Reduction in abdominal symptoms (CFAbd-Score), faecal M2-pyruvate-kinase and Calprotectin over one year of treatment with Elexacaftor-Tezacaftor-Ivacaftor in people with CF aged ≥12 years – The RECOVER study
Authors: Mainz Jochen G. , Lester Karen , Elnazir Basil , Williamson Michael , McKone Ed , Cox Des , Linnane Barry , Zagoya Carlos , Duckstein Franziska , Barucha Anton , Davies Jane C. , McNally Paul ,   RECOVER Study Group
Published: July 2023

Background

RECOVER is a multicentre post-approval study of Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pwCF in Ireland and the UK. The CFAbd-Score is the first validated CF-specific patient reported outcome measure (PROM) focusing on gastrointestinal symptoms; it comprises 28 items in 5 domains. In a preliminary study, we previously reported reductions in abdominal symptoms (AS) in pwCF after 26 weeks of ETI-therapy using the CFAbd-Score.

Aim: to assess changes in AS in a second, large cohort and explore novel GI-biomarkers of gut inflammation and cell-proliferation in pwCF over one year of ETI-therapy.

Methods

Participants were recruited as part of the RECOVER study at 8 sites (Ireland&UK). The CFAbd-Score was administered prior to ETI-initiation, and subsequently at 1,2,6 and 12 months on treatment. Faecal M2-pyruvate kinase (M2-PK) and calprotectin (FC) were quantified in samples collected at baseline, 1 and 6 months.

Results

108 CFAbd-Scores and 73 stool samples were collected at baseline. After 12 months of ETI-therapy, total CFAbd-Scores had significantly declined (15.0±1.4→9.8±1.2pts/p<0.001), and so had all its five domains of “pain” (16.9±2.0pts→9.9±1.8pts/p<0.01), “GERD” (14.4±1.8→9.9±1.6/p<0.05), “disorders of bowel movements” (19.2±1.4→14.1±1.5/p<0.01), “appetite” (7.0±1.1→4.6±1.2/p<0.01) and “impaired-QoL” (13.3±1.9→7.5±1.5/p<0.001). Levels of M2-PK and FC significantly decreased during ETI-therapy.

Discussion

In-depth analysis of AS with the CFAbd-Score reveals a statistically significant, clinically relevant and sustained improvement with ETI. We attribute this to high sensitivity of the implemented CF-specific PROM, developed and validated following FDA-guidelines.

Furthermore, for the first time during ETI-therapy a significant decline in faecal M2-PK, a marker of inflammation and cell-proliferation, was found, in parallel to FC.

Graphical Abstract

Statistically significant and clinically relevant sustained decline in GI symptoms using the CFAbd-Score in pwCF over 12 months of therapy with Elexacaftor-Tezacaftor-Ivacaftor (ETI) as part of the RECOVER study. Changes over time in total CFAbd-Scores as well as of the 5 included domains are shown before (0), as well as 1,2,6 and 12 months after initiation of ETI

Highlights

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The present study uses the first validated CF-specific patient reported outcome measure focusing on gastrointestinal symptoms (CFAbd-Score) to demonstrate that ETI leads to substantial and sustained reduction in GI-symptom burden

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Symptom improvement is rapid, being evident at 1 month, peaking 2 months and stabilising thereafter

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Previous studies assessing effects of ETI on GI-symptoms had generated conflicting results

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For the first time, significant improvements in faecal M2-pyruvate Kinase (M2-PK), a marker of cell proliferation were seen on ETI, in addition to reductions in faecal calprotectin as previously reported