Advertisement

Budesonide Oral Suspension Improves Symptomatic, Endoscopic, and Histologic Parameters Compared With Placebo in Patients With Eosinophilic Esophagitis

Open AccessPublished:November 23, 2016DOI:https://doi.org/10.1053/j.gastro.2016.11.021

      Background & Aims

      Pharmacologic treatment of eosinophilic esophagitis (EoE) is limited to off-label use of corticosteroids not optimized for esophageal delivery. We performed a randomized, controlled phase 2 trial to assess the ability of budesonide oral suspension (BOS), a novel muco-adherent topical steroid formulation, to reduce symptoms and esophageal eosinophilia in adolescents and adults with EoE.

      Methods

      In this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 93 EoE patients between the ages of 11 and 40 years with dysphagia and active esophageal eosinophilia were randomized to receive either BOS 2 mg or placebo twice daily for 12 weeks. Co-primary outcomes were change in Dysphagia Symptom Questionnaire (DSQ) score from baseline, and proportion of patients with a histologic response (≤6 eosinophils/high-power field) after treatment. Endoscopic severity scores and safety parameters were assessed.

      Results

      At baseline, mean DSQ scores were 29.3 and 29.0, and mean peak eosinophil counts were 156 and 130 per hpf in the BOS and placebo groups, respectively. After treatment, DSQ scores were 15.0 and 21.5, and mean peak eosinophil counts were 39 and 113 per high-power field, respectively (P < .05 for all). For BOS vs placebo, change in DSQ score was −14.3 vs −7.5 (P = .0096), histologic response rates were 39% vs 3% (P < .0001), and change in endoscopic severity score was −3.8 vs 0.4 (P < .0001). Adverse events were similar between groups.

      Conclusions

      Treatment with BOS was well tolerated in adolescent and young adult patients with EoE and resulted in improvement in symptomatic, endoscopic, and histologic parameters using validated outcome instruments. ClinicalTrials.gov ID NCT01642212.

      Keywords

      Abbreviations used in this paper:

      ANCOVA (analysis of covariance), BOS (budesonide oral suspension), CI (confidence interval), DSQ (Dysphagia Symptom Questionnaire), EoE (eosinophilic esophagitis), eos/hpf (eosinophils per high-power field), EREFS (Endoscopic Reference Score), OR (odds ratio), PPI (proton pump inhibitor), PRO (patient-reported outcome), SD (standard deviation)
      See Covering the Cover synopsis on page 671.
      Eosinophilic esophagitis (EoE) is an allergen/immune-mediated condition characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophilic infiltration of the esophageal mucosa.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      • Dellon E.S.
      • Gonsalves N.
      • Hirano I.
      • et al.
      ACG clinical guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis.
      • Furuta G.T.
      • Katzka D.A.
      Eosinophilic esophagitis.
      Typical symptoms include dysphagia and food impaction in adolescents and adults, and heartburn, regurgitation, vomiting, and feeding intolerance in children.
      • Furuta G.T.
      • Liacouras C.A.
      • Collins M.H.
      • et al.
      Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.
      Over the past 2 decades, EoE has rapidly emerged as a major cause of upper gastrointestinal morbidity, and it is now the most common cause of food bolus impaction
      • Desai T.K.
      • Stecevic V.
      • Chang C.H.
      • et al.
      Association of eosinophilic inflammation with esophageal food impaction in adults.
      • Sperry S.L.
      • Crockett S.D.
      • Miller C.B.
      • et al.
      Esophageal foreign-body impactions: epidemiology, time trends, and the impact of the increasing prevalence of eosinophilic esophagitis.
      and the second most common cause of esophagitis.
      • Kidambi T.
      • Toto E.
      • Ho N.
      • et al.
      Temporal trends in the relative prevalence of dysphagia etiologies from 1999–2009.
      • Dellon E.S.
      Epidemiology of eosinophilic esophagitis.
      • Gawron A.J.
      • Hirano I.
      Eosinophilic esophagitis – emerging epidemic or misdiagnosed malady?.
      The incidence and prevalence of EoE are increasing,
      • Dellon E.S.
      Epidemiology of eosinophilic esophagitis.
      • Hruz P.
      • Straumann A.
      • Bussmann C.
      • et al.
      Escalating incidence of eosinophilic esophagitis: a 20-year prospective, population-based study in Olten County.
      • Dellon E.S.
      • Jensen E.T.
      • Martin C.F.
      • et al.
      Prevalence of eosinophilic esophagitis in the United States.
      and health care expenditure related to EoE in the United States approaches $1 billion annually.
      • Jensen E.T.
      • Kappelman M.D.
      • Martin C.F.
      • et al.
      Health-care utilization, costs, and the burden of disease related to eosinophilic esophagitis in the United States.
      Corticosteroids are the first-line pharmacologic therapy for patients diagnosed with EoE.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      • Dellon E.S.
      • Gonsalves N.
      • Hirano I.
      • et al.
      ACG clinical guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      • Rothenberg M.E.
      Molecular, genetic, and cellular bases for treating eosinophilic esophagitis.
      These medications are used topically: asthma preparations are swallowed rather than inhaled to coat the esophagus, but are suboptimal for use in EoE. For example, inadequate esophageal delivery and undesired pulmonary deposition can result from medication administered into the mouth using metered-dose inhalers, and variable drug concentrations are possible when patients mix aqueous forms into viscous slurries.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      Although data support the use of both fluticasone
      • Teitelbaum J.E.
      • Fox V.L.
      • Twarog F.J.
      • et al.
      Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate.
      • Noel R.J.
      • Putnam P.E.
      • Collins M.H.
      • et al.
      Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.
      • Konikoff M.R.
      • Noel R.J.
      • Blanchard C.
      • et al.
      A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.
      • Schaefer E.T.
      • Fitzgerald J.F.
      • Molleston J.P.
      • et al.
      Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children.
      • Alexander J.A.
      • Jung K.W.
      • Arora A.S.
      • et al.
      Swallowed fluticasone improves histologic but not symptomatic responses of adults with eosinophilic esophagitis.
      • Butz B.K.
      • Wen T.
      • Gleich G.J.
      • et al.
      Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis.
      • Moawad F.J.
      • Veerappan G.R.
      • Dias J.A.
      • et al.
      Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for esophageal eosinophilia.
      • Lucendo A.J.
      • Arias A.
      • De Rezende L.C.
      • et al.
      Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: a prospective study.
      • Peterson K.A.
      • Thomas K.L.
      • Hilden K.
      • et al.
      Comparison of esomeprazole to aerosolized, swallowed fluticasone for eosinophilic esophagitis.
      and budesonide,
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      • Aceves S.S.
      • Bastian J.F.
      • Newbury R.O.
      • et al.
      Oral viscous budesonide: a potential new therapy for eosinophilic esophagitis in children.
      • Aceves S.S.
      • Dohil R.
      • Newbury R.O.
      • et al.
      Topical viscous budesonide suspension for treatment of eosinophilic esophagitis.
      • Dohil R.
      • Newbury R.
      • Fox L.
      • et al.
      Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial.
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      neither are approved by the Food and Drug Administration for this indication. In addition, although these agents can decrease or resolve esophageal eosinophilia, symptom response has been inconsistent.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      • Alexander J.A.
      • Jung K.W.
      • Arora A.S.
      • et al.
      Swallowed fluticasone improves histologic but not symptomatic responses of adults with eosinophilic esophagitis.
      • Butz B.K.
      • Wen T.
      • Gleich G.J.
      • et al.
      Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      • Hirano I.
      Therapeutic end points in eosinophilic esophagitis: is elimination of esophageal eosinophils enough?.
      In addition, published trials have not evaluated EoE symptoms using a validated patient-reported outcome (PRO) measure.
      • Rothenberg M.E.
      • Aceves S.
      • Bonis P.A.
      • et al.
      Working with the US Food and Drug Administration: progress and timelines in understanding and treating patients with eosinophilic esophagitis.
      • Fiorentino R.
      • Liu G.
      • Pariser A.R.
      • et al.
      Cross-sector sponsorship of research in eosinophilic esophagitis: a collaborative model for rational drug development in rare diseases.
      Budesonide oral suspension (BOS) is a novel muco-adherent medication formulated specifically for use in EoE, with standardized viscosity and concentration. It has previously been shown to induce a dose-dependent histologic response in children with EoE,
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      but has not been assessed in adults. The aim of this phase 2 study was to determine whether BOS was superior to placebo in decreasing symptoms of dysphagia, as measured by a validated instrument, and decreasing esophageal eosinophil counts in adolescents and adults with EoE.

