Respiratory Trials·org

Topic

Cystic fibrosis

Mucolytics, inhaled antibiotics, and the CFTR modulators.

Before the modulators, three drugs changed the disease. Dornase alfa cut exacerbations by about a third (Fuchs 1994); cycled inhaled tobramycin raised FEV1 by 10% and reduced hospitalisation in Pseudomonas infection (Ramsey 1999); and hypertonic saline missed its primary endpoint of lung function slope but improved absolute lung function and cut exacerbations (Elkins 2006). All three are cheap, and two of the three are now being deprescribed — SIMPLIFY tested stopping hypertonic saline and dornase alfa, not tobramycin.

CFTR modulators corrected the basic defect, and the sweat chloride fall in the first positive trial made that literally measurable (STRIVE). Ivacaftor gave a 10-point FEV1 gain but only to the 4% of patients carrying G551D.

Triple therapy extended that to roughly 90% of patients. Elexacaftor-tezacaftor-ivacaftor produced a 14-point improvement in predicted FEV1 and cut exacerbations by 63% in genotypes where earlier modulators had failed (VX17-445-102) — the trial that changed the trajectory of the disease. A once-daily successor is non-inferior on lung function and reduces treatment burden (SKYLINE).

The field's question is now what to stop. In patients on triple modulator therapy with well-preserved lung function, discontinuing hypertonic saline or dornase alfa for six weeks was non-inferior to continuing (SIMPLIFY). Six weeks is short and the participants were well, so this licenses deprescribing in stable patients rather than in everyone.

CFTR modulators

Trial Year Therapy Effect Finding
SKYLINE 2025 Vanzacaftor/tezacaftor/deutivacaftor The once-daily triple matched the twice-daily standard on lung function
VX18-445-104 2021 Elexacaftor/tezacaftor/ivacaftor Triple therapy added a further 3.7 points of FEV1 even in patients already on an effective modulator
VX17-445-102 2019 Elexacaftor/tezacaftor/ivacaftor Triple modulator therapy gave a 14-point FEV1 gain to the 90% of CF patients with a single Phe508del allele
STRIVE 2011 Ivacaftor Ivacaftor produced a 10-point FEV1 gain in G551D cystic fibrosis — the first drug to correct the basic defect

Mucolytic therapy

Trial Year Therapy Effect Finding
Elkins 2006 2006 Hypertonic saline Hypertonic saline did not change the slope of decline but improved lung function and cut exacerbations
Fuchs 1994 1994 Dornase alfa Dornase alfa cut exacerbations by about a third and gave a small lung function gain

De-escalating older therapies

Trial Year Therapy Effect Finding
SIMPLIFY 2023 Hypertonic saline and dornase alfa withdrawal Patients on triple modulator therapy could stop hypertonic saline or dornase alfa without losing lung function

Duration of exacerbation treatment

Trial Year Therapy Effect Finding
STOP2 2021 Shorter intravenous antimicrobial courses Ten days of intravenous antibiotics matched fourteen in early responders, and twenty-one beat nothing in slow responders

Inhaled antibiotics

Trial Year Therapy Effect Finding
Ramsey 1999 1999 Inhaled tobramycin Cycled inhaled tobramycin improved FEV1 by 10% and reduced hospitalisation in Pseudomonas infection

Key references

Guidelines, standards and reviews for this topic.