Rationale
CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms.
Objectives
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.
Methods
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
1
after 12 weeks. Secondary endpoints included change from baseline in trough FEV
1
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
post hoc
analyses, respectively.
Measurements and Main Results
Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose–response relationship for change from baseline in trough FEV
1
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
1
, 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.
Conclusions
The primary endpoint was negative, as icenticaftor did not improve trough FEV
1
over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV
1
; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks.
Clinical trial registered with
www.clinicaltrials.gov
(NCT 04072887).
Although evidence exists of the potential impact of stress, co-incident with corrosive environments at high temperature, for single crystal turbine blades, the mechanism responsible is not fully understood. This work explores the effect of CaSO4, Na2SO4 and sea salt on the scale formation and crack initiation of CMSX-4 at 550°C in 50 ppm of SO2 and synthetic air under a static stress of 800 MPa. The cross-sectional analysis showed that the CaSO4 and the Na2SO4 salted specimens did not undergo a significant degree of corrosion degradation and no cracks were detected after 400 hours of exposure. However, sea salt caused significant degradation to the scale and cracks were detected by X-ray CT scanning after 400 hours of exposure. The findings from this study suggests that the sulfation of chlorine containing species in sea salt led to the formation, vaporisation and re-oxidation of metal chlorides and this mechanism was found to play a key role in the formation of a non-protective scale. An active oxidation mechanism has been proposed to interpret the results. In conclusion, it is hypothesized that due to the synergistic effect of stress and the formation of a non-protective scale, fast diffusion paths for sulfur, oxygen and chlorine ingress were formed. Further work is currently being undertaken to understand the effect of these species on the local embrittlement of CMSX-4 that ultimately led to the initiation of cracks in the specimen.
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