      Materials and Methods

       Study Design and Participants

      This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2 trial conducted from July 2012 to October 2014 at 25 centers throughout the United States (see Supplementary Material). The study was approved by the Institutional Review Board at each center, registered at ClinicalTrials.gov (NCT01642212), performed in accordance with the provisions of the Declaration of Helsinki, and reported per the CONSORT (Consolidated Standards of Reporting Trials) statement. Participants or parents/legal guardians provided written informed consent before taking part in the study. Participants did not receive a stipend from the study sponsor.
      Potential study participants were aged 11−40 years. The lower bound of the age range was selected as this was considered to be the minimum age at which patients would be able to self-assess dysphagia, understand the Dysphagia Symptom Questionnaire (DSQ) and complete the daily DSQ entries. The upper bound of the age range was chosen as, at the time of the study design, it was felt to be the most appropriate cutoff to exclude older patients who are more likely to have fibrostenotic disease and typically are not amenable to anti-inflammatory treatment alone.
      • Hirano I.
      Therapeutic end points in eosinophilic esophagitis: is elimination of esophageal eosinophils enough?.
      • Safroneeva E.
      • Straumann A.
      • Coslovsky M.
      • et al.
      Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis.
      Patients aged younger than 18 years were also included in this study, as the previous pediatric study did not measure symptom response using a validated instrument.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      Study participants were also required to have a confirmed diagnosis of EoE using 2011 consensus guidelines:
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      specifically, symptoms of esophageal dysfunction and at least 15 intra-epithelial eosinophils per high-power field (eos/hpf) (hpf area: 0.3 mm2) after an 8-week, high-dose (refers to a total daily dose, which could be administered as a once or twice daily dosing regimen), proton pump inhibitor (PPI) trial using any approved PPI. The PPI trial was either historical or could have been performed during the screening period of this study; PPI-responsive EoE was defined as <15 eos/hpf, as recommended by the current guidelines.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      Other potential causes of esophageal eosinophilia had also been excluded. For inclusion, patients with EoE were required to have at least 15 eos/hpf from at least 2 esophageal levels on screening endoscopy, at least 4 days with symptoms of dysphagia over the last 2 weeks of a 4-week blinded placebo run-in period, and at least 70% compliance with a daily symptom diary. The purpose of these criteria was to include patients with active EoE who were highly symptomatic and whose symptoms persisted during the placebo run-in period. The exclusion criteria included presence of any of the following: non-EoE gastrointestinal diseases, including eosinophilic gastroenteritis/colitis, inflammatory bowel disease, celiac disease, Helicobacter pylori infection, esophageal candidiasis (defined based on investigator discretion), or esophageal varices; diseases causing systemic eosinophilia; or esophageal stricture on screening endoscopy that precluded passage of an adult upper endoscope. Gastroesophageal reflux disease and erosive esophagitis were not formal exclusion criteria, but patients with esophageal eosinophilia related to gastroesophageal reflux disease were excluded, as based on PPI-responsive eosinophilia. Other exclusion criteria were: use of corticosteroids (topical or systemic) in the 4 weeks preceding the screening endoscopy; use of immunomodulatory therapy in the 8 weeks preceding the screening endoscopy; change in dosing regimen of PPIs, allergy medications, or inhaled corticosteroids; pregnancy; and medical instability.

       Randomization, Interventions, and Outcomes

      After a screening upper endoscopy and biopsy, symptoms were assessed during a 4-week placebo-run-in period, during which all patients received single-blind placebo. If patients met histology and symptom eligibility criteria, they were randomized 1:1 to either BOS 2 mg twice daily (given as 10 mL, once in the morning after breakfast and once in the evening before bedtime to provide a total daily dose of 4 mg), or a placebo suspension twice daily, for 12 weeks. BOS is formulated in a viscous suspension designed to increase the time the drug is in contact with the surface of the esophagus after swallowing. The pre-mixed suspension uses a combination of 2 viscosity-modifying agents to give the suspension a syrup-like consistency (as opposed to a slurry), along with buffers, preservatives, and flavoring agents. Patients were instructed not to eat, drink, brush their teeth or rinse their mouth for 30 minutes after taking BOS. After 30 minutes, patients were instructed to rinse their mouth with water.
      The randomization schedule was generated by SynteractHCR, Inc. and was verified for accuracy using strict quality-control procedures. Randomization was stratified by site with a block size of 4. Participants eligible for randomization received sequentially generated randomization numbers issued by Clinical Supplies Management, Inc., which were matched to the number on their study drug kit. The randomization number was not used to identify a patient’s study data. Instead, all patients were assigned a unique 6-digit patient identification number at screening. Participants, investigators, the sponsor, study site personnel, and the central pathologist were blinded to patients’ treatment, until after all patients had completed the treatment period and the database was locked. Treatment assignment was only to be unblinded in a situation where unblinding was absolutely necessary for the management of patient safety or for regulatory reporting purposes to the Food and Drug Administration. However, no patients required treatment assignment unblinding before the database lock in this study. Active study medication and placebo were dispensed in identical amber glass bottles to maintain the blind.
      Compliance was measured by residual volume in the medication bottles. At the end of the treatment period, repeat endoscopy and biopsy were performed. The co-primary outcomes were the change in DSQ score from baseline; and the proportion of patients with a histologic response, defined as ≤6 eos/hpf. This cutoff of ≤6 eos/hpf was used in the previous pediatric study of BOS,
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      and is supported by a number of studies in the literature.
      • DeBrosse C.W.
      • Collins M.H.
      • Buckmeier Butz B.K.
      • et al.
      Identification, epidemiology, and chronicity of pediatric esophageal eosinophilia, 1982–1999.
      • DeBrosse C.W.
      • Franciosi J.P.
      • King E.C.
      • et al.
      Long-term outcomes in pediatric-onset esophageal eosinophilia.
      Secondary end points included endoscopic findings and safety.
      The DSQ is a 3-question daily diary that has been validated for the measurement of dysphagia frequency and severity in patients with EoE.
      • Dellon E.S.
      • Irani A.M.
      • Hill M.R.
      • et al.
      Development and field testing of a novel patient-reported outcome measure of dysphagia in patients with eosinophilic esophagitis.
      • Hudgens S.
      • Evans C.
      • Philips E.
      • et al.
      Psychometric validation of the Dysphagia Symptom Questionnaire in eosinophilic esophagitis patients treated with oral budesonide suspension.
      The questions ask whether solid food has been eaten; whether food has gone down slowly or become stuck; and what, if any, measures have been taken to achieve relief. DSQ scores are calculated on the basis of the responses to these questions over a 2-week period. The scores for questions 2 and 3 are summed, then divided by the number of days for which the diary has been completed and multiplied by 14. Scores can range from 0 to 84, with higher values indicating more frequent and severe dysphagia. A DSQ score of 0 represents an absence of dysphagia symptoms. DSQ scores over the last 14 days of the 12-week treatment period were used for the symptom outcome measure using the algorithm above. Two prespecified secondary end points were also examined: the proportion of patients with a ≥30% or a ≥50% reduction in DSQ score from baseline; and 2) patients who had this symptom response combined with a histologic response (≤6 eos/hpf).
      For histology assessment, 2 to 4 esophageal biopsies were obtained from each level of the esophagus (proximal, mid, and distal). Biopsies were reviewed centrally by the study pathologist (M.H.C., who was blinded to treatment allocation). All biopsies from each site in the esophagus were examined, and intraepithelial eosinophils were counted in the areas of greatest eosinophil density.
      • Collins M.H.
      Histopathology of eosinophilic esophagitis.
      Counts were reported as the number of eos/hpf (hpf area = 0.3 mm2) and multiple hpfs were analyzed until the peak count was clearly identified. In addition, gastric and duodenal biopsies were obtained and reviewed centrally during the screening period to exclude patients with concomitant eosinophilic gastroenteritis.
      Upper endoscopy was performed using standard techniques. Endoscopic findings (esophageal rings, white plaques or exudates, linear furrows, decreased vascularity or edema, and strictures) were recorded and quantified using the validated EoE Endoscopic Reference Score (EREFS);
      • Hirano I.
      • Moy N.
      • Heckman M.G.
      • et al.
      Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system.
      esophageal biopsies were obtained at the same time. The total EREFS was calculated by summing the severity scores of the individual components of the EREFS (edema 0−2, rings 0−3, exudates 0−2, furrows 0−2, strictures 0−1) assessed for both the proximal and distal esophagus, and ranged from 0 to 20, with higher scores indicating more severe endoscopic findings.
      Safety was assessed at each study visit by carrying out a physical examination and recording height, weight, and vital signs. Clinical laboratory tests were also performed, including assessment of a morning cortisol level to monitor the adrenal axis. Patients received a follow-up telephone call 4 weeks after receiving their last dose of the study drug. All clinical laboratory tests were performed by a centralized clinical laboratory (LabConnect, LLC).

