Abstract
Objectives
CFTR modulators like ivacaftor have revolutionised cystic fibrosis (CF) management by partially restoring CFTR function, showing marked short-term benefits in clinical trials. However, as these therapies become the standard of care, controlling for a real-world long-term evaluation is difficult, limiting traditional between-subject analyses. This study compares within-subject and between-subject analyses without contemporary controls to evaluate the long-term effectiveness of ivacaftor in preserving lung function.
Methods
This retrospective cohort study used data from the US CF Foundation Patient Registry (2003–2016). We evaluated the 6-year effectiveness of ivacaftor in ppFEV1 through: (i) within-subject comparisons of ppFEV1 before and after ivacaftor initiation and (ii) comparisons between ivacaftor-treated and untreated individuals with similar disease pathology.
Results
We modelled data from 560 ivacaftor-treated individuals with the G551D variant. For between-subject comparisons, we used propensity scores to match the treated group with 2,800 untreated F508del homozygous individuals. Results showed an initial improvement in ppFEV1, followed by a slower decline in adults. Within-subject analysis estimated an initial improvement ranging from 3.50 to 5.58 (95% confidence interval [CI]), with a change in the annual rate of decline from -0.33 to 0.77 (95% CI). The within- and between-subject comparisons were broadly consistent, although small differences highlight the influence of underlying assumptions, particularly for younger individuals.
Conclusion
Ivacaftor was associated with improved ppFEV1 across all age groups, with the magnitude of improvement approximately 50% of that observed in clinical trials. The results support the use of within-subject analysis in future modulator effectiveness studies, but caution is advised in younger individuals due to developmental changes that may affect pre- and post-treatment comparability.
CFTR modulators like ivacaftor have revolutionised cystic fibrosis (CF) management by partially restoring CFTR function, showing marked short-term benefits in clinical trials. However, as these therapies become the standard of care, controlling for a real-world long-term evaluation is difficult, limiting traditional between-subject analyses. This study compares within-subject and between-subject analyses without contemporary controls to evaluate the long-term effectiveness of ivacaftor in preserving lung function.
Methods
This retrospective cohort study used data from the US CF Foundation Patient Registry (2003–2016). We evaluated the 6-year effectiveness of ivacaftor in ppFEV1 through: (i) within-subject comparisons of ppFEV1 before and after ivacaftor initiation and (ii) comparisons between ivacaftor-treated and untreated individuals with similar disease pathology.
Results
We modelled data from 560 ivacaftor-treated individuals with the G551D variant. For between-subject comparisons, we used propensity scores to match the treated group with 2,800 untreated F508del homozygous individuals. Results showed an initial improvement in ppFEV1, followed by a slower decline in adults. Within-subject analysis estimated an initial improvement ranging from 3.50 to 5.58 (95% confidence interval [CI]), with a change in the annual rate of decline from -0.33 to 0.77 (95% CI). The within- and between-subject comparisons were broadly consistent, although small differences highlight the influence of underlying assumptions, particularly for younger individuals.
Conclusion
Ivacaftor was associated with improved ppFEV1 across all age groups, with the magnitude of improvement approximately 50% of that observed in clinical trials. The results support the use of within-subject analysis in future modulator effectiveness studies, but caution is advised in younger individuals due to developmental changes that may affect pre- and post-treatment comparability.
| Original language | English |
|---|---|
| Pages (from-to) | S41-S42 |
| Journal | Journal of Cystic Fibrosis |
| Volume | 24 |
| Issue number | Suppl. 1 |
| DOIs | |
| Publication status | Published - Jun 2025 |