Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events.

Abstract

BACKGROUND:

Increased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV1) of <40%. We evaluated the safety, tolerability, and efficacy of tezacaftor/ivacaftor in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.

METHODS:

Participants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.

RESULTS:

Of 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV1 at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV1 from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.

CONCLUSIONS:

Tezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.

• Authors: Carsten Schwarz, Sivagurunathan Sutharsan, Ralph Epaud, Ross C Klingsberg, Rainald Fischer, Steven M Rowe, Paul K Audhya, Neil Ahluwalia, Xiaojun You, Thomas J Ferro, Margaret E Duncan, Bote G Bruinsma
• Journal: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society (J Cyst Fibros) Vol. 20 Issue 2 Pg. 228-233 (03 2021) ISSN: 1873-5010 [Electronic] Netherlands
• PMID: 32586736 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Aminophenols
• Aminopyridines
• Benzodioxoles
• Chloride Channel Agonists
• Drug Combinations
• Indoles
• Quinolones
• lumacaftor, ivacaftor drug combination
• tezacaftor, ivacaftor drug combination
• Cystic Fibrosis Transmembrane Conductance Regulator

Topics

• Adolescent
• Adult
• Aminophenols (adverse effects, therapeutic use)
• Aminopyridines (adverse effects)
• Benzodioxoles (adverse effects, therapeutic use)
• Chloride Channel Agonists (adverse effects, therapeutic use)
• Cystic Fibrosis (drug therapy, genetics, physiopathology)
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics)
• Double-Blind Method
• Drug Combinations
• Female
• Humans
• Indoles (therapeutic use)
• Male
• Quinolones (adverse effects, therapeutic use)
• Respiratory Function Tests