| Autor: |
Kerem, Eitan, Cohen-Cymberknoh, Malena, Tsabari, Reuven, Wilschanski, Michael, Reiter, Joel, Shoseyov, David, Gileles-Hillel, Alex, Pugatsch, Thea, Davies, Jane C., Short, Christopher, Saunders, Clare, DeSouza, Cynthia, Sullivan, James C., Doyle, Jamie R., Chandarana, Keval, Kinnman, Nils |
| Předmět: |
|
| Zdroj: |
Annals of the American Thoracic Society; Mar2021, Vol. 18 Issue 3, p433-441, 9p |
| Abstrakt: |
Rationale: Ivacaftor's clinical effects in the residual function mutations 3849 + 10kb C→T and D1152H warrant further characterization.Objectives: To evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with 3849 + 10kb C→T or D1152H residual function mutations and to explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor.Methods: Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and in vitro intestinal organoid-based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function.Results: Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index2.5 with ivacaftor versus placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor's known safety profile. Dose-dependent swelling was observed in 23 of 25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low.Conclusions: In people with cystic fibrosis aged ≥6 years with a 3849 + 10kb C→T or D1152H mutation, ivacaftor treatment improved clinical endpoints compared with placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations.Clinical trial registered with ClinicalTrials.gov (NCT03068312). [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
