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

Jochen G Mainz; Karen Lester; Basil Elnazir; Michael Williamson; Ed McKone; Des Cox; Barry Linnane; Carlos Zagoya; Franziska Duckstein; Anton Barucha; Jane C Davies; Paul McNally; RECOVER Study Group

doi:10.1016/j.jcf.2023.10.001

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

J Cyst Fibros. 2023 Oct 7:S1569-1993(23)00922-0. doi: 10.1016/j.jcf.2023.10.001. Online ahead of print.

Authors

Affiliations

¹ Brandenburg Medical School (MHB) University. Klinikum Westbrandenburg, Brandenburg an der Havel, Germany. Electronic address: j.mainz@uk-brandenburg.de.
² RCSI University of Medicine and Health Sciences, Dublin, Ireland.
³ Children's Health Ireland, Dublin, Ireland.
⁴ St Vincent's University Hospital, Dublin, Ireland.
⁵ University of Limerick School of Medicine, Limerick, Ireland.
⁶ Brandenburg Medical School (MHB) University. Klinikum Westbrandenburg, Brandenburg an der Havel, Germany.
⁷ Brandenburg Medical School (MHB) University. Klinikum Westbrandenburg, Brandenburg an der Havel, Germany; Department of Gastroenterology, Brandenburg Medical School (MHB) University, Brandenburg an der Havel, Germany.
⁸ National Heart & Lung Institute, Imperial College London, UK; Royal Brompton Hospital, Guy's & St Thomas' NHS Trust, London, UK.
⁹ RCSI University of Medicine and Health Sciences, Dublin, Ireland; Children's Health Ireland, Dublin, Ireland.

PMID: 37806792
DOI: 10.1016/j.jcf.2023.10.001

Abstract

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.

Keywords: CFTR; faecal elastase; gastro-intestinal (GI); modulation; patient reported outcome measure (PROM).