Vertex Pharmaceuticals Incorporated.

This clinical intervention reduced the number of medicines prescribed to elderly people in nursing homes, with minimal impact on their morbidity and mortality.

Background Ivacaftor, approved for treatment of cystic fibrosis (CF) patients aged ≥6 years with G551D-CFTR or other gating mutations, was evaluated in subjects with R117H-CFTR, a residual function mutation. Methods A 24 week, placebo-controlled, double-blind, randomized clinical trial (RCT) enrolled 69 CF subjects aged ≥6 years with R117H-CFTR and percent predicted forced expiratory volume in 1 second (ppFEV1) ≥40. Primary outcome was absolute change from baseline in ppFEV1 through week 24. Secondary outcomes included sweat chloride, CF Questionnaire-Revised (CFQ-R) respiratory domain, and safety. An open-label extension enrolled 65 RCT subjects after washout; after 12 weeks, an interim analysis was performed. Findings After 24 weeks, treatment difference in mean absolute change in ppFEV1 between ivacaftor (n=34) and placebo (n=35) was 2.1 percentage points (p=0·20). Ivacaftor treatment resulted in significant RCT treatment differences in sweat chloride (−24.0 mmol/L; p<0.001) and CFQ-R respiratory domain (8.4; p=0.009). In prespecified subgroup analyses, ppFEV1 significantly improved with ivacaftor in subjects aged ≥18 years (treatment difference vs placebo: 5.0 percentage points; p=0.01), but not in subjects aged 6 to 11 years (−6.3 percentage points; p=0.03). In the extension study, both placebo/ivacaftor and ivacaftor/ivacaftor groups showed ppFEV1 improvement (absolute change from postwashout baseline at week 12: 5.5 percentage points; p<0.0001). No new safety concerns were identified. Interpretation Although this RCT did not meet the primary outcome, secondary outcomes and subgroup analyses suggest that ivacaftor significantly improves lung function in adult patients with R117H-CFTR and may benefit patients with established disease.

The preliminary results support the need for the continuing main HYVET trial. It is possible that treatment of 1000 patients for 1 year may reduce stroke events by 19 (nine non-fatal), but may be associated with 20 extra non-stroke deaths.

These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).