Observational Study

. 2023 Mar;22(2):282-289.

doi: 10.1016/j.jcf.2022.10.003. Epub 2022 Oct 21.

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

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.

PMID: 36280527
PMCID: PMC10144072
DOI: 10.1016/j.jcf.2022.10.003

Observational Study

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

Sarah Jane Schwarzenberg et al. J Cyst Fibros. 2023 Mar.

. 2023 Mar;22(2):282-289.

doi: 10.1016/j.jcf.2022.10.003. Epub 2022 Oct 21.

Authors

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.

PMID: 36280527
PMCID: PMC10144072
DOI: 10.1016/j.jcf.2022.10.003

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.

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Conflict of interest statement

Declaration of Competing Interest SJS-Consultant for UpToDate, Abbvie, Mirium, Nestle; Grant funding from Gilead, Cystic Fibrosis Foundation, NIH. SDF – Consultant for UpToDate, Abbvie, Nestle, Synspira; Grant funding from NIH, Cystic Fibrosis Foundation, Amagma Therapeutics. MRN – Consultant for UpToDate, Vertex: Grant funding from Gilead, AbbVie, Cystic Fibrosis Foundation, NIH SMR: Consultant for Vertex; Grant funding from Vertex, Cystic Fibrosis Foundation, NIH DPN: Consultant for Vertex, Genentech; Grant funding from Vertex, Cystic Fibrosis Foundation, NIH GMS: Consultant for Genentech, Electromed; Grant Funding from Vertex, Cystic Fibrosis Foundation, NIH DG: Consultant for Vertex, Abbvie, Chiesi USA, Eli Lilly AK: Grant funding from NIH, Cystic Fibrosis Foundation, SDS – Grant funding from Cystic Fibrosis Foundation and NIH MSS—Grant funding from Cystic Fibrosis Foundation

Figures

**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).

See this image and copyright information in PMC

References

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

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

Authors

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Conflict of interest statement

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