Effects of tezacaftor/ivacaftor (TEZ/IVA) treatment in patients heterozygous for F508del-CFTR and a residual function mutation: patient-reported outcomes in a Phase 3, randomised, controlled trial (EXPAND)

Objective To examine the impact of TEZ/IVA vs. placebo on disease-related symptoms, functioning and wellbeing as measured by the Cystic Fibrosis (CF) Questionnaire–Revised (CFQ-R) in patients heterozygous for F508del and a second allele with a CFTR mutation predicted to have residual function (F508del/RF). Improvement in the respiratory domain of CFQ-R has been reported previously. Here we report on the other health domains of CFQ-R.

Methods TEZ/IVA (100 mg QD/150 mg BID) was evaluated vs. placebo in patients age ≥ 12 years with CF and F508del/RF in EXPAND (NCT02392234), a Phase 3, randomised, double-blind, placebo-controlled, crossover design trial. CFQ-R consists of 12 domains, including respiratory symptoms (a key secondary endpoint in EXPAND), and was assessed at baseline (BL) and weeks 4 and 8. In the prespecified analysis, a linear mixed-effects model was used to estimate the mean absolute change in each domain score from BL to the average of weeks 4 and 8 scores. In the post hoc analysis, cumulative distribution functions (CDF) were used to compare the distribution of change in scores from BL to week 8 between TEZ/IVA and placebo. No multiplicity adjustment was used in the analyses. CDF differences were assessed using the Anderson–Darling test (nominal P values).

Results Data from 244 patients with a BL CFQ-R assessment were included in the prespecified analysis; patients with BL and week 8 scores (n = 240) were included in the post hoc analysis. In the prespecified analysis, a TEZ/IVA treatment effect vs. placebo was observed in health perceptions, vitality, physical functioning, role functioning, social functioning, weight, treatment burden and emotional functioning (Table). The post hoc CDF analysis demonstrated consistent findings in a subset of domains (8/12), including respiratory symptoms, as well as in health perceptions, vitality, physical functioning, role functioning, social functioning, treatment burden and body image (all P < 0.05). The remaining domains (4/12) demonstrated no difference.

Conclusions Treatment with TEZ/IVA demonstrated improvement in patient-reported health outcomes beyond respiratory symptoms in CF patients with F508del/RF. These findings highlight the treatment impact on patientsʼ functioning and further support the overall value of TEZ/IVA treatment benefit.

Tab. 1 

Domain	Prespecified linear mixed-effects model for absolute change in CFQ-R domain scores to the average of weeks 4 and 8 (95% CI)
Health perceptions	9.2 (6.7, 11.7)
Vitality	8.3 (5.6, 10.9)
Physical functioning	7.1 (4.5, 9.7)
Role functioning	3.3 (1.0, 5.6)
Social functioning	3.1 (1.3, 4.9)
Weight	3.1 (0.3, 5.8)
Tretment burden	2.8 (0.8, 4.8)
Emotional functioning	2.6 (0.8, 4.3)
Body image	1.6 (0.0, 3.3)
Eating problems	1.4 (−0.3, 3.1)
Digestive symptoms	−2.6 (−4.8, −0.5)

 

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