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@article{Kerem:2020:10.1513/AnnalsATS.202006-659OC,
author = {Kerem, E and Cohen-Cymberknoh, M and Tsabari, R and Wilschanski, M and Reiter, J and Shoseyov, D and Gileles-Hillel, A and Pugatsch, T and Davies, JC and Short, C and Saunders, C and DeSouza, C and Sullivan, JC and Doyle, JR and Chandarana, K and Kinnman, N},
doi = {10.1513/AnnalsATS.202006-659OC},
journal = {Annals of the American Thoracic Society},
pages = {433--441},
title = {Ivacaftor in people with cystic fibrosis and a 3849+10kb C →T or D1152H residual function mutation.},
url = {http://dx.doi.org/10.1513/AnnalsATS.202006-659OC},
volume = {18},
year = {2020}
}

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TY  - JOUR
AB  - Rationale: Ivacaftor's clinical effects in the residual function mutations 3849+10kb C →T and D1152H warrant further characterization. Objectives: Evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with 3849+10kb C→T or D1152H residual function mutations; 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 vs placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor's known safety profile. Dose-dependent swelling was observed in 23/25 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 vs 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 (NCT0306831
AU  - Kerem,E
AU  - Cohen-Cymberknoh,M
AU  - Tsabari,R
AU  - Wilschanski,M
AU  - Reiter,J
AU  - Shoseyov,D
AU  - Gileles-Hillel,A
AU  - Pugatsch,T
AU  - Davies,JC
AU  - Short,C
AU  - Saunders,C
AU  - DeSouza,C
AU  - Sullivan,JC
AU  - Doyle,JR
AU  - Chandarana,K
AU  - Kinnman,N
DO  - 10.1513/AnnalsATS.202006-659OC
EP  - 441
PY  - 2020///
SN  - 1546-3222
SP  - 433
TI  - Ivacaftor in people with cystic fibrosis and a 3849+10kb C →T or D1152H residual function mutation.
T2  - Annals of the American Thoracic Society
UR  - http://dx.doi.org/10.1513/AnnalsATS.202006-659OC
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33095038
UR  - https://www.atsjournals.org/doi/10.1513/AnnalsATS.202006-659OC
UR  - http://hdl.handle.net/10044/1/86158
VL  - 18
ER  -

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