(224) Elexacaftor/Tezacaftor/Ivacaftor alters Gastrointestinal Symptoms and Inflammation: Report of PROMISE Peds GI

Background: CFTR mutations are known to affect fluid secretion and intestinal pH which are believed to contribute to inflammation, dysmotility and dysbiosis in the CF intestine. Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR corrector/potentiator approved for CF patients 6 and older with at least one ETI-responsive CFTR allele. While CFTR modulator medications such as ETI have shown pulmonary benefit, their efficacy on gastrointestinal (GI) outcomes is less clear. The PROMISE GI study demonstrated changes in GI symptoms and intestinal inflammation in participants 12 years and older after initiation of ETI therapy. PROMISE PEDS examines GI symptoms and fecal biomarkers in children with CF 6 to < 12 years of age who recently initiated ETI with the goal of assessing clinical efficacy, specimen collection, and evaluating potential biomarkers.

Methods: We report on changes in GI symptoms and inflammation pre- and post-initiation of ETI from the PROMISE PEDS study presently underway involving CF participants from 20 centers, age 6 to < 12 years old at ETI initiation with at least one F508del allele. Outcomes reported here include Patient-Reported Outcome Measures (PROMs) from 3 validated GI questionnaires and one stool-specific questionnaire (all completed by the participants’ guardians), and fecal biomarkers. For this abstract, we present preliminary 1-month (1mo) data as a preview to the 6-month data. The mean difference and 95% confidence intervals are obtained from linear regression with adjustment for prior modulator use and sex at birth.

Results: Over 5 months there were 125 participants enrolled, of which 124 initiated ETI. There were 110 participants who fully completed at least 1 PROM. The mean (SD) for PAGI-SYM, PAC-SYM, and PAC-QOL total scores at baseline (BL) were 0.31 (0.42), 0.26 (0.33), and 0.41 (0.37), respectively (scale 0-5 for PAGI-SYM and 0-4 for the other two; higher score indicates more severity). The PAGI-SYM symptom domains with the greatest severity at BL were bloating and fullness. The corresponding sex- and prior-modulator-adjusted 1mo changes (95% CI) in total scores were 0.02 (-0.10, 0.13), -0.01 (-0.09, 0.07), and -0.07 (-0.16, 0.03). At BL, 14 (14.4%) had self-described constipation, 7 (7.2%) had < 3 weekly bowel movements, 10 (10.3%) reported Bristol stool type 1 or 2, and 4 (4.1%) reported stool leakage. At 1mo, self-described constipation decreased to 4 (4.8%). Among 87 participants who had fecal calprotectin obtained at BL, mean (SD) fecal calprotectin was 82.5 (76.1) μg/g with only 42 (48.3%) of values classified as clinically normal. Out of 65 participants who had data at both BL and 1mo by the time of analysis, 48 (73.8%) were classified as clinically normal, with an estimated sex- and prior-modulator-adjusted change (95% CI) of -33.3μg/g (-49.8, -16.8). There was no statistically significant change in fecal elastase-1 or steatocrit after one month of ETI.

Conclusions: After one month of ETI, report of constipation decreased. Intestinal inflammation, measured as fecal calprotectin, decreased, but fecal elastase-1 did not change. We speculate that 6 month data may show further changes in GI symptoms and function.

Acknowledgements: Supported by the Cystic Fibrosis Foundation

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