       Statistical Analyses

      Data were collected by investigators at each site and the database was managed by the study sponsor. All authors had access to the study data and reviewed and approved the final manuscript. There were 2 analysis sets. The safety analysis set included all patients who received any study drug. The modified intention-to-treat analysis set included all randomized patients who received at least 1 dose of study drug and had both an evaluable post-treatment DSQ score and a post-treatment biopsy. Characteristics of the treatment and placebo arms were summarized with descriptive statistics. The change in DSQ score and change in EREFS were each compared using analysis of covariance, and the proportion of patients with a histologic response was compared using Fisher’s exact test. We also compared levels of symptom, histologic, and endoscopic response using Fisher’s exact test. For exploratory analyses based on histologic response, odds ratios (for categorical variables) and differences (for continuous variables) with 95% confidence intervals were calculated.
      The planned sample size was to have at least 40 patients in each arm complete the study. This would yield >90% power to detect an 88% difference in histologic response,
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      and 89% power to detect a 35% difference in symptom response. Assuming a 20% dropout rate, the goal was to enroll 50 patients in each arm.

       Role of the Funding Source

      Meritage Pharma, Inc, now part of the Shire group of companies, contributed to the design and conduct of the study; collection and management of the data; and reviewed the manuscript for medical accuracy. Approval of the manuscript, and the decision to submit the manuscript for publication was the responsibility of the authors.

      Results

       Patient Flow and Baseline Characteristics

      Of the 203 patients screened, 119 met eligibility criteria and entered the blinded placebo run-in period. Of these, 26 were excluded, primarily for experiencing dysphagia on too few days, and 93 were randomized, 51 to BOS and 42 to placebo. This group comprised the safety analysis set. Of the randomized patients, 5 dropped out, 2 in the BOS arm (1 because of an adverse event and 1 owing to lack of compliance) and 3 in the placebo arm (1 because of lack of efficacy, 1 because of lack of compliance, and 1 owing to pregnancy); 1 additional patient in the placebo arm did not have an evaluable post-treatment biopsy. Therefore, 87 were included in the outcome analysis set (49 on BOS and 38 on placebo) (Supplementary Figure 1).
      The BOS and placebo groups had similar baseline characteristics (Table 1). The BOS and placebo groups also had a similarly high prevalence of endoscopic findings, such as esophageal rings (61% and 64%), white plaques (73% and 69%), linear furrows (94% and 86%), and edema (80% and 76%, respectively). Compliance with study medication was high in both the BOS and the placebo groups, with 86% and 88% receiving the intended dose.
      Table 1Demographics and Baseline Measures in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension or Placebo
      CharacteristicBOS (n = 51)Placebo (n = 42)
      Age, y, mean ± SD22.3 ± 7.920.8 ± 7.5
       Younger than 18 y, n (%)18 (35)17 (41)
       Age of those younger than 18 y, mean ± SD14.6 ± 2.213.6 ± 1.6
      Male, n (%)35 (69)29 (69)
      White, n (%)48 (94)40 (95)
      Months since EoE diagnosis, mean ± SD38.5 ± 34.336.5 ± 42.6
      Height, cm, mean ± SD173.6 ± 9.9170.7 ± 13.0
      Weight, kg, mean ± SD72.0 ± 16.967.8 ± 17.3
      Previous medication, n (%)
       Corticosteroids14 (28)13 (31)
       Systemic, oral2 (4)2 (5)
       Systemic, intravenous5 (10)5 (12)
       Inhaled2 (4)4 (10)
       Intranasal7 (14)6 (14)
      Antihistamines8 (16)3 (7)
      Leukotriene antagonists6 (12)6 (14)
      Proton pump inhibitors
       Past35 (69)29 (69)
       Current36 (71)28 (67)
      Endoscopic findings, n (%)
       Normal1 (2)2 (5)
       Esophageal rings31 (61)27 (64)
       White plaques or exudates37 (73)29 (69)
       Linear furrows48 (94)36 (86)
       Edema or decreased vascularity41 (80)32 (76)
       Esophageal stricture7 (14)4 (10)
       Total EREFS, mean ± SD
      The total EREFS was calculated by summing the scores for the 5 major individual findings (grade 0−3 for esophageal rings; grade 0−2 for white plaques or exudates, edema or decreased vascularity, and linear furrows; and grade 0−1 for esophageal stricture) from both the proximal and distal esophagus.
      7.7 ± 3.57.0 ± 3.3
      DSQ score, mean ± SD
      DSQ score calculated based on patient responses to questions 2 and 3 of the questionnaire (frequency and intensity of dysphagia) over a 2-week period. Scores from these questions were summed, divided by number of days for which the diary was completed, and multiplied by 14 (days). Scores could range from 0 to 84.
      30.4 ± 15.929.0 ± 13.5
      Peak eosinophil counts, eos/hpf, mean ± SD
       Overall157.8 ± 96.1133.0 ± 81.6
       By esophageal location
      Proximal100.9 ± 99.653.4 ± 58.5
      Mid103.8 ± 67.594.4 ± 80.5
      Distal107.4 ± 79.595.6 ± 74.8
      a The total EREFS was calculated by summing the scores for the 5 major individual findings (grade 0−3 for esophageal rings; grade 0−2 for white plaques or exudates, edema or decreased vascularity, and linear furrows; and grade 0−1 for esophageal stricture) from both the proximal and distal esophagus.
      b DSQ score calculated based on patient responses to questions 2 and 3 of the questionnaire (frequency and intensity of dysphagia) over a 2-week period. Scores from these questions were summed, divided by number of days for which the diary was completed, and multiplied by 14 (days). Scores could range from 0 to 84.

