Volume 147, Issue 2, Pages e5 (August 2014)

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Volume 147, Issue 2, Pages 324-333.e5 (August 2014) Efficacy, Dose Reduction, and Resistance to High-Dose Fluticasone in Patients With Eosinophilic Esophagitis  Bridget K. Butz, Ting Wen, Gerald J. Gleich, Glenn T. Furuta, Jonathan Spergel, Eileen King, Robert E. Kramer, Margaret H. Collins, Emily Stucke, Colleen Mangeot, W. Daniel Jackson, Molly O'Gorman, J. Pablo Abonia, Scott Pentiuk, Philip E. Putnam, Marc E. Rothenberg  Gastroenterology  Volume 147, Issue 2, Pages 324-333.e5 (August 2014) DOI: 10.1053/j.gastro.2014.04.019 Copyright © 2014 AGA Institute Terms and Conditions

Figure 1 Flow diagram of the study participants. Fifty-one participants were screened for the study; 9 were excluded and 42 were randomized. Of the 42 randomized participants, 28 received FP and 14 received placebo. Thirty-six participants completed phase 1, and 34 participants completed phases 1 and 2 of the study. NR, no response. Gastroenterology 2014 147, 324-333.e5DOI: (10.1053/j.gastro.2014.04.019) Copyright © 2014 AGA Institute Terms and Conditions

Figure 2 Responsiveness in phase 1. Response was defined as a peak count of 1 or fewer eosinophils/HPF in (A) both the proximal and distal esophagus, (B) proximal only, and (C) distal only. Additional definitions were calculated on the basis of peak counts of 6 or fewer and 14 or fewer eosinophils/HPF, mean counts of 1 or fewer and 2 or fewer eosinophils/HPF, and decreases of 90% or greater and 95% or greater in eosinophil levels. *P < .01, **P < .001, ***P < .0001. (A) P = 0 for a peak of 6 or fewer eosinophils/HPF. (B) P = 0 for a peak of 1 or fewer eosinophils/HPF. Gastroenterology 2014 147, 324-333.e5DOI: (10.1053/j.gastro.2014.04.019) Copyright © 2014 AGA Institute Terms and Conditions

Figure 3 Effect of dose reduction on phase 1 FP responders. FP responders had their dosage of FP reduced from 1760 to 880 mcg/day in an open-label study and had a repeat esophagogastroduodenoscopy after 3 months. The peak eosinophil value is for the distal and proximal esophagus. Each solid line represents a unique patient. Dashed lines represent the 15 eosinophils/HPF threshold for diagnosing EoE by consensus recommendations and 1 eosinophil/HPF for CR. Gastroenterology 2014 147, 324-333.e5DOI: (10.1053/j.gastro.2014.04.019) Copyright © 2014 AGA Institute Terms and Conditions

Figure 4 Esophageal transcriptome analysis. Total RNA from separately acquired biopsy specimens was subjected to EDP signature analysis. (A) The heat diagram depicts the changes after FP exposure in the bidirectional gene dysregulation in each group with reference historical EoE and normal (NL) cohorts (n = 15 and 14, respectively), and the samples at screening (no FP exposure) on the left. At the end of phases 1 and 2, expression signatures from FP nonresponders (NRs), FP responders with partial remission (PRs), and FP responders with complete remission (CRs) are shown in the heat diagram (yellow, increased expression; blue, decreased expression). (B) On the basis of the expression levels of the 77 diagnostic genes and a dimensionality reduction algorithm, an EoE score reflecting the EoE disease activity was calculated at the end of phase 1 (**P < .001, ***P < .0001, 2-tailed Student t test). (C) To assess the prediction value of the EDP on FP responsiveness, samples at screening (ie, pre-FP exposure) and the placebo samples at the end of phase 1 (ie, pre-FP exposure) were screened by bioinformatics in the context of their subsequent FP responsiveness on the basis of the CR criteria of fewer than 2 eosinophils/HPF in the distal esophagus, where the biopsy specimens were acquired. The 15-gene cluster listed shows a potential for FP efficacy prediction with a P value of less than .05 and fold change greater than 2.0. Gastroenterology 2014 147, 324-333.e5DOI: (10.1053/j.gastro.2014.04.019) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 1 Response was defined as a peak count of ≤ eosinophil/HPF in (A) both the proximal and distal esophagus, (B) proximal only, and (C) distal only. Additional definitiions were calculated on the basis of peak counts ≤6 and ≤14 eosinophil/HPF, mean counts of ≤1 and ≤2 eosinophil/HPF, and decreases of ≥90% and ≥95% in eosinophil levels. FP, fluticasone propionate. Gastroenterology 2014 147, 324-333.e5DOI: (10.1053/j.gastro.2014.04.019) Copyright © 2014 AGA Institute Terms and Conditions