Effects of tezacaftor/ivacaftor (TEZ/IVA) treatment in patients with cystic fibrosis and F508del/F508del-CFTR: patient-reported outcomes in a Phase 3, randomised, controlled trial (EVOLVE)

Objective To examine the impact of TEZ/IVA on disease-related symptoms, functioning and wellbeing as measured by the Cystic Fibrosis (CF) Questionnaire–Revised (CFQ-R) in patients with CF homozygous for F508del-CFTR (F508del/F508del). Improvement in the respiratory domain of CFQ-R has been reported previously. Here we report on the other health domains of CFQ-R.

Methods EVOLVE (NCT02347657), a Phase 3, randomised, double-blind, placebo-controlled trial, evaluated TEZ/IVA (100 mg QD/150 mg BID) in patients age ≥ 12 years with CF and F508del/F508del. CFQ-R consists of 12 domains, including respiratory symptoms (a key secondary endpoint in EVOLVE), and was assessed at baseline (BL) and weeks 4, 8, 12, 16 and 24. A mixed-effects model for repeated measures (MMRM) was used in the prespecified analysis of the absolute change in score from BL through week 24. In a post hoc analysis, cumulative distribution functions (CDF) were used to compare the distribution of change in scores from BL to week 24 across the two treatment groups. No multiplicity adjustment was used in the analyses. CDF differences were assessed using nominal P values obtained from the Anderson–Darling test.

Results Data from 504 patients with a BL CFQ-R assessment were included in the prespecified analyses; patients with BL and week 24 scores (n = 481) were included in the post hoc analyses. In the prespecified analysis, an improvement was observed favouring TEZ/IVA over placebo on the following CFQ-R domains: physical functioning, treatment burden, health perceptions, vitality and social functioning (Table). In the post hoc CDF analyses, differences favouring TEZ/IVA were observed in a subset (5/12) of domains, including respiratory symptoms, as well as physical functioning, health perceptions, emotional functioning and treatment burden (all P < 0.05). The remaining domains (7/12) demonstrated no difference.

Conclusions The present analyses demonstrate TEZ/IVA treatment benefit across a broad range of patient-reported health outcomes beyond respiratory symptoms, including physical functioning. These findings further support the value of TEZ/IVA treatment in patients with CF with F508del/F508del.

Tab. 1 

Domain	Prespecified MMRM analysis of absolute change in CFQ-R domain scores through week 24 (95% CI)
Physical functioning	3.8 (1.9, 5.8)
Treatment burden	3.4 (1.6, 5.1)
Health perceptions	3.2 (1.2, 5.2)
Vitality	2.3 (0.1, 4.5)
Social functioning	1.5 (0.0, 3.0)
Role functioning	1.5 (−0.3, 3.4)
Eating problems	1.1 (−0.6, 2.7)
Emotional functioning	0.6 (−1.0, 2.2)
Weight	0.5 (−2.9, 3.9)
Digestive symptoms	−0.1 (−1.9, 1.7)
Body image	−0.5 (−2.3, 1.3)