       Symptomatic, Histologic, and Endoscopic Outcomes

      The baseline mean DSQ scores were 29.3 in the BOS group and 29.0 in the placebo group. After treatment, these decreased to 15.0 and 21.5, respectively. There was a significantly larger decrease in the BOS group (−14.3) than the placebo group (−7.5; P = .0096) (Table 2; Figure 1A). The first of the co-primary end points was therefore met. When examining symptom thresholds (prespecified secondary end point), 34 patients (69%) in the BOS group had a ≥30% reduction in DSQ score compared with 17 patients (45%) in the placebo group (P = .021). Similarly, 31 patients (63%) in the BOS group had a ≥50% reduction in DSQ score compared with 15 patients (40%) in the placebo group (P = .028). The number of patients who experienced complete symptom resolution (DSQ score 0) at week 12 was reported as an exploratory outcome, and was higher in the BOS group (20% [10 of 49]) than in the placebo group (13% [5 of 38]).
      Table 2Baseline and Post-Treatment Measures in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension or Placebo
      VariableBOS (n = 49)Placebo (n = 38)P value
      DSQ score, mean ± SD
      DSQ score calculated based on patient responses to questions 2 and 3 of the questionnaire (frequency and intensity of dysphagia) over a 2-week period. Scores from these questions were summed, divided by number of days for which the diary was completed, and multiplied by 14 (days). Scores could range from 0 to 84.
       Baseline29.3 ± 15.129.0 ± 13.9
       Post-treatment15.0 ± 16.921.5 ± 16.0
       Difference−14.3 ± 13.0−7.5 ± 10.7.0096
      Proportion of histologic responders, n (%)
      Proportion of histologic responders post-treatment; histologic response defined as ≤6 eos/hpf.
      19 (39)1 (3)<.0001
      Peak eosinophil count, eos/hpf, mean ± SD
       Baseline156.3 ± 97.6130.2 ± 81.8
       Post-treatment39.3 ± 48.1112.9 ± 84.3
       Difference−117.0 ± 111.6−17.3 ± 83.8<.0001
      EREFS, mean ± SD
      The total EREFS was calculated by summing the scores for the 5 major individual parameters (grade 0−3 for esophageal rings; grade 0−2 for white plaques or exudates, edema or decreased vascularity, and linear furrows; and grade 0−1 for esophageal stricture) from both the proximal and distal esophagus.
       Baseline7.7 ± 3.66.9 ± 3.4
       Post-treatment3.9 ± 3.37.3 ± 4.0
       Difference−3.8 ± 3.90.4 ± 6.7<.0001
      a DSQ score calculated based on patient responses to questions 2 and 3 of the questionnaire (frequency and intensity of dysphagia) over a 2-week period. Scores from these questions were summed, divided by number of days for which the diary was completed, and multiplied by 14 (days). Scores could range from 0 to 84.
      b Proportion of histologic responders post-treatment; histologic response defined as ≤6 eos/hpf.
      c The total EREFS was calculated by summing the scores for the 5 major individual parameters (grade 0−3 for esophageal rings; grade 0−2 for white plaques or exudates, edema or decreased vascularity, and linear furrows; and grade 0−1 for esophageal stricture) from both the proximal and distal esophagus.
      Figure thumbnail gr1
      Figure 1Study outcomes in patients with eosinophilic esophagitis receiving budesonide oral suspension vs placebo. (A) Change in DSQ score; (B) histologic outcomes; and (C) endoscopic outcomes from baseline.
      At baseline, the means of the peak eosinophil counts were 156 eos/hpf in the BOS group and 130 eos/hpf in the placebo group. Post-treatment, these were 39 and 113, respectively (P < .0001; Table 2). The distribution of peak eosinophil counts for patients in the BOS and placebo groups at baseline (safety analysis set) by esophageal region is shown in Supplementary Figure 2. A total of 19 patients (39%) in the BOS group achieved the histologic response end point of ≤6 eos/hpf, compared with 1 patient (3%) in the placebo group (P < .0001) (Table 2; Figure 1B), thus meeting the second of the co-primary end points. Illustrative pre- and post-treatment biopsies are shown in Figure 2. When examining additional histologic response thresholds, a total of 23 patients (47%) in the BOS group had ≤15 eos/hpf vs 3 (8%) in the placebo group (P = .0001), and 15 (31%) patients in the BOS group had ≤1 eos/hpf vs none in the placebo group (P < .0001).
      Figure thumbnail gr2
      Figure 2Baseline and post-treatment endoscopies with corresponding esophageal biopsies for 2 patients with eosinophilic esophagitis receiving budesonide oral suspension. Pretreatment images show esophageal rings, linear furrows, and edema (patient 1 [A]), and white plaques and edema (patient 2, [C]). Both biopsy specimens have elevated mucosal eosinophilia, indicated by arrows (A, C). Post-treatment images show normalization of the esophageal mucosa and the epithelium (B, D). Histology images: stained with H&E; 200× original magnification.
      An additional secondary efficacy end point showed that a higher proportion of patients in the BOS group had both a histologic response and a ≥30% reduction in DSQ score compared with patients in the placebo group (27% vs 3%; P = .0026); a higher proportion of patients receiving BOS also experienced both a histologic response and a ≥50% reduction in DSQ score compared with placebo (20% vs 3%; P = .0199).
