Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR

Abstract

Rationale: In a prior study, lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function.

Objectives: To evaluate an optimized lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR.

Methods: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1 (ppFEV1) of 40 to 90 were randomized to lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at Day 56 and safety. Other disease markers were evaluated.

Measurements and main results: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1 values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo group. Absolute changes in ppFEV1 (least squares mean [SE]) at Day 56 were -0.6 (0.8) percentage points in the active treatment group and -1.2 (0.8) percentage points in the placebo group (P = 0.60). CF respiratory symptom scores in the active treatment group improved by a mean of 5.7 points versus a decrease of -0.8 in the placebo group (P < 0.01). No changes in body mass index occurred. Changes from baseline in sweat chloride (least squares mean [SE]) at Day 56 were -11.8 (1.3) mmol/L in the active treatment group and -0.8 (1.2) mmol/L in the placebo group (P < 0.0001).

Conclusions: Sweat chloride and respiratory symptom scores improved with lumacaftor/ivacaftor, though no meaningful benefit was seen in ppFEV1 or body mass index in patients heterozygous for F508del-CFTR. Clinical trial registered with www.clinicaltrials.gov (NCT01225211).

Keywords: adverse events; percent predicted forced expiratory volume in 1 second; sweat chloride.

Figures

Figure 1.

Study design. *The first dose of study drug was administered on Day 1. †On Day 56, the last dose of study drug was administered in the morning. ‡Patients who prematurely discontinued study drug treatment 7 or more days before the Day 56 visit were not required to complete a safety follow-up visit. q12h = every 12 hours.

Figure 2.

Patient disposition. *Did not meet inclusion criterion ofF508del-CFTR mutation on one allele. †One patient discontinued treatment prior to Day 56 but completed required Day 56 visit off study treatment. q12h = every 12 hours.

Figure 3.

Absolute change from baseline in (A) ppFEV1 by visit, (B) CFQ-R respiratory domain score by visit, (C) sweat chloride concentration by visit, and (D) body mass index by visit. *P = 0.01 versus placebo; †P < 0.0001 versus placebo. BMI = body mass index; CFQ-R = Cystic Fibrosis Questionnaire–Revised; LS = least squares; ppFEV1 = percent predicted FEV1; q12h = every 12 hours; lumacaftor/ivacaftor (n = 62), placebo (n = 63).