Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: Report of promise-GI

Abstract

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.

Methods: PROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex.

Results: 438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change.

Conclusions: After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.

Trial registration: ClinicalTrials.gov NCT04038047.

Keywords: Inflammation; Modulators; Pancreatic insufficiency; Patient-reported outcomes measures.

Figure 1. Changes in PAGI-SYM, PAC-SYM, and PAC-QOL scores at 6 months

: Changes from baseline in total and domain scores for PAGI-SYM, PAC-SYM, and PAC-QOL at 6 months were evaluated in linear regression models with adjustments for age group at enrollment and sex at birth. Positive value of adjusted change indicates lower score (symptom improvement) at 6 months compared to baseline.

Figure 2:. Distributions of fecal calprotectin at baseline, 1 month, and 6 months

Distributions of fecal calprotectin (μg/g) were summarized for visits at baseline, 1 month, and 6 months. Changes from baseline at follow-up visits were evaluated in linear regression models with adjustments for age group at enrollment, sex at birth, and prior modulator use, among participants who had available data at both baseline and the corresponding follow-up visits (N=113 at 1 month and N=99 at 6 months).