of the FE NMAs were preferred either due to having a lower DIC in the homozygous F508del (F/F) genotype analysis (6.2 FE vs 8.0 RE), or due to the RE model producing implausibly wide credible intervals in the F/Gating genotype analysis. In the most common genotype (F/F), in people 12+ years, CFTR modulators were associated with a statistically significant increase in ppFEV1 compared to placebo: ELX/TEZ/IVA 10.20 (95% Credible Interval [95% CrI]: 8.25 to 12.16), LUM/IVA 2.83 (95% CrI: 1.84 to 3.81), and TEZ/IVA 4.00 (95% CrI: 3.15 to 4.85). A similar pattern of relative effectiveness was seen across all other genotypes assessed, with the smallest effect in F/RF.
CONCLUSIONS: CFTR modulators lead to acute improvements in ppFEV1 for people with CF. The magnitude of this improvement is considerably larger for ELX/TEZ/IVA. While there is a strong evidence base for the acute improvements, modelling long-term changes in ppFEV1 decline following CFTR modulator therapy remains challenging.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
CO4
Topic
Clinical Outcomes
Topic Subcategory
Comparative Effectiveness or Efficacy
Disease
Respiratory-Related Disorders (Allergy, Asthma, Smoking, Other Respiratory)