TY - JOUR
T1 - Icenticaftor, a CFTR Potentiator, in COPD
T2 - A Multicenter, Parallel-Group, Double-Blind Clinical Trial
AU - Martinez, Fernando J
AU - Criner, Gerard J
AU - Gessner, Christian
AU - Jandl, Margret
AU - Scherbovsky, Fernando
AU - Shinkai, Masaharu
AU - Siler, Thomas M
AU - Vogelmeier, Claus F
AU - Voves, Robert
AU - Wedzicha, Jadwiga A
AU - Bartels, Christian
AU - Bottoli, Ivan
AU - Byiers, Stuart
AU - Cardenas, Pamela
AU - Eckert, Joerg H
AU - Gutzwiller, Florian S
AU - Knorr, Barbara
AU - Kothari, Mahavir
AU - Parlikar, Rutvick
AU - Tanase, Ana-Maria
AU - Franssen, Frits M E
PY - 2023/8/15
Y1 - 2023/8/15
N2 - CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25?mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV after 12?weeks. Secondary endpoints included change from baseline in trough FEV and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24?weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24?weeks were assessed in exploratory and analyses, respectively. Nine hundred seventy-four patients were randomized. After 12?weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24?weeks for trough FEV , E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300?mg b.i.d. was consistently the most effective. Improvements for 300?mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. The primary endpoint was negative, as icenticaftor did not improve trough FEV over 12?weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV ; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24?weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).
AB - CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25?mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV after 12?weeks. Secondary endpoints included change from baseline in trough FEV and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24?weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24?weeks were assessed in exploratory and analyses, respectively. Nine hundred seventy-four patients were randomized. After 12?weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24?weeks for trough FEV , E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300?mg b.i.d. was consistently the most effective. Improvements for 300?mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. The primary endpoint was negative, as icenticaftor did not improve trough FEV over 12?weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV ; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24?weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).
KW - CFTR dysfunction
KW - CFTR potentiator
KW - COPD
KW - chronic bronchitis
KW - icenticaftor
KW - Humans
KW - Cystic Fibrosis Transmembrane Conductance Regulator/genetics
KW - Cough/drug therapy complications
KW - Pulmonary Disease, Chronic Obstructive
KW - Bronchitis, Chronic
KW - Double-Blind Method
KW - Forced Expiratory Volume
KW - Treatment Outcome
U2 - 10.1164/rccm.202303-0458OC
DO - 10.1164/rccm.202303-0458OC
M3 - Article
SN - 1073-449X
VL - 208
SP - 417
EP - 427
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 4
ER -