      The baseline mean EREFSs were 7.7 in the BOS group and 6.9 in the placebo group. After treatment, these were 3.9 and 7.3, respectively. There was a significantly larger decrease in the BOS group (−3.8) than in the placebo group (0.4; P < .0001) (Table 2; Figure 1C). In addition to the improvement in total EREFS, significant improvements within each EREFS component (with the exception of strictures) from baseline were also observed for patients receiving BOS compared with those receiving placebo (Figure 3). The severity score for esophageal rings in the BOS group decreased (improved) from 1.7 to 1.0, but was unchanged in the placebo group (1.4 to 1.7) (change from baseline: −0.7 vs +0.3; P = .006). Similarly, the severity score for esophageal exudates in the BOS group decreased from 1.6 to 0.4, but was unchanged in the placebo group (1.4 to 1.3) (change from baseline: −1.2 vs −0.1; P < .001). Severity scores for furrows in the BOS group decreased from 2.3 to 1.2 without a change in the placebo group (2.0 to 2.1) (change from baseline: −1.1 vs +0.1; P < .0001. Severity scores for edema in the BOS group decreased from 1.9 to 1.1, again without any change in the placebo group (1.9 to 2.1) (change from baseline: −0.8 vs +0.2; P = .004) (Figure 3). These scores were calculated from 2 levels of the esophagus (proximal and distal); and the data are presented by location in Supplementary Table 1. These results show an improvement in endoscopic features in the BOS group from baseline in both the proximal and distal regions of the esophagus. Furthermore, a total of 7 patients (14%) in the BOS group and 1 patient (3%) in the placebo group had normal endoscopic findings (EREFS 0) after treatment. Illustrative pre- and post-treatment endoscopic images are shown in Figure 2.
      Figure thumbnail gr3
      Figure 3Baseline and post-treatment changes in endoscopic severity for individual components of the EREFS for patients with eosinophilic esophagitis receiving budesonide oral suspension vs placebo. Findings for esophageal edema, rings, exudates, furrows, and strictures are presented at baseline and post-treatment for the BOS and placebo groups. P values compare change in scores from baseline between treatment arms.
      Given that symptoms, histology, and endoscopic severity all improved with BOS compared with placebo, we investigated correlations between these responses. In the BOS group, there was a weak correlation between change in peak eosinophil count and change in DSQ score (R = 0.04) and between change in DSQ score and change in EREFS (R = 0.05), but a moderate correlation between change in peak eosinophil count and change in EREFS (R = 0.33).
      Overall, clinical, endoscopic, and histologic baseline characteristics were similar in patients treated with BOS who did and did not have a histologic response (Table 3). However, compared with histologic responders, nonresponders had been diagnosed with the disease for almost twice as long (46 vs 25 months) and were more than 10 kg heavier (76 vs 65 kg). Symptoms and endoscopic findings improved more in histologic responders than in nonresponders. The mean change in the DSQ score was −16.2 in histologic responders and −9.9 in nonresponders (P < .001). Similarly, the mean change in total EREFS was −5.1 in histologic responders and −2.9 in nonresponders (P = .06).
      Table 3Comparison of Baseline Characteristics in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension According to Histologic Response (≤6 eos/hpf)
      CharacteristicPatients with histologic response
      Histologic responders defined as ≤6 eos/hpf; nonresponders defined as >6 eos/hpf.
      Responders (n = 19)Nonresponders (n = 30)OR or difference (95% CI)
      Age, y, mean ± SD22.5 ± 7.721.7 ± 7.60.9 (−3.7 to 5.4)
       Younger than 18 y, n (%)8 (42)10 (33)0.69 (0.21 to 2.25)
      Male, n (%)11 (58)24 (80)2.91 (0.81 to 10.4)
      White, n (%)16 (84)30 (100)
      Time since EoE diagnosis, mo, mean ± SD25.2 ± 22.345.5 ± 36.8−20.3 (−39.9 to −0.8)
      Height, cm, mean ± SD172.5 ± 8.3174.8 ± 11.0−2.4 (−8.3 to 3.5)
      Weight, kg, mean ± SD64.6 ± 10.576.4 ± 18.4−11.7 (−21.0 to −2.3)
      Previous medication, n (%)
       Corticosteroids (any)5 (26)9 (30)1.20 (0.33 to 4.34)
       Antihistamines5 (16)4 (13)0.82 (0.16 to 4.15)
       Leukotriene antagonists1 (5)5 (17)3.60 (0.39 to 33.5)
       Current proton pump inhibitors15 (79)20 (67)0.53 (0.14 to 2.03)
      Endoscopic findings, n (%)
       Esophageal rings10 (53)20 (67)1.80 (0.55 to 5.84)
       White plaques or exudates15 (79)20 (67)0.53 (0.14 to 2.03)
       Linear furrows18 (95)28 (93)0.78 (0.07 to 9.22)
       Edema or decreased vascularity14 (74)25 (83)1.79 (0.44 to 7.25)
       Esophageal stricture2 (11)5 (17)1.70 (0.29 to 9.80)
       Total EREFS, mean ± SD
      The total EREFS was calculated by summing the scores for the 5 major individual findings (grade 0−3 for esophageal rings; grade 0−2 for white plaques or exudates, edema or decreased vascularity, and linear furrows; and grade 0−1 for esophageal stricture) from both the proximal and distal esophagus.
      7.4 ± 3.77.8 ± 3.6−0.4 (−2.5 to 1.8)
      DSQ score, mean ± SD
      DSQ score calculated based on patient responses to questions 2 and 3 of the questionnaire (frequency and intensity of dysphagia) over a 2-week period. Scores from these questions were summed, divided by number of days for which the diary was completed, and multiplied by 14 (days). Scores could range from 0 to 84.
      30.9 ± 15.128.2 ± 15.32.6 (−6.3 to 11.6)
      Peak eosinophil counts, eos/hpf, mean ± SD
       Overall154.2 ± 98.0157.7 ± 99.0−3.5 (−61.7 to 54.6)
       By esophageal location
        Proximal86.7 ± 78.8104.1 ± 113.0−17.4 (−78.0 to 43.2)
        Mid102.9 ± 50.3106.1 ± 78.6−3.2 (−45.2 to 38.9)
        Distal113.1 ± 96.2105.2 ± 71.27.8 (−40.3 to 56.0)
      By baseline eosinophil count, n (%)
       >50 eos/hpf19 (100)27 (90)
       >100 eos/hpf11 (58)21 (70)1.70 (0.51 to 5.63)
      a Histologic responders defined as ≤6 eos/hpf; nonresponders defined as >6 eos/hpf.
      b The total EREFS was calculated by summing the scores for the 5 major individual findings (grade 0−3 for esophageal rings; grade 0−2 for white plaques or exudates, edema or decreased vascularity, and linear furrows; and grade 0−1 for esophageal stricture) from both the proximal and distal esophagus.
      c DSQ score calculated based on patient responses to questions 2 and 3 of the questionnaire (frequency and intensity of dysphagia) over a 2-week period. Scores from these questions were summed, divided by number of days for which the diary was completed, and multiplied by 14 (days). Scores could range from 0 to 84.

