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

Sarah Jane Schwarzenberg; Phuong T Vu; Michelle Skalland; Lucas R Hoffman; Christopher Pope; Daniel Gelfond; Michael R Narkewicz; David P Nichols; Sonya L Heltshe; Scott H Donaldson; Carla A Frederick; Andrea Kelly; Jessica E Pittman; Felix Ratjen; Margaret Rosenfeld; Scott D Sagel; George M Solomon; Michael S Stalvey; John P Clancy; Steven M Rowe; Steven D Freedman; Promise Study Group

doi:10.1016/j.jcf.2022.10.003

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

J Cyst Fibros. 2023 Mar;22(2):282-289. doi: 10.1016/j.jcf.2022.10.003. Epub 2022 Oct 21.

Authors

Sarah Jane Schwarzenberg¹, Phuong T Vu², Michelle Skalland², Lucas R Hoffman³, Christopher Pope⁴, Daniel Gelfond⁵, Michael R Narkewicz⁶, David P Nichols⁷, Sonya L Heltshe⁷, Scott H Donaldson⁸, Carla A Frederick⁹, Andrea Kelly¹⁰, Jessica E Pittman¹¹, Felix Ratjen¹², Margaret Rosenfeld¹³, Scott D Sagel⁶, George M Solomon¹⁴, Michael S Stalvey¹⁵, John P Clancy¹⁶, Steven M Rowe¹⁴, Steven D Freedman¹⁷; Promise Study Group

Affiliations

¹ Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Academic Office Building, 2450 Riverside Ave S AO-201, Minneapolis, MN 55454, USA. Electronic address: schwa005@umn.edu.
² Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle, WA, USA.
³ Department of Pediatrics and Department of Microbiology, University of Washington School of Medicine, Seattle, WA, USA.
⁴ Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
⁵ Western New York Pediatric Gastroenterology, NY, USA.
⁶ Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
⁷ Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
⁸ Department of Medicine, University of North Carolina at Chapel Hill, NC, USA.
⁹ Jacobs School of Medicine and Biomedical Sciences of the University of Buffalo, NY, USA.
¹⁰ Division of Endocrinology & Diabetes, Children's Hospital of Philadelphia; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹¹ Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.
¹² Division of Respiratory Medicine, Department of Pediatrics, Translational Medicine, Hospital for Sick Children, University of Toronto, Canada.
¹³ Department of Epidemiology and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
¹⁴ Department of Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁵ Department of Pediatrics and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁶ Cystic Fibrosis Foundation, Bethesda, MD, USA.
¹⁷ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

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.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Aminophenols
Benzodioxoles / therapeutic use
Constipation
Cystic Fibrosis Transmembrane Conductance Regulator / genetics
Cystic Fibrosis* / complications
Cystic Fibrosis* / diagnosis
Cystic Fibrosis* / drug therapy
Humans
Mutation
Pancreatic Elastase
Prospective Studies
Quality of Life

Substances

elexacaftor
ivacaftor
tezacaftor
Aminophenols
Benzodioxoles
Cystic Fibrosis Transmembrane Conductance Regulator
Pancreatic Elastase

Associated data

ClinicalTrials.gov/NCT04038047

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding