Advertisement

Budesonide Oral Suspension Improves Outcomes in Patients With Eosinophilic Esophagitis: Results from a Phase 3 Trial

Open AccessPublished:April 18, 2021DOI:https://doi.org/10.1016/j.cgh.2021.04.022

      Abstract

      Background & Aims

      Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease for which there is currently no pharmacologic therapy approved by the US Food and Drug Administration.

      Methods

      In this double-blind, placebo-controlled, phase 3 trial, patients 11–55 years of age with EoE and dysphagia were randomized 2:1 to receive budesonide oral suspension (BOS) 2.0 mg twice daily or placebo for 12 weeks at academic or community care practices. Co-primary endpoints were the proportion of stringent histologic responders (≤6 eosinophils/high-power field) or dysphagia symptom responders (≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] score) over 12 weeks. Changes in DSQ score (key secondary endpoint) and EoE Endoscopic Reference Score (EREFS) (secondary endpoint) from baseline to week 12, and safety parameters were examined.

      Results

      Overall, 318 patients (BOS, n = 213; placebo, n = 105) were randomized and received ≥1 dose of study treatment. More BOS-treated than placebo-treated patients achieved a stringent histologic response (53.1% vs 1.0%; Δ52% [95% confidence interval (CI), 43.3%–59.1%]; P < .001) or symptom response (52.6% vs 39.1%; Δ13% [95% CI, 1.6%–24.3%]; P = .024) over 12 weeks. BOS-treated patients also had greater improvements in least-squares mean DSQ scores and EREFS over 12 weeks than placebo-treated patients: DSQ, –13.0 (SEM 1.2) vs –9.1 (SEM 1.5) (Δ–3.9 [95% CI, –7.1 to –0.8]; P = .015); EREFS, –4.0 (SEM 0.3) vs –2.2 (SEM 0.4) (Δ–1.8 [95% CI, –2.6 to –1.1]; P < .001). BOS was well tolerated; most adverse events were mild or moderate in severity.

      Conclusions

      In patients with EoE, BOS 2.0 mg twice daily was superior to placebo in improving histologic, symptomatic, and endoscopic outcomes over 12 weeks. BOS 2.0 mg twice daily was well tolerated. ClinicalTrials.gov number: NCT02605837.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      BOS (budesonide oral suspension), BOT (budesonide orodispersible tablets), CI (confidence interval), CMH (Cochran–Mantel–Haenszel), DSQ (Dysphagia Symptom Questionnaire), EoE (eosinophilic esophagitis), EoEHSS (Eosinophilic Esophagitis Histology Scoring System), eos/hpf (eosinophils/high-power field), EREFS (Eosinophilic Esophagitis Endoscopic Reference Score), LS (least-squares), TEAE (treatment-emergent adverse event)

       Background

      Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease for which there is currently no Food and Drug Administration–approved therapy. Budesonide oral suspension (BOS) is a viscous topical corticosteroid developed for patients with EoE.

       Findings

      Treatment with BOS 2.0 mg twice daily resulted in significant improvements in histologic, symptomatic, and endoscopic outcomes in patients with EoE (11–55 years of age) after 12 weeks vs placebo.

       Implications for patient care

      In this phase 3 trial of patients with EoE, BOS 2.0 mg twice daily was superior to placebo in improving histologic, symptomatic, and endoscopic endpoints measured using validated outcome instruments.
      Eosinophilic esophagitis (EoE) is a chronic, immune-mediated, inflammatory disease of the esophagus.
      • Dellon E.S.
      • Liacouras C.A.
      • Molina-Infante J.
      • et al.
      Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference.
      EoE is characterized by esophageal dysfunction and eosinophilic infiltration of the esophageal epithelium.
      • Dellon E.S.
      • Liacouras C.A.
      • Molina-Infante J.
      • et al.
      Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference.
      Patients with EoE can experience a range of signs and symptoms,
      • Dellon E.S.
      • Liacouras C.A.
      • Molina-Infante J.
      • et al.
      Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference.
      ,
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias A.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      one of the most common being dysphagia.
      • Dellon E.S.
      • Gibbs W.B.
      • Fritchie K.J.
      • et al.
      Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease.
      Significant morbidity may be associated with frequent food impactions and esophageal strictures requiring repeated esophageal dilations.
      • Hirano I.
      • Aceves S.S.
      Clinical implications and pathogenesis of esophageal remodeling in eosinophilic esophagitis.
      Topical corticosteroids, proton pump inhibitors, and elimination diets are recommended therapies for EoE.
      • Hirano I.
      • Chan E.S.
      • Rank M.A.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters clinical guidelines for the management of eosinophilic esophagitis.
      Currently there are no pharmacologic therapies approved by the U.S. Food and Drug Administration for EoE.
      • Hirano I.
      • Chan E.S.
      • Rank M.A.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters clinical guidelines for the management of eosinophilic esophagitis.
      ,
      • Hirano I.
      • Spechler S.
      • Furuta G.
      • et al.
      AGA white paper: drug development for eosinophilic esophagitis.
      Topical corticosteroid formulations, designed for asthma, are often used off-label. These are not formulated for esophageal delivery and thus are neither standardized nor optimized for EoE.
      • Hirano I.
      • Spechler S.
      • Furuta G.
      • et al.
      AGA white paper: drug development for eosinophilic esophagitis.
      Inadequate treatment due to suboptimal drug delivery may fail to control inflammation, which can be associated with an increased risk of food impaction, as well as with increased utilization of and decreased responsiveness to esophageal dilation.
      • Schupack D.A.
      • Ravi K.
      • Geno D.M.
      • et al.
      Effect of maintenance therapy for eosinophilic esophagitis on need for recurrent dilation.
      • Kuchen T.
      • Straumann A.
      • Safroneeva E.
      • et al.
      Swallowed topical corticosteroids reduce the risk for long-lasting bolus impactions in eosinophilic esophagitis.
      • Kim J.P.
      • Weingart G.
      • Hiramoto B.
      • et al.
      Clinical outcomes of adults with eosinophilic esophagitis with severe stricture.
      • Runge T.M.
      • Eluri S.
      • Cotton C.C.
      • et al.
      Outcomes of esophageal dilation in eosinophilic esophagitis: safety, efficacy, and persistence of the fibrostenotic phenotype.
      Furthermore, patients commonly encounter difficulties obtaining insurance coverage for off-label medications.
      • Hirano I.
      • Spechler S.
      • Furuta G.
      • et al.
      AGA white paper: drug development for eosinophilic esophagitis.
      Therefore, a significant unmet medical need exists for EoE.
      Budesonide oral suspension (BOS) is an immediate-release topical corticosteroid optimized as a viscous suspension to lengthen its residence time on the esophageal mucosal surface following oral administration in patients with EoE. Efficacy and safety of BOS 2.0 mg twice daily have been previously evaluated in 2 phase 2, randomized, double-blind, placebo-controlled trials in pediatric (NCT00762073)
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      and adolescent and adult (NCT01642212)
      • Dellon E.S.
      • Katzka D.A.
      • Collins M.H.
      • et al.
      Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.
      patients with EoE.
      The objective of this phase 3 trial was to evaluate the efficacy and safety of BOS therapy (2.0 mg twice daily) compared with placebo in adolescents and adults with EoE over 12 weeks.

      Materials and Methods

       Trial Design and Conduct

      This phase 3, multicenter, randomized, double-blind, placebo-controlled trial (ORBIT1/SHP621-301/NCT02605837) was conducted at 66 centers in the United States between 2015 and 2019, and evaluated the efficacy and safety of BOS in patients with EoE and dysphagia. The protocol was approved by an institutional review board for each center and was performed in accordance with the International Conference on Harmonisation and Good Clinical Practice Guidelines and reported as per the Consolidated Standards of Reporting Trials statement. Patients provided written informed consent/assent before participating. After the 3- to 6-week screening period, a 4-week, single-blind placebo lead-in was implemented to assess compliance with twice-daily dosing and to reduce anticipated symptom response to placebo. Patients who completed the Dysphagia Symptom Questionnaire (DSQ) on <70% of days and who had fewer than 4 days of dysphagia in the last 2 weeks of the single-blind placebo lead-in period were excluded. Eligible patients were then randomly assigned 2:1 via computer-generated randomization to receive BOS 2.0 mg twice daily (10 mL at a concentration of 0.2 mg/mL) or placebo for 12 weeks (Supplementary Figure 1).

       Study Participants

      Patients were 11–55 years of age with histologic evidence of EoE (≥15 eosinophils/high-power field [eos/hpf] from at least 2 levels of the esophagus) during screening, with dysphagia on at least 4 days in any 2 consecutive weeks during screening and in the 2 weeks before randomization measured using the DSQ.
      • Hudgens S.
      • Evans C.
      • Philips E.
      • et al.
      Psychometric validation of the Dysphagia Symptom Questionnaire in patients with eosinophilic esophagitis treated with oral budesonide suspension.

       Prespecified Study Endpoints and Assessments

      The co-primary efficacy endpoints were (1) the proportion of stringent histologic responders (≤6 eos/hpf across all available esophageal levels [proximal, middle, or distal]) and (2) the proportion of dysphagia symptom responders (≥30% reduction in DSQ score) from baseline to week 12 of therapy. The key secondary efficacy endpoint was the change in DSQ score from baseline to week 12 of treatment.
      Other secondary efficacy endpoints included the proportion of full responders, defined as a combined stringent histologic response and dysphagia symptom response (≤6 eos/hpf and ≥30% reduction in DSQ score); the mean change in EoE Endoscopic Reference Score (EREFS) and maximum peak eosinophil count; the proportion of patients achieving a deep histologic response or histologic response (deep histologic response, ≤1 eos/hpf; histologic response,<15 eos/hpf); and the mean change in the EoE Histology Scoring System (EoEHSS) total score ratios from baseline to week 12 of therapy.
      Safety assessments included monitoring of adverse events at every study visit, physical examinations, measurement of vital signs, body weight and height (stadiometry for patients 11–17 years of age), dual x-ray absorptiometry for bone mineral density (for patients 11–17 years of age), and routine clinical laboratory and adrenocorticotropic hormone (ACTH) stimulation tests. Adverse events of esophageal and oral candidiasis were diagnosed clinically by physical examination (with or without biopsy) by the investigator or study pathologist.

       Statistical Analyses

      Efficacy was analyzed by treatment randomization group using the full analysis set, which included all randomized patients who received ≥1 dose of study treatment during the double-blind phase. The per-protocol set included all patients in the full analysis set excluding those with major protocol deviations. The co-primary efficacy endpoints were also analyzed using the per-protocol analysis set (prespecified sensitivity analysis). Safety was analyzed using the safety set, which included all patients who received ≥1 dose of study treatment during the double-blind phase; data were analyzed according to the assigned treatment.
      In the primary analysis of the co-primary efficacy endpoints, treatment groups were compared using the Cochran–Mantel–Haenszel (CMH) test adjusted for the randomization stratification factors: <18 years of age or ≥18 years of age and no diet restriction or any diet restriction; patients with missing values were imputed as nonresponders. CMH test analyses were also performed on dysphagia symptom response by considering patients as nonresponders when 4 or more days of DSQ diary data in either week of the last 2 weeks before the final treatment evaluation were missing. An analysis of covariance model was generated for the key secondary efficacy endpoint, with treatment and age group as factors and the baseline DSQ score as a continuous covariate.
      All authors had access to the study data and reviewed and approved the final manuscript. Additional information regarding study methodology is provided in the Supplementary Material.

      Results

       Patient Disposition and Baseline Characteristics

      Of the 985 patients screened, 450 entered the placebo lead-in and 322 were randomized. Of these, 318 individuals (BOS, n = 213; placebo, n = 105) received at least 1 dose of study treatment (Figure 1), and 296 patients completed the treatment phase (BOS, n = 202; placebo, n = 94). Patient demographics were similar between treatment arms (Table 1). Notably, 41.8% of the total population (BOS, 41.3%; placebo, 42.9%) reported having a prior esophageal dilation (Table 1).
      Figure thumbnail gr1
      Figure 1CONSORT (Consolidated Standards of Reporting Trials) flow diagram. BOS, budesonide oral suspension; EoE, eosinophilic esophagitis. aOther reasons for study discontinuation were the following: physician decision to withdraw, n = 9; lost to follow-up, n = 4; parent/guardian decision to withdraw, n = 2; adverse event, n = 1; pregnancy, n = 1; protocol deviation, n = 1. bOther reasons for study discontinuation were the following: lost to follow-up, n = 4; noncompliance with study treatment, n = 4; lack of histologic evidence of EoE, n = 2; adverse event, n = 1.
      Table 1Patient Demographics and Characteristics at Baseline by Treatment Arm
      CharacteristicBOS 2.0 mg Twice Daily (n = 213)Placebo (n = 105)Total (N = 318)
      Age, y33.8 ± 11.933.9 ± 12.133.9 ± 12.0
      Age <18 y27 (12.7)14 (13.3)41 (12.9)
      Male129 (60.6)62 (59.0)191 (60.1)
      Race
       White200 (93.9)101 (96.2)301 (94.7)
       Black or African American5 (2.3)0 (0.0)5 (1.6)
       Native Hawaiian or other Pacific Islander0 (0.0)1 (1.0)1 (0.3)
       American Indian or Alaska Native1 (0.5)0 (0.0)1 (0.3)
       Other7 (3.3)3 (2.9)10 (3.1)
      BMI, kg/m227.5 ± 6.028.2 ± 6.327.7 ± 6.1
      Diagnosed with EoE before the study200 (93.9)99 (94.3)299 (94.0)
      Current diet restriction21 (9.9)11 (10.5)32 (10.1)
      Prior medications/procedure for EoE
       Diet therapy54 (25.4)26 (24.8)80 (25.2)
       Budesonide slurry
      Prior treatment with budesonide slurry did not include the BOS formulation used in this trial.
      49 (23.0)17 (16.2)66 (20.8)
       Fluticasone aerosol (swallowed)77 (36.2)33 (31.4)110 (34.6)
       Systemic (oral) corticosteroids18 (8.5)7 (6.7)25 (7.9)
       Diet therapy or budesonide slurry
      Prior treatment with budesonide slurry did not include the BOS formulation used in this trial.
      or fluticasone aerosol (swallowed)
      123 (57.7)52 (49.5)175 (55.0)
       Budesonide slurry
      Prior treatment with budesonide slurry did not include the BOS formulation used in this trial.
      or fluticasone aerosol (swallowed)
      101 (47.4)42 (40.0)143 (45.0)
       Esophageal dilation88 (41.3)45 (42.9)133 (41.8)
      If yes, number of times dilated
      Once45 (21.1)16 (15.2)61 (19.2)
      Twice or more43 (20.2)29 (27.6)72 (22.6)
      Concomitant medications
       Inhaled/nasal corticosteroids40 (18.8)19 (18.1)59 (18.6)
       PPIs176 (82.6)92 (87.6)268 (84.3)
      DSQ score (range 0–84)
      BOS, n = 211; placebo, n = 105; total, N = 316.
      30.3 ± 13.930.4 ± 13.130.4 ± 13.7
      Maximum peak eosinophil count, eos/hpf
      BOS, n = 213; placebo, n = 104; total, N = 317.
      74.5 ± 39.276.6 ± 45.075.2 ± 41.1
      EoEHSS grade total score ratio
      BOS, n = 213; placebo, n = 104; total, N = 317.
      0.4 ± 0.10.4 ± 0.10.4 ± 0.1
      EoEHSS stage total score ratio
      BOS, n = 213; placebo, n = 104; total, N = 317.
      0.3 ± 0.10.3 ± 0.10.3 ± 0.1
      EREFS (range 0–20)7.6 ± 3.68.2 ± 3.37.8 ± 3.5
      NOTE. Values are mean ± SD or n (%).
      BMI, body mass index; BOS, budesonide oral suspension; DSQ, Dysphagia Symptom Questionnaire; EoE, eosinophilic esophagitis; EoEHSS, Eosinophilic Esophagitis Histology Scoring System; eos/hpf, eosinophils per high-power field; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; PPI, proton pump inhibitor.
      a Prior treatment with budesonide slurry did not include the BOS formulation used in this trial.
      b BOS, n = 211; placebo, n = 105; total, N = 316.
      c BOS, n = 213; placebo, n = 104; total, N = 317.

       Co-primary, Key Secondary, and Other Efficacy Endpoints

      Significantly more BOS-treated patients than placebo-treated patients achieved a stringent histologic response or dysphagia symptom response after 12 weeks (BOS vs placebo: stringent histologic responders, 53.1% vs 1.0%; Δ52% [95% CI, 43.3%–59.1%]; P < .001 [after adjustment with the CMH test]; dysphagia symptom responders, 52.6% vs 39.1%; Δ13% [95% CI, 1.6%–24.3%]; P = .024) (Figure 2A and B). Results were similar for the per-protocol set (Supplementary Figure 2). Significantly more BOS-treated patients than placebo-treated patients achieved a full response, defined as a stringent histologic response and dysphagia symptom response (BOS vs placebo: 30.0% vs 0.0%; Δ30% [95% CI, 23.7%–36.0%]; P < .001). A post hoc analysis of these data demonstrated that 75.6% of BOS-treated patients achieved a stringent histologic response, dysphagia symptom response, or full response after 12 weeks of therapy.
      Figure thumbnail gr2
      Figure 2(A, B) Co-primary endpoints and (C) key secondary efficacy endpoint (full analysis set): (A) proportion of patients achieving a stringent histologic response (≤6 eos/hpf) after 12 weeks of therapy; (B) proportion of patients achieving a dysphagia symptom response (≥30% reduction in DSQ score) after 12 weeks of therapy; (C) change in DSQ score from baseline to week 12 of therapy. b.i.d., twice daily; BOS, budesonide oral suspension; CI, confidence interval; DSQ, Dysphagia Symptom Questionnaire; eos/hpf, eosinophils per high-power field; LS, least-squares; SEM, standard error of the mean.
      Additionally, BOS-treated patients had a significantly greater improvement in least-squares (LS) mean DSQ scores from baseline than placebo-treated patients (BOS vs placebo: –13.0 [SEM 1.2] vs –9.1 [SEM 1.5]; Δ–3.9 [95% CI, –7.1 to –0.8]; P = .015 [with analysis of covariance adjusted for baseline DSQ score]) (Figure 2C).

       Secondary Efficacy Endpoints

      Greater reductions in LS mean total EREFS and maximum peak eosinophil counts were observed in BOS-treated than placebo-treated patients from baseline to week 12 (BOS vs placebo: EREFS, –4.0 [SEM 0.3] vs –2.2 [SEM 0.4]; Δ–1.8 [95% CI, –2.6 to –1.1]; P < .001; maximum peak eosinophil counts, –55.2 [SEM 3.4] vs –7.6 [SEM 4.3]; Δ–47.6 [95% CI, –56.4 to –38.8]; P < .001) (Figure 3A and B). Significantly more BOS-treated patients than placebo-treated patients achieved a deep histologic response (≤1 eos/hpf; BOS vs placebo: 32.4% vs 0.0%; Δ33% [95% CI, 26.6%–39.2%]; P = .001) and a histologic response (<15 eos/hpf; BOS vs placebo: 62.0% vs 1.0%; Δ61% [95% CI, 52.2%–67.6%]; P < .001) after 12 weeks (Figure 3C). Greater reductions were also observed in LS mean EoEHSS score ratios in BOS-treated patients than in placebo-treated patients from baseline to week 12 (grade, P < .001; stage, P < .001) (Figure 3D). Baseline and week 12 values for these endpoints are presented in Supplementary Table 1. Changes in EREFS, peak eosinophil counts, and EoEHSS score ratios between BOS and placebo groups were also comparable by esophageal region (Supplementary Figure 3).
      Figure thumbnail gr3
      Figure 3Secondary efficacy endpoints (full analysis set): (A) change in total EREFS from baseline to week 12 of therapy; (B) change in maximum peak eosinophil count from baseline to week 12 of therapy; (C) proportion of deep histologic responders and histologic responders (≤1 eos/hpf and <15 eos/hpf, respectively) after 12 weeks of therapy; (D) change in EoEHSS grade and stage total score ratios from baseline to week 12 of therapy. b.i.d., twice daily; BOS, budesonide oral suspension; CI, confidence interval; EoE, eosinophilic esophagitis; eos/hpf, eosinophils per high-power field; EREFS, EoE Endoscopic Reference Score; EoEHSS, EoE Histology Scoring System; LS, least-squares; SEM, standard error of the mean.

       Safety Outcomes

      Overall, BOS was well tolerated; treatment-emergent adverse events (TEAEs) were similar for BOS (61.0%) and placebo (61.0%) groups after 12 weeks; most TEAEs reported were mild or moderate in severity (Table 2). The most common TEAEs (≥2.5% of the total population) included (BOS vs placebo) nasopharyngitis (5.2% vs 3.8%), sinusitis (4.2% vs 2.9%), esophageal candidiasis (3.8% vs 1.9%), oral candidiasis (3.8% vs 0.0%), nausea (2.8% vs 2.9%), abnormal ACTH stimulation test (2.8% vs 2.9%), and cough (2.8% vs 2.9%) (Table 2). All TEAEs of candidiasis were mild or moderate in severity.
      Table 2Summary of TEAEs by Treatment Group, and by System Organ Class, Preferred Term, and Treatment Group (Safety Set)
      CategoryBOS

      2.0 mg twice daily (n = 213)
      Placebo (n = 105)Total (N = 318)
      Any nonserious TEAE130 (61.0)64 (61.0)194 (61.0)
       Any mild TEAE69 (32.4)38 (36.2)107 (33.6)
       Any moderate TEAE56 (26.3)24 (22.9)80 (25.2)
       Any severe TEAE5 (2.3)2 (1.9)7 (2.2)
      Any serious TEAE2 (0.9)1 (1.0)3 (0.9)
      Any life-threatening TEAE0 (0.0)0 (0.0)0 (0.0)
      TEAE related to study treatment45 (21.1)23 (21.9)68 (21.4)
      TEAE related to EoE11 (5.2)6 (5.7)17 (5.3)
      Death due to TEAE0 (0.0)0 (0.0)0 (0.0)
      Hospitalization due to TEAE2 (0.9)1 (1.0)3 (0.9)
      TEAE leading to dose discontinuation3 (1.4)5 (4.8)8 (2.5)
      TEAE leading to study discontinuation1 (0.5)3 (2.9)4 (1.3)
      TEAEs experienced by ≥2.5% of the total population
      Infections and infestations
       Nasopharyngitis11 (5.2)4 (3.8)15 (4.7)
       Sinusitis9 (4.2)3 (2.9)12 (3.8)
       Esophageal candidiasis8 (3.8)2 (1.9)10 (3.1)
       Oral candidiasis8 (3.8)0 (0.0)8 (2.5)
      Gastrointestinal disorders
       Nausea6 (2.8)3 (2.9)9 (2.8)
       Vomiting4 (1.9)4 (3.8)8 (2.5)
      Investigations
       ACTH stimulation test abnormal6 (2.8)3 (2.9)9 (2.8)
      Respiratory, thoracic, and mediastinal disorders
       Cough6 (2.8)3 (2.9)9 (2.8)
      Skin and subcutaneous tissue disorders
       Acne5 (2.3)3 (2.9)8 (2.5)
      Nervous system disorders
       Headache7 (3.3)1 (1.0)8 (2.5)
      NOTE. Values are n (%).
      Percentages are based on the number of patients in the safety set for each treatment group who experienced the event. Patients were counted once per category or preferred term per treatment.
      ACTH, adrenocorticotropic hormone; BOS, budesonide oral suspension; EoE, eosinophilic esophagitis; TEAE, treatment-emergent adverse event.
      Serious TEAEs were reported in 3 patients (BOS, n = 2; placebo, n = 1; Table 2). One BOS-treated patient experienced acute gastroenteritis and sepsis (2 events) and the other BOS-treated patient had localized intra-abdominal fluid collection (1 event). All 3 events were considered unrelated to study drug. One patient receiving placebo had a serious adverse event of ovarian cyst, which was also deemed unrelated to study treatment. TEAEs led to study discontinuation in 4 patients (Table 2). There were no life-threatening TEAEs or deaths reported.
      Adrenal suppression and insufficiency were reported in patients receiving BOS (1.4% [n = 3] and 0.9% [n = 2], respectively); these events were not associated with symptoms except in 1 patient who experienced an associated clinical TEAE of fatigue. No patients receiving placebo had TEAEs related to adrenal function. Several patients (BOS, 8.2% [n = 16]; placebo, 3.6% [n = 3]) had a reduction in peak cortisol levels from >18 μg/dL to ≤18 μg/dL after ACTH stimulation testing at week 12 of therapy (Supplementary Table 2); most shifts in ACTH-stimulated cortisol in BOS-treated patients were not clinically substantial.
      Additional information relating to TEAEs leading to study discontinuation, TEAEs of candidiasis, and adrenal function abnormality is provided in the Supplementary Material.

      Discussion

      This study represents the first U.S. phase 3 trial of a pharmacologic therapy for EoE and the largest clinical trial for EoE conducted to date. It is also the first phase 3 trial using multiple validated disease-specific instruments to examine comprehensive and complementary endpoints of histology, symptoms, and endoscopy and includes the largest prospective collection of safety data in EoE.
      BOS is an immediate-release topical corticosteroid optimized as a viscous suspension and designed specifically for patients with EoE.
      • Dellon E.S.
      • Katzka D.A.
      • Collins M.H.
      • et al.
      Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.
      This phase 3 trial demonstrated that 12 weeks of BOS therapy resulted in statistically significant improvements in histologic, symptomatic, and endoscopic outcomes in adolescents and adults with EoE vs placebo, building on the findings of the previous phase 2 trials,
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      ,
      • Dellon E.S.
      • Katzka D.A.
      • Collins M.H.
      • et al.
      Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.
      as well as a greater percentage of BOS- than placebo-treated patients achieving a full response (≤6 eos/hpf and ≥30% reduction in DSQ score). BOS was well tolerated and most TEAEs were mild or moderate in severity.
      Currently, no pharmacologic therapies are approved by the Food and Drug Administration for EoE.
      • Hirano I.
      • Chan E.S.
      • Rank M.A.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters clinical guidelines for the management of eosinophilic esophagitis.
      ,
      • Hirano I.
      • Spechler S.
      • Furuta G.
      • et al.
      AGA white paper: drug development for eosinophilic esophagitis.
      As a result, patients often resort to using off-label corticosteroids formulated for asthma leading to suboptimal esophageal delivery,
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      and experience difficulties with medical insurance coverage owing to the off-label utilization.
      • Hirano I.
      • Spechler S.
      • Furuta G.
      • et al.
      AGA white paper: drug development for eosinophilic esophagitis.
      Several preparations of budesonide and fluticasone propionate have been evaluated for EoE, including slurries, inhalers, and nebulizers.
      • 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.
      ,
      • 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.
      • van Rhijn B.D.
      • Verheij J.
      • van den Bergh Weerman M.A.
      • et al.
      Histological response to fluticasone propionate in patients with eosinophilic esophagitis is associated with improved functional esophageal mucosal integrity.
      • Moawad F.J.
      • Veerappan G.R.
      • Dias J.A.
      • et al.
      Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for esophageal eosinophilia.
      These formulations have been shown to improve histologic, symptomatic, or endoscopic outcomes in patients with EoE
      • 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.
      ,
      • 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.
      ,
      • van Rhijn B.D.
      • Verheij J.
      • van den Bergh Weerman M.A.
      • et al.
      Histological response to fluticasone propionate in patients with eosinophilic esophagitis is associated with improved functional esophageal mucosal integrity.
      but not in all cases.
      • Moawad F.J.
      • Veerappan G.R.
      • Dias J.A.
      • et al.
      Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for esophageal eosinophilia.
      Inconsistencies in dosing and inadvertent inhalation from nebulized formulations have been reported.
      • Hirano I.
      • Spechler S.
      • Furuta G.
      • et al.
      AGA white paper: drug development for 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.
      ,
      • Moawad F.J.
      • Veerappan G.R.
      • Dias J.A.
      • et al.
      Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for esophageal eosinophilia.
      This, in addition to the heterogeneous nature of studies and their design or methodology, may explain, in part, the wide range of response rates reported for topical corticosteroids in EoE.
      • Ma C.
      • van Rhijn B.D.
      • Jairath V.
      • et al.
      Heterogeneity in clinical, endoscopic, and histologic outcome measures and placebo response rates in clinical trials of eosinophilic esophagitis: a systematic review.
      Only one other phase 3 pharmacologic study has been published for EoE to date, assessing budesonide orodispersible tablets (BOT) in a multicenter European trial.
      • Lucendo A.J.
      • Miehlke S.
      • Schlag C.
      • et al.
      Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial.
      BOT is approved by the European Medicines Agency for adults with EoE.
      European Medicines Agency
      EPAR summary for the public. Jorveza (budesonide).
      Rates of histologic, symptomatic, and endoscopic response were ostensibly lower in this trial of BOS than in the trial of BOT.
      • Lucendo A.J.
      • Miehlke S.
      • Schlag C.
      • et al.
      Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial.
      However, the degree of heterogeneity between the 2 phase 3 trials makes it difficult to compare outcomes. Differences between the 2 trials included the histologic and symptom inclusion criteria; exclusion of patients who were receiving concomitant topical corticosteroids in the BOT trial (~19% of patients in the BOS trial were receiving concomitant nasal or inhaled corticosteroids); and a higher rate of prior esophageal dilation in the BOS trial vs the BOT trial (~42% vs ~16% of patients, respectively).
      • Lucendo A.J.
      • Miehlke S.
      • Schlag C.
      • et al.
      Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial.
      Higher baseline disease severity (indicated by higher rates of prior esophageal dilation)
      • Eluri S.
      • Selitsky S.R.
      • Perjar I.
      • et al.
      Clinical and molecular factors associated with histologic response to topical steroid treatment in patients with eosinophilic esophagitis.
      ,
      • 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.
      and persistence of active histology despite concomitant use of inhaled corticosteroids
      • Harer K.N.
      • Enders F.T.
      • Lim K.G.
      • et al.
      An allergic phenotype and the use of steroid inhalers predict eosinophilic oesophagitis in patients with asthma.
      may have impacted treatment response.
      In this study, a dysphagia symptom response was observed in placebo-treated patients; this is interesting considering the marked difference in histologic response between BOS-treated and placebo-treated patients. Furthermore, the study included a placebo lead-in to reduce anticipated symptom response to placebo. A symptomatic response to placebo has been reported in patients with EoE
      • Ma C.
      • van Rhijn B.D.
      • Jairath V.
      • et al.
      Heterogeneity in clinical, endoscopic, and histologic outcome measures and placebo response rates in clinical trials of eosinophilic esophagitis: a systematic review.
      ,
      • Hirano I.
      • Dellon E.S.
      • Collins M.H.
      • et al.
      Clinical features at baseline cannot predict symptom response to placebo in patients with eosinophilic esophagitis.
      and in patients with other gastrointestinal disorders.
      • Elsenbruch S.
      • Enck P.
      Placebo effects and their determinants in gastrointestinal disorders.
      BOS was well tolerated and most TEAEs were mild or moderate in severity. Importantly, rates of esophageal and oral candidiasis in this phase 3 trial were comparable with those reported in the previous phase 2 trial.
      • Dellon E.S.
      • Katzka D.A.
      • Collins M.H.
      • et al.
      Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.
      Assessment of adrenal dysfunction demonstrated that some patients had a reduction in peak cortisol levels to ≤18 μg/dL following ACTH stimulation. TEAEs of adrenal function were uncommon in patients receiving BOS, with only 1 patient experiencing an associated clinical TEAE (fatigue), demonstrating the need to assess for adrenal function in patients receiving corticosteroids.
      The study population was heterogeneous in terms of prior or concomitant medical or dietary therapies for EoE. This study potentially enrolled a proportion of patients with more severe disease (compared with another phase 3 study)
      • Lucendo A.J.
      • Miehlke S.
      • Schlag C.
      • et al.
      Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial.
      owing to stringent inclusion criteria, including a higher proportion of patients with a history of esophageal stricture (although patients with a high-grade stricture at the screening esophagogastroduodenoscopy were excluded) and patients who did not respond to initial proton pump inhibitor therapy as per consensus guidelines in effect at the time of the study.
      • 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: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE).
      Whether individuals with milder presentations would respond similarly to BOS is unknown, although the results of prior studies suggest comparable or even greater treatment effects in patients with less severe EoE.
      • Kim J.P.
      • Weingart G.
      • Hiramoto B.
      • et al.
      Clinical outcomes of adults with eosinophilic esophagitis with severe stricture.
      ,
      • Eluri S.
      • Runge T.M.
      • Cotton C.C.
      • et al.
      The extremely narrow-caliber esophagus is a treatment resistant sub-phenotype of eosinophilic esophagitis.
      Furthermore, this study utilized stringent efficacy endpoints, including a range of histologic response thresholds and a full response endpoint. However, only 30% of patients achieved a full response, highlighting that achieving both histologic and symptom endpoints is difficult even in a clinical trial setting.
      This phase 3 trial demonstrated that patients receiving BOS 2.0 mg twice daily for 12 weeks had superior improvements in histologic, symptomatic, and endoscopic outcomes compared with those receiving placebo. The co-primary and key secondary efficacy endpoints were met, and BOS was well tolerated. To date this is the largest clinical trial of a pharmacologic therapy for EoE employing modern trial design elements, including daily electronic symptom diaries, a placebo lead-in period, and validated outcome metrics. This study addresses the existing unmet medical need of patients with EoE in the United States.

      Acknowledgments

      All ORBIT1/SHP621-301 investigators are listed in the Supplementary Material. The authors would like to thank the ORBIT1/SHP621-301 investigators and the participants of this study. The authors would also like to thank Abigail M. Wojtowicz, PhD, and Mena Boules, MD, of Takeda Pharmaceuticals USA for their valuable contribution to the development of this manuscript. Medical writing support was provided by Luci Witcomb, PhD, of PharmaGenesis London and was funded by Takeda Pharmaceuticals USA. The datasets, including individual participants’ data supporting the results reported in this article, will be made available within 3 months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. The redacted clinical trial protocol is available at cghjournal.org.

      Supplementary Material

      Tabled 1
      Primary InvestigatorStudy Site
      Satyaprasad AlapatiGastroenterology Associates, LLC, Baton Rouge, Louisiana
      Curtis BaumCotton O'Neil Clinical Research Center, Topeka, Kansas
      Pradeep BekalConsultants for Clinical Research Inc., Cincinnati, Ohio
      Mirna ChehadeMount Sinai Hospital, New York City, New York
      Antonella CianferoniChildren's Hospital of Philadelphia, Philadelphia, Pennsylvania
      Neil CohenSouth Jersey Gastroenterology, Marlton, New Jersey
      Evan DellonUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina
      Reed DimmittChildren's Hospital, Birmingham, Alabama
      David DulitzClinical Trials Management LLC, Metairie, Louisiana
      Gary FalkUniversity of Pennsylvania, Philadelphia, Pennsylvania
      Ronald FogelClinical Research Institute of Michigan, Chesterfield, Michigan
      Keith FriedenbergGreat Lakes Gastroenterology Research, Mentor, Ohio
      Scott GabbardCleveland Clinic, Cleveland, Ohio
      John GancaycoSan Antonio Military Medical Center, Fort Sam Houston, Texas
      Andrew GentryBozeman Health Deaconess Hospital, Bozeman, Montana
      Satinder GillEmeritas Research Group, Lansdowne, Virginia
      Benjamin GoldChildren’s Center for Digestive Healthcare, Atlanta, Georgia
      Gary GottliebDel Sol Research Management, Tucson, Arizona
      Ikuo HiranoNorthwestern University, Chicago, Illinois
      Karen Hsu-BlatmanBrigham and Women’s Hospital, Chestnut Hill, Massachusetts
      Vikram JayantyHouston Endoscopy and Research Center, Houston, Texas
      Douglas JohnstonClinical Research of Charlotte, Charlotte, North Carolina
      David KatzkaMayo Clinic, Rochester, Minnesota
      Vidhya KunnathurUniversity of Cincinnati, Cincinnati, Ohio
      John LeeBoston Children's Hospital, Boston, Massachusetts
      John LeungTufts Medical Center, Boston, Massachusetts
      Sameer MathurUniversity of Wisconsin, Madison, Wisconsin
      Jonathan MarkowitzGreenville Hospital System, Greenville, South Carolina
      Calies Menard-KatcherColorado Children's Hospital, Aurora, Colorado
      Benjamin MitlyngMinnesota Gastroenterology PA, Plymouth, Minnesota
      Sam MoussaAdobe Clinical Research, Tucson, Arizona
      Vincent MukkadaCincinnati Children's Hospital Medical Center, Cincinnati, Ohio
      Molly O’GormanPrimary Children's Hospital, Salt Lake City, Utah
      Juan OlazagastiCarilion Clinic, Roanoke, Virginia
      John ProvenzaLouisiana Research Center, Shreveport, Louisiana
      Timothy RitterTexas Digestive Disease Consultants, Southlake, Texas
      Joel RubensteinUniversity of Michigan, Ann Arbor, Michigan
      Wael SayejConnecticut Children's Medical Center, Hartford, Connecticut
      Shauna SchroederPhoenix Children’s Hospital, Phoenix, Arizona
      Shahriar SedghiGastroenterology Associates of Central Georgia, Macon, Georgia
      Yamen SmadiOrlando Health, Orlando, Florida
      Daniel SoteresAsthma and Allergy Associates PC, Colorado Springs, Colorado
      Michael VaeziVanderbilt University Medical Center, Nashville, Tennessee
      Tom WhitlockAsheville Gastroenterology Associates, Asheville, North Carolina
      John WoIndiana University, Indianapolis, Indiana
      Ziad YounesGastro One, Germantown, Tennessee
      Elizabeth YuRady Children's Hospital San Diego, San Diego, California
      Salam ZakkoConnecticut Clinical Research Foundation, Bristol, Connecticut
      NCBaylor College of Medicine, Houston, Texas
      NCUniversity of Iowa Stead Family Children's Hospital, Iowa City, Iowa
      NCAdvanced Research Institute, Sandy, Utah
      NCConnecticut GI – Research Division, Farmington, Connecticut
      NCBlue Ridge Medical Research, Lynchburg, Virginia
      NCGreenville Hospital System, Greenville, South Carolina
      NCGastrointestinal and Liver Diseases Consultants PC, Dayton, Ohio
      NCClinical Trials of America-LA LLC, Monroe, Louisiana
      NCDigestive Health Center, Pasadena, Texas
      NCLong Island Gastrointestinal Research Group, Great Neck, New York
      NCEncore Borland Groover Clinical Research, Jacksonville, Florida
      NCCenter for Children's Digestive Health, Park Ridge, Illinois
      NCUniversity of Illinois College of Medicine at Peoria Pediatric Subspecialty Clinic, Peoria, Illinois
      NCGastroenterology Health Partners PLLC, New Albany, Indiana
      NCNature Coast Clinical Research (Inverness), Inverness, Florida
      NCAdvanced Research Institute, Ogden, Utah
      NCDigestive Disease Specialists, Inc., Oklahoma City, Oklahoma
      NCArkansas Gastroenterology, North Little Rock, Arkansas
      NCClinical Trials of America (North Carolina), Mount Airy, North Carolina
      NCRocky Mountain Pediatric Gastroenterology, Lone Tree, Colorado
      NCGrand Teton Research Group, Idaho Falls, Idaho
      NCGW Research, Inc., Chula Vista, California
      NC, not contactable.
      a Primary investigators listed are those who enrolled at least 1 patient (ie, entered the placebo lead-in period).

      Supplementary Methods

       Trial Design and Conduct

      The randomization was performed centrally via Interactive Web-based Response System and stratified by age group (<18 years of age or ≥18 years of age) and current diet restriction (no diet restriction or diet restriction). Fixed-block randomization was used to ensure that patients were assigned to budesonide oral suspension (BOS) or placebo in a ratio of 2:1, respectively. To protect the integrity of the study blind in this trial and in the 36-week, placebo-controlled extension trial (ORBIT2/SHP621-302/NCT02736409),
      ClinicalTrials.gov
      An extension study to evaluate maintenance of efficacy and long-term treatment effect of oral budesonide suspension (OBS) in adults and adolescents with eosinophilic esophagitis (EoE).
      which followed this 12-week trial (SHP621-301), the post-randomization central histology and Dysphagia Symptom Questionnaire (DSQ) patient-level data were segregated in separate case report forms and were not available to the blinded study team, study sites or patients until the final database lock of the extension trial. A firewalled unblinded data team was established to handle the processing, review, and validation of all histology and DSQ data; this team operated independently of the blinded study team. Patients completing SHP621-301 were eligible to enroll in the aforementioned 36-week, double-blind, placebo-controlled extension trial to evaluate the long-term efficacy of BOS.

       Study Participants

      Patients enrolled in this trial were 11–55 years of age. The lower limit of the age range chosen was considered to be the minimum age at which patients with eosinophilic esophagitis (EoE) could self-report symptoms using the DSQ and was also the lower-bound age for which the DSQ had been validated. In addition, pediatric patients can present with different signs and symptoms than older patients with EoE.
      • Moawad F.J.
      • Dellon E.S.
      • Achem S.R.
      • et al.
      Effects of race and sex on features of eosinophilic esophagitis.
      The upper limit of the age range was chosen as 55 years because patients older than this may present with fibrostenotic disease, so they are less likely to respond to anti-inflammatory therapy alone.
      • Dellon E.S.
      • Gibbs W.B.
      • Fritchie K.J.
      • et al.
      Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease.
      ,
      • Hirano I.
      • Aceves S.S.
      Clinical implications and pathogenesis of esophageal remodeling in eosinophilic esophagitis.
      Other key inclusion criteria included a history of clinical symptoms of esophageal dysfunction intermittently or continuously at screening as previously described; an absence of histologic response to 6–8 weeks of high-dose proton pump inhibitor (PPI) therapy, as per consensus guidelines in effect at the time of study onset (high-dose therapy refers to the total daily dose, which may have been administered as once- or twice-daily dosing)
      • Hirano I.
      • Chan E.S.
      • Rank M.A.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters clinical guidelines for the management of eosinophilic esophagitis.
      ,
      • Hirano I.
      • Spechler S.
      • Furuta G.
      • et al.
      AGA white paper: drug development for eosinophilic esophagitis.
      ; and a stable diet for at least 3 months before screening. A PPI trial may have occurred at the time of the qualifying esophagogastroduodenoscopy (EGD); in which case, the same PPI regimen was to continue, or this may have been done previously (in which case, PPI therapy may have been stopped if there was no response to therapy based on esophageal biopsy results). If PPI responsiveness was excluded by a previous EGD and biopsy, the historical EGD and biopsy must have been performed after the patient had been on a minimum of 6 weeks of high-dose PPI therapy.
      Key exclusion criteria included the following: immunomodulatory therapy use 8 weeks before the qualifying EGD or anticipated use during the study; use of swallowed topical corticosteroids for EoE or systemic corticosteroids for any condition 4 weeks before the qualifying EGD and baseline or anticipated use during the study; presence of a high-grade esophageal stricture (defined as the presence of a lesion not allowing passage of a diagnostic adult upper endoscope [insertion tube diameter >9 mm]); or following either a pure liquid diet or a 6-food elimination diet. In addition to having a stable (ie, no changes) diet ≥3 months before screening, dosing with inhaled or nasal corticosteroids and PPIs was to be stable for a specified period of time (inhaled corticosteroids for ≥3 months before screening; nasal corticosteroids and PPIs for ≥4 weeks prior to qualifying EGD).

       Prespecified Study Endpoints and Assessments

       Efficacy Endpoints and Assessments

      Both histologic and symptom outcomes were assessed as part of the co-primary efficacy endpoints of this trial, as there is often a disconnect between histologic and symptom outcomes in clinical trials for EoE.
      • Hirano I.
      • Spechler S.
      • Furuta G.
      • et al.
      AGA white paper: drug development for eosinophilic esophagitis.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Pentiuk S.
      • Putnam P.E.
      • Collins M.H.
      • et al.
      Dissociation between symptoms and histological severity in pediatric eosinophilic esophagitis.
      The histologic and dysphagia symptom response thresholds (≤6 eosinophils per high-power field [eos/hpf] and ≥30% reduction in DSQ score, respectively) were selected based on discussions on meaningful change with the U.S. Food and Drug Administration; discussions regarding the histologic response threshold were supported by literature available at the time of study initiation.
      • Aceves S.S.
      • Bastian J.F.
      • Newbury R.O.
      • et al.
      Oral viscous budesonide: a potential new therapy for eosinophilic esophagitis in children.
      • 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.
      Stringent histologic responders were defined as patients having a peak eosinophil count of ≤6 eos/hpf across all available esophageal levels. For histologic assessments, at least 2 biopsies from each esophageal level (proximal, middle, and distal) were obtained (at the screening EGD and after 12 weeks of therapy). These were then processed at the central pathology laboratory for review, including determination of peak eosinophil counts and EoE Histology Scoring System (EoEHSS) scores, by the study pathologist who was blinded to treatment allocation (M.H.C.).
      • Collins M.H.
      • Martin L.J.
      • Alexander E.S.
      • et al.
      Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.
      • Hudgens S.
      • Evans C.
      • Philips E.
      • et al.
      Psychometric validation of the Dysphagia Symptom Questionnaire in patients with eosinophilic esophagitis treated with oral budesonide suspension.
      • 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.
      Peak eosinophil counts were reported as eos/hpf with a hpf area of 0.3 mm2. Peak eosinophil counts were available for proximal, middle, and distal regions of the esophagus.
      The DSQ comprises 3 questions relating to dysphagia with a standalone question (question 4) relating to pain with swallowing.
      • Collins M.H.
      • Martin L.J.
      