       Safety and Adverse Events

      Reports of treatment-emergent adverse events were similar in the BOS (47%) and placebo (50%) groups (Supplementary Table 2). There was 1 severe adverse event in the BOS group related to an episode of food poisoning and deemed unrelated to the study drug, and a second adverse event in the BOS group that led to withdrawal because of chest pain, dyspnea, nausea, and vomiting, which was deemed related to the study drug. Nasopharyngitis, upper respiratory infection, and oropharyngeal pain were the most commonly reported adverse events in both groups. There was 1 case each of esophageal candidiasis and oral candidiasis in the BOS group. There were no laboratory-related treatment-emergent adverse events. Additionally, there were no notable differences between groups in cortisol levels (Supplementary Table 3) or growth characteristics (for those aged younger than 18 years; Supplementary Table 4), and vital signs remained stable for all participants.

      Discussion

      Topical corticosteroids are the first-line pharmacologic treatment option for patients with EoE, but none are Food and Drug Administration−approved or designed for EoE and none have previously been assessed using a validated PRO instrument.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      • Dellon E.S.
      • Gonsalves N.
      • Hirano I.
      • et al.
      ACG clinical guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis.
      • Furuta G.T.
      • Liacouras C.A.
      • Collins M.H.
      • et al.
      Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      • Rothenberg M.E.
      • Aceves S.
      • Bonis P.A.
      • et al.
      Working with the US Food and Drug Administration: progress and timelines in understanding and treating patients with eosinophilic esophagitis.
      • Fiorentino R.
      • Liu G.
      • Pariser A.R.
      • et al.
      Cross-sector sponsorship of research in eosinophilic esophagitis: a collaborative model for rational drug development in rare diseases.
      This multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2 trial aimed to determine whether BOS was superior to placebo in decreasing symptoms of dysphagia and esophageal eosinophil counts. Not only did BOS induce a histologic response in a significantly higher proportion of patients than placebo, we show for the first time that it also significantly decreased symptoms of dysphagia as assessed by a validated PRO instrument. Importantly, the decrease in symptom score was clinically meaningful with dysphagia being experienced on approximately 3 fewer days over 2 weeks in the BOS group than in the placebo group. Furthermore, the study is the first to demonstrate improvement in endoscopic severity scores, assessed using the validated EREFS instrument. In addition, patients with a histologic response experienced greater improvements in dysphagia symptoms and endoscopic severity compared with nonresponders. No safety issues related to BOS were identified during the 12-week treatment period, and patients were highly compliant. There were only 2 cases of esophageal candidiasis in patients receiving BOS; this is lower than the reported rates in the literature for other swallowed corticosteroids;
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      however, this finding is consistent with a previous study of this budesonide formulation.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      Several formulations of budesonide have previously been used in clinical trials, including a slurry created by mixing an aqueous form with sucralose,
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      • Dohil R.
      • Newbury R.
      • Fox L.
      • et al.
      Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial.
      a nebulized form (allowing aerosolized droplets to be swallowed),
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.
      a pre-mixed viscous solution,
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      and an effervescent dissolvable tablet.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      Doses in these studies were 1−4 mg/d, with treatment periods of 2−12 weeks. Histologic responses were variable (27%−100% depending on the age group, formulation, and histologic response threshold studied) and symptom response rates were equally variable. None of these studies used a validated symptom instrument, and in 3 of the 5 trials there were discordant symptomatic and histologic responses.
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      In addition to these individual studies, a number of systematic reviews/meta-analyses have been performed to examine the efficacy of current pharmacologic treatments for EoE. These reviews have shown that patients treated with topical corticosteroids typically experience improvements in histologic outcomes compared with placebo (or therapy control); however, a clear symptom response is often less evident,
      • Tan N.D.
      • Xiao Y.L.
      • Chen M.H.
      Steroids therapy for eosinophilic esophagitis: systematic review and meta-analysis.
      • Chuang M.Y.
      • Chinnaratha M.A.
      • Hancock D.G.
      • et al.
      Topical steroid therapy for the treatment of eosinophilic esophagitis (EoE): a systematic review and meta-analysis.
      • Sawas T.
      • Dhalla S.
      • Sayyar M.
      • et al.
      Systematic review with meta-analysis: pharmacological interventions for eosinophilic oesophagitis.
      • Murali A.R.
      • Gupta A.
      • Attar B.M.
      • et al.
      Topical steroids in eosinophilic esophagitis: Systematic review and meta-analysis of placebo-controlled randomized clinical trials.
      in part due to the absence of a validated clinical outcome assessment for EoE.
      In the previous study of BOS,
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      children were treated with age-based dosing, and of those receiving the highest dose (2 mg twice daily), 94% had a histologic response compared with 6% in the placebo group. The present study had a lower histologic response rate than this. However, our observed response rate is consistent with the range of responses that have been reported for topical steroids overall in the literature.
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      • Konikoff M.R.
      • Noel R.J.
      • Blanchard C.
      • et al.
      A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.
      • Schaefer E.T.
      • Fitzgerald J.F.
      • Molleston J.P.
      • et al.
      Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children.
      • Butz B.K.
      • Wen T.
      • Gleich G.J.
      • et al.
      Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis.
      • Dohil R.
      • Newbury R.
      • Fox L.
      • et al.
      Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial.
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      • Wolf W.A.
      • Cotton C.C.
      • Green D.J.
      • et al.
      Predictors of response to steroid therapy for eosinophilic esophagitis and treatment of steroid-refractory patients.
      The reasons for the difference in histologic response observed in this study and the previous study of BOS
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      are not known, but earlier studies of pediatric EoE have shown that age, body mass, and height are predictors of steroid response.
      • Konikoff M.R.
      • Noel R.J.
      • Blanchard C.
      • et al.
      A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.
      The lower histologic response observed in the present study may also be a result of the study design, in particular the inclusion criteria. For enrollment in the current study, patients were required to have active inflammation and also to be highly symptomatic, with at least 4 days of dysphagia in the 2 weeks before study entry. In addition, patients had to maintain this high level of symptomatology during a blinded placebo run-in period in order to be randomized. They also had to have eosinophilic inflammation at 2 levels in the esophagus, a stringent inclusion criterion used only in the previous BOS study.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      This probably resulted in a more severe disease phenotype than seen in other studies,
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      which might also have been more treatment resistant. For example, the peak baseline eosinophil count in this study, 156.3 eos/0.3 mm2 hpf (or 521 eos/mm2) in the BOS arm, is among the highest reported in the literature; in other studies of budesonide using this as an outcome measure, peak baseline eosinophil densities were 320−421 eos/mm2 (after conversion of counts based on hpf area).
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      To our knowledge, no other published study has been designed to enroll a comparably symptomatic and histologically severe population of patients with EoE. Indeed, Eluri and colleagues have recently identified disease severity as a significant predictor of response to steroids.
      • Eluri S.
      • Runge T.M.
      • Cotton C.C.
      • et al.
      The extremely narrow-caliber esophagus is a treatment-resistant subphenotype of eosinophilic esophagitis.
      Finally, although a number of studies have reported high (>90%) histologic response rates in patients receiving topical corticosteroids,
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      no statistically significant difference in symptom response compared with placebo was observed in these earlier studies.
      We found few predictors of histologic response; only shorter disease duration and lower body weight were associated with response. However, these results may have been found by chance, and as such, may not reflect a true difference between responders and nonresponders. As mentioned previously, lower body weight, shorter stature, and younger age were identified as predictors in a pediatric study using topical fluticasone.
      • Konikoff M.R.
      • Noel R.J.
      • Blanchard C.
      • et al.
      A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.
      There are few published data on predictors of response to topical budesonide. In 1 large retrospective study,
      • Wolf W.A.
      • Cotton C.C.
      • Green D.J.
      • et al.
      Predictors of response to steroid therapy for eosinophilic esophagitis and treatment of steroid-refractory patients.
      esophageal dilation was associated with nonresponse, and other studies have shown that the prevalence of esophageal strictures (and hence the need for dilation) increased with increasing disease duration.
      • Schoepfer A.M.
      • Safroneeva E.
      • Bussmann C.
      • et al.
      Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.
      • Dellon E.S.
      • Kim H.P.
      • Sperry S.L.
      • et al.
      A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease.
      Additionally, we observed no statistically significant difference in EREFS between responders and nonresponders at baseline, which is consistent with the study by van Rhijn and colleagues,
      • van Rhijn B.D.
      • Verheij J.
      • Smout A.J.
      • et al.
      The Endoscopic Reference Score shows modest accuracy to predict histologic remission in adult patients with eosinophilic esophagitis.
      which identified limitations in the correlation between EREFS and histologic remission.
      Limitations of this study include a restricted age range (11−40 years), so results may not be applicable to young children or older adults. There was also an imbalance with regards to patient numbers after randomization (BOS, n = 51; placebo, n = 42), which was due to the site stratification method used (block size of 4), a site randomization error that occurred at 2 of the sites (these 2 sites skipped random numbers in error), and a number of sites only enrolling 1 patient per site. Specifically, there were 5 sites where only 1 patient was enrolled and 3 sites where there was an imbalance (of 1−3 patients per site). Patients with severe strictures were excluded at screening to avoid esophageal dilation as a confounder to symptom response; although patients with mild strictures were included, none of these patients developed severe strictures during the 12-week treatment period. It should also be noted that patients were allowed to remain on a stable dose of PPI during the trial, which could have impacted the treatment effect size. However, this would have been unlikely to introduce bias, as patients in the BOS and placebo groups had similar levels of PPI use. Finally, although the 12-week treatment period is longer than some previous trials,
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      long-term efficacy data are needed. This study was not powered to assess treatment effect by age (ie, adolescents vs adults); however, this would be useful to examine in future studies of BOS.
      A key strength of the study is that this was a rigorously conducted, multicenter, randomized, blinded, placebo-controlled, parallel-group trial that is the largest study of topical corticosteroids to date in patients with EoE. The strict inclusion criteria yielded a histologically severe and symptomatic population of patients with EoE. Safety monitoring was comprehensive. Finally, this is the first trial to use validated symptom and endoscopy outcome measures specifically developed for EoE,
      • Dellon E.S.
      • Irani A.M.
      • Hill M.R.
      • et al.
      Development and field testing of a novel patient-reported outcome measure of dysphagia in patients with eosinophilic esophagitis.
      • Hirano I.
      • Moy N.
      • Heckman M.G.
      • et al.
      Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system.
      as well as the first to show improvement in symptomatic, endoscopic, and histologic outcomes. Recent clinical trials of topical steroids in EoE have failed to show this relationship with nonvalidated symptom measures.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      These design elements, including the blinded placebo run-in period, should help to inform future therapeutic trials in EoE.
      In conclusion, compared with placebo, 12 weeks of BOS treatment significantly improved both esophageal eosinophilia and symptoms of dysphagia in adolescents and adults with active EoE. There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used. In addition, this is the first prospective study to use a validated PRO instrument and a validated endoscopy classification to demonstrate improvement in dysphagia symptoms and endoscopic severity scores. BOS is therefore a promising formulation for treatment of EoE.

      Acknowledgments

      The authors would like to thank the MPI-101-06 Investigators and the participants of this study. MP-101-06 investigators were as follows: Amir Kagalwalla, Jeffrey Lewis, Jonathan Markowitz, Samuel Nurko, John Wo, Evan Dellon, Thirumazhisai S. Gunasekaran, Ikuo Hirano, Sandeep Gupta, Brad Pasternak, Mark Ellis, Kathryn Peterson, Gary Falk, John Leung, Laurel Prestridge, Michael Hart, Neal Leleiko, Michael Vaezi, Rebecca Cherry, David Katzka, Keith Friedenberg, Yehudith Assouline-Dayan, and Vincent Mukkada.
      Writing assistance: Catherine Hill, PhD, and Luci Witcomb, PhD of PharmaGenesis London, provided medical editorial support funded by Shire Development LLC.

      Supplementary Material

       MPI-101-06 Investigators and Sites That Randomized Patients

      Yehudith Assouline-Dayan, MD, University of Iowa Hospitals and Clinics, Iowa City, IA
      Rebecca Cherry, MD, Rady Children's Hospital, San Diego, CA
      Margaret H. Collins, MD, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
      Evan Dellon, MD, University of North Carolina Chapel Hill, Chapel Hill, NC
      Mark Ellis, MD, Children’s Hospital of Orange County Pediatric Subspecialty Faculty, AMC, Division of Allergy, Asthma & Immunology, Orange, CA
      Gary Falk, MD, University of Pennsylvania, Philadelphia, PA
      Keith Freidenberg, MD, Great Lakes Gastroenterology, Mentor, OH
      Thirumazhisai S. Gunasekaran, MD, Center for Children's Digestive Health, Park Ridge, IL
      Sandeep Gupta, MD, Riley Hospital for Children, Indianapolis, IN
      Michael Hart, MD, Carilion Clinic, Pediatric GI Clinic, Roanoke, VA
      Ikuo Hirano, MD, Northwestern School of Medicine, Chicago, IL
      Amir Kagalwalla, MD, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
      David Katzka, MD, Mayo Clinic, Rochester, MN
      Robert Kramer, MD, The Children’s Hospital, Aurora, CO
      Neal LeLeiko, MD, Rhode Island Hospital, Providence, RI
      John Leung, MD, Tufts Medical Center, Institute for Clinical Research and Health Policy Studies, Boston, MA
      Jeffery Lewis, MD, Children's Center for Digestive Healthcare, LLC, Atlanta, GA
      Jonathan Markowitz, MD, Children's Center for Digestive Health, Greenville, SC
      Vincent Mukkada, MD, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
      Samuel Nurko, MD, Children’s Hospital Boston, Boston, MA
      Brad Pasternak, MD, Phoenix Children's Hospital, Phoenix, AZ
      Kathryn Peterson, MD, University of Utah Healthcare, Salt Lake City, UT
      Laurel Prestridge, MD, Boys Town National Research Hospital, Boys Town, NE
      John Tung, MD, South Jersey Pediatric Gastroenterology, Mays Landing, NJ
      Michael Vaezi, MD, Vanderbilt University Medical Center, Nashville, TN
      John Wo, MD, Indiana University Health University Hospital, Indianapolis, IN
      Figure thumbnail fx1
      Supplementary Figure 1CONSORT (Consolidated Standards of Reporting Trials) diagram showing patient flow. Of 203 screened, 119 met initial eligibility criteria. The majority of those who were ineligible did not meet histologic or symptom thresholds. Of the 119 eligible, 26 were excluded, primarily for experiencing dysphagia on too few days. In total, 93 participants were randomized and comprised the safety analysis set. Of these, 87 patients were included in the outcome analysis set.
      Figure thumbnail fx2
      Supplementary Figure 2Distribution of mean peak eosinophil counts by esophageal region and their mean maximum counts for patients receiving budesonide oral suspension (A) or placebo (B) (safety analysis set). Boxplots show mean (diamond), median (middle line), interquartile ranges ([IQR]; top and bottom edges of box), minimum and maximum values (error bars, within 1.5 × IQR), and values considered to be outliers (circles, values < or >1.5 × IQR).
      Supplementary Table 1Baseline and Post-Treatment Total Endoscopic Reference Score and Individual Component Scores From Proximal and Distal Regions of the Esophagus in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension or Placebo
      Estimates were determined using an ANCOVA model including treatment group and baseline value as a covariate.
      ProximalDistal
      BOS (n = 49)Placebo (n = 38)P valueBOS (n = 49)Placebo (n = 38)P value
      EREFS
      The total EREFS was calculated by summing the scores for the 5 major individual parameters (grade 0−3 for esophageal rings; grade 0−2 for white plaques or exudates, edema or decreased vascularity, and linear furrows; and grade 0−1 for esophageal stricture).
       Baseline3.4 ± 2.23.3 ± 2.04.3 ± 1.93.6 ± 1.6
       Post-treatment1.5 ± 1.83.4 ± 2.22.4 ± 1.83.9 ± 2.2
       Difference−1.8 ± 2.20.1 ± 2.2.0001−1.9 ± 2.10.3 ± 2.0<.0001
      Fixed rings
       Baseline0.8 ± 0.80.7 ± 0.70.8 ± 0.80.7 ± 0.7
       Post-treatment0.4 ± 0.70.9 ± 0.90.6 ± 0.80.8 ± 0.8
       Difference−0.4 ± 0.70.2 ± 0.8.0046−0.2 ± 0.80.1 ± 0.9.1394
      Exudates
       Baseline0.7 ± 0.70.7 ± 0.70.9 ± 0.70.8 ± 0.7
       Post-treatment0.2 ± 0.50.6 ± 0.80.2 ± 0.50.8 ± 0.8
       Difference−0.6 ± 0.8−0.1 ± 0.9.0142−0.6 ± 0.80.0 ± 0.8.0006
      Furrows
       Baseline1.0 ± 0.71.0 ± 0.61.4 ± 0.61.1 ± 0.6
       Post-treatment0.4 ± 0.70.9 ± 0.70.8 ± 0.71.2 ± 0.7
       Difference−0.6 ± 0.70.0 ± 0.7.0007−0.6 ± 0.70.2 ± 0.7<.0001
      Edema
       Baseline0.8 ± 0.70.9 ± 0.81.1 ± 0.71.0 ± 0.7
       Post-treatment0.4 ± 0.70.9 ± 0.70.7 ± 0.71.2 ± 0.7
       Difference−0.3 ± 0.80.0 ± 0.7.0281−0.4 ± 0.80.2 ± 0.7.0012
      Strictures
       Baseline0.0 ± 0.20.1 ± 0.20.1 ± 0.40.1 ± 0.3
       Post-treatment0.0 ± 0.20.1 ± 0.30.1 ± 0.30.1 ± 0.3
       Difference0.0 ± 0.30.0 ± 0.3.66980.0 ± 0.30.0 ± 0.2.4470
      NOTE. Values are expressed as mean ± SD unless otherwise indicated.
      ANCOVA, analysis of covariance.
      a Estimates were determined using an ANCOVA model including treatment group and baseline value as a covariate.
      b The total EREFS was calculated by summing the scores for the 5 major individual parameters (grade 0−3 for esophageal rings; grade 0−2 for white plaques or exudates, edema or decreased vascularity, and linear furrows; and grade 0−1 for esophageal stricture).
      Supplementary Table 2Treatment-Emergent Adverse Events in Patients Receiving Budesonide Oral Suspension or Placebo
      TEAEBOS (n = 51)Placebo (n = 42)
      All TEAEs24 (47)21 (50)
       TEAEs related to study drug5 (10)4 (10)
       Severe TEAEs1 (2)
      Episode of food poisoning, deemed not related to the study drug.
      0 (0)
       Serious adverse events1 (2)0 (0)
       TEAEs leading to withdrawal from study1 (2)0 (0)
       TEAEs related to study drug and leading to withdrawal from study1 (2)
      Due to chest pain, dyspnea, nausea, and vomiting, deemed related to the study drug.
      0 (0)
      Infections and infestations13 (25)7 (17)
       Nasopharyngitis3 (6)4 (10)
       Upper respiratory tract infection3 (6)2 (5)
       Sinusitis2 (4)1 (2)
      Clostridium difficile infection1 (2)0 (0)
       Oral candidiasis1 (2)0 (0)
       Esophageal candidiasis1 (2)0 (0)
      Gastrointestinal disorders3 (6)9 (21)
       Diarrhea0 (0)1 (2)
       Food poisoning2 (4)0 (0)
       Vomiting1 (2)1 (2)
       Abdominal pain/discomfort0 (0)3 (7)
      Respiratory disorders6 (12)3 (7)
       Oropharyngeal pain2 (4)2 (5)
       Cough1 (2)0 (0)
       Dyspnea1 (2)0 (0)
       Allergic rhinitis1 (2)0 (0)
      Skin disorders3 (6)3 (7)
       Acne1 (2)0 (0)
       Contact dermatitis1 (2)0 (0)
       Eczema0 (0)1 (2)
      General3 (6)2 (5)
       Fever1 (2)1 (2)
       Fatigue1 (2)0 (0)
      NOTE. Values are expressed as n (%).
      TEAE, treatment-emergent adverse event.
      a Episode of food poisoning, deemed not related to the study drug.
      b Due to chest pain, dyspnea, nausea, and vomiting, deemed related to the study drug.
      Supplementary Table 3Morning Serum Cortisol Results in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension and Placebo
      BOS
      Baseline, 4-wk, and end-of-treatment data were available for 49, 50, and 51 patients in the BOS group, and 42, 41, and 42 patients in the placebo group.
      Placebo
      Baseline, 4-wk, and end-of-treatment data were available for 49, 50, and 51 patients in the BOS group, and 42, 41, and 42 patients in the placebo group.
      Absolute value, μg/dL, mean ± SD
       Baseline visit10.4 ± 3.910.9 ± 4.3
       After 4 wks of study drug10.1 ± 4.312.0 ± 11.1
       End of treatment9.6 ± 4.211.3 ± 4.6
      Change from baseline, μg/dL, mean ± SD
       After 4 wks of study drug−0.3 ± 5.01.2 ± 3.0
       End of treatment−0.7 ± 4.40.4 ± 4.2
      Below the lower limit of normal, n (%)
       Baseline visit0 (0)0 (0)
       After 4 wks of study drug3 (6)1 (2)
       End of treatment3 (6)2 (5)
      a Baseline, 4-wk, and end-of-treatment data were available for 49, 50, and 51 patients in the BOS group, and 42, 41, and 42 patients in the placebo group.
      Supplementary Table 4Growth Characteristics in Patients With Eosinophilic Esophagitis Aged Younger Than 18 Years Receiving Budesonide Oral Suspension and Placebo
      VariableBOSPlacebo
      Growth velocity, cm/y
       Total number1714
       Mean ± SD4.0 ± 4.85.8 ± 3.4
       Median (range)4.1 (−5.8 to 12.0)5.1 (0.7 to 13.7)
      Sex-matched height-for-age Z score
       Baseline
      Total number1815
      Mean ± SD0.15 ± 0.520.03 ± 0.60
      Median (range)0.17 (−0.70 to 1.00)0.12 (−1.16 to 0.86)
       End of treatment
      Total number1714
      Mean ± SD0.31 ± 0.600.16 ± 0.57
      Median (range)0.23 (−0.55 to 1.64)0.35 (−0.99 to 1.02)

      References

        • Liacouras C.A.
        • Furuta G.T.
        • Hirano I.
        • et al.
        Eosinophilic esophagitis: updated consensus recommendations for children and adults.
        J Allergy Clin Immunol. 2011; 128: 3-20.e6
        • Dellon E.S.
        • Gonsalves N.
        • Hirano I.
        • et al.
        ACG clinical guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis.
        Am J Gastroenterol. 2013; 108: 679-692
        • Furuta G.T.
        • Katzka D.A.
        Eosinophilic esophagitis.
        N Engl J Med. 2015; 373: 1640-1648
        • Furuta G.T.
        • Liacouras C.A.
        • Collins M.H.
        • et al.
        Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.
        Gastroenterology. 2007; 133: 1342-1363
        • Desai T.K.
        • Stecevic V.
        • Chang C.H.
        • et al.
        Association of eosinophilic inflammation with esophageal food impaction in adults.
        Gastrointest Endosc. 2005; 61: 795-801
        • Sperry S.L.
        • Crockett S.D.
        • Miller C.B.
        • et al.
        Esophageal foreign-body impactions: epidemiology, time trends, and the impact of the increasing prevalence of eosinophilic esophagitis.
        Gastrointest Endosc. 2011; 74: 985-991
        • Kidambi T.
        • Toto E.
        • Ho N.
        • et al.
        Temporal trends in the relative prevalence of dysphagia etiologies from 1999–2009.
        World J Gastroenterol. 2012; 18: 4335-4341
        • Dellon E.S.
        Epidemiology of eosinophilic esophagitis.
        Gastroenterol Clin North Am. 2014; 43: 201-218
        • Gawron A.J.
        • Hirano I.
        Eosinophilic esophagitis – emerging epidemic or misdiagnosed malady?.
        Clin Gastroenterol Hepatol. 2014; 12: 597-598
        • Hruz P.
        • Straumann A.
        • Bussmann C.
        • et al.
        Escalating incidence of eosinophilic esophagitis: a 20-year prospective, population-based study in Olten County.
        Switzerland. J Allergy Clin Immunol. 2011; 128: 1349-1350.e5
        • Dellon E.S.
        • Jensen E.T.
        • Martin C.F.
        • et al.
        Prevalence of eosinophilic esophagitis in the United States.
        Clin Gastroenterol Hepatol. 2014; 12: 589-596.e1
        • Jensen E.T.
        • Kappelman M.D.
        • Martin C.F.
        • et al.
        Health-care utilization, costs, and the burden of disease related to eosinophilic esophagitis in the United States.
        Am J Gastroenterol. 2015; 110: 626-632
        • Dellon E.S.
        • Liacouras C.A.
        Advances in clinical management of eosinophilic esophagitis.
        Gastroenterology. 2014; 147: 1238-1254
        • Rothenberg M.E.
        Molecular, genetic, and cellular bases for treating eosinophilic esophagitis.
        Gastroenterology. 2015; 148: 1143-1157
        • Dellon E.S.
        • Sheikh A.
        • Speck O.
        • et al.
        Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
        Gastroenterology. 2012; 143: 321-324.e1
        • Teitelbaum J.E.
        • Fox V.L.
        • Twarog F.J.
        • et al.
        Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate.
        Gastroenterology. 2002; 122: 1216-1225
        • Noel R.J.
        • Putnam P.E.
        • Collins M.H.
        • et al.
        Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2004; 2: 568-575
        • Konikoff M.R.
        • Noel R.J.
        • Blanchard C.
        • et al.
        A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.
        Gastroenterology. 2006; 131: 1381-1391
        • Schaefer E.T.
        • Fitzgerald J.F.
        • Molleston J.P.
        • et al.
        Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children.
        Clin Gastroenterol Hepatol. 2008; 6: 165-173
        • Alexander J.A.
        • Jung K.W.
        • Arora A.S.
        • et al.
        Swallowed fluticasone improves histologic but not symptomatic responses of adults with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2012; 10: 742-749.e1
        • Butz B.K.
        • Wen T.
        • Gleich G.J.
        • et al.
        Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis.
        Gastroenterology. 2014; 147: 324-333.e5
        • Moawad F.J.
        • Veerappan G.R.
        • Dias J.A.
        • et al.
        Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for esophageal eosinophilia.
        Am J Gastroenterol. 2013; 108: 366-372
        • Lucendo A.J.
        • Arias A.
        • De Rezende L.C.
        • et al.
        Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: a prospective study.
        J Allergy Clin Immunol. 2011; 128: 1037-1046
        • Peterson K.A.
        • Thomas K.L.
        • Hilden K.
        • et al.
        Comparison of esomeprazole to aerosolized, swallowed fluticasone for eosinophilic esophagitis.
        Dig Dis Sci. 2010; 55: 1313-1319
        • Aceves S.S.
        • Bastian J.F.
        • Newbury R.O.
        • et al.
        Oral viscous budesonide: a potential new therapy for eosinophilic esophagitis in children.
        Am J Gastroenterol. 2007; 102: 2271-2279
        • Aceves S.S.
        • Dohil R.
        • Newbury R.O.
        • et al.
        Topical viscous budesonide suspension for treatment of eosinophilic esophagitis.
        J Allergy Clin Immunol. 2005; 116: 705-706
        • Dohil R.
        • Newbury R.
        • Fox L.
        • et al.
        Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial.
        Gastroenterology. 2010; 139: 418-429
        • Straumann A.
        • Conus S.
        • Degen L.
        • et al.
        Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.
        Gastroenterology. 2010; 139 (1537.e1): 1526-1537
        • Gupta S.K.
        • Vitanza J.M.
        • Collins M.H.
        Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2015; 13: 66-76.e3
        • Miehlke S.
        • Hruz P.
        • Vieth M.
        • et al.
        A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
        Gut. 2016; 65: 390-399
        • Hirano I.
        Therapeutic end points in eosinophilic esophagitis: is elimination of esophageal eosinophils enough?.
        Clin Gastroenterol Hepatol. 2012; 10: 750-752
        • Rothenberg M.E.
        • Aceves S.
        • Bonis P.A.
        • et al.
        Working with the US Food and Drug Administration: progress and timelines in understanding and treating patients with eosinophilic esophagitis.
        J Allergy Clin Immunol. 2012; 130: 617-619
        • Fiorentino R.
        • Liu G.
        • Pariser A.R.
        • et al.
        Cross-sector sponsorship of research in eosinophilic esophagitis: a collaborative model for rational drug development in rare diseases.
        J Allergy Clin Immunol. 2012; 130: 613-616
        • Safroneeva E.
        • Straumann A.
        • Coslovsky M.
        • et al.
        Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis.
        Gastroenterology. 2015; 150: 581-590
        • DeBrosse C.W.
        • Collins M.H.
        • Buckmeier Butz B.K.
        • et al.
        Identification, epidemiology, and chronicity of pediatric esophageal eosinophilia, 1982–1999.
        J Allergy Clin Immunol. 2010; 126: 112-119
        • DeBrosse C.W.
        • Franciosi J.P.
        • King E.C.
        • et al.
        Long-term outcomes in pediatric-onset esophageal eosinophilia.
        J Allergy Clin Immunol. 2011; 128: 132-138
        • Dellon E.S.
        • Irani A.M.
        • Hill M.R.
        • et al.
        Development and field testing of a novel patient-reported outcome measure of dysphagia in patients with eosinophilic esophagitis.
        Aliment Pharmacol Ther. 2013; 38: 634-642
        • Hudgens S.
        • Evans C.
        • Philips E.
        • et al.
        Psychometric validation of the Dysphagia Symptom Questionnaire in eosinophilic esophagitis patients treated with oral budesonide suspension.
        Value Health. 2015; 18: A226
        • Collins M.H.
        Histopathology of eosinophilic esophagitis.
        Dig Dis. 2014; 32: 68-73
        • Hirano I.
        • Moy N.
        • Heckman M.G.
        • et al.
        Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system.
        Gut. 2013; 62: 489-495
        • Tan N.D.
        • Xiao Y.L.
        • Chen M.H.
        Steroids therapy for eosinophilic esophagitis: systematic review and meta-analysis.
        J Dig Dis. 2015; 16: 431-442
        • Chuang M.Y.
        • Chinnaratha M.A.
        • Hancock D.G.
        • et al.
        Topical steroid therapy for the treatment of eosinophilic esophagitis (EoE): a systematic review and meta-analysis.
        Clin Transl Gastroenterol. 2015; 6: e82
        • Sawas T.
        • Dhalla S.
        • Sayyar M.
        • et al.
        Systematic review with meta-analysis: pharmacological interventions for eosinophilic oesophagitis.
        Aliment Pharmacol Ther. 2015; 41: 797-806
        • Murali A.R.
        • Gupta A.
        • Attar B.M.
        • et al.
        Topical steroids in eosinophilic esophagitis: Systematic review and meta-analysis of placebo-controlled randomized clinical trials.
        J Gastroenterol Hepatol. 2016; 31: 1111-1119
        • Wolf W.A.
        • Cotton C.C.
        • Green D.J.
        • et al.
        Predictors of response to steroid therapy for eosinophilic esophagitis and treatment of steroid-refractory patients.
        Clin Gastroenterol Hepatol. 2015; 13: 452-458
        • Eluri S.
        • Runge T.M.
        • Cotton C.C.
        • et al.
        The extremely narrow-caliber esophagus is a treatment-resistant subphenotype of eosinophilic esophagitis.
        Gastrointest Endosc. 2016; 83: 1142-1148
        • Schoepfer A.M.
        • Safroneeva E.
        • Bussmann C.
        • et al.
        Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.
        Gastroenterology. 2013; 145 (e1–2): 1230-1236
        • Dellon E.S.
        • Kim H.P.
        • Sperry S.L.
        • et al.
        A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease.
        Gastrointest Endosc. 2014; 79: 577-585.e4
        • van Rhijn B.D.
        • Verheij J.
        • Smout A.J.
        • et al.
        The Endoscopic Reference Score shows modest accuracy to predict histologic remission in adult patients with eosinophilic esophagitis.
        Neurogastroenterol Motil. 2016; 28: 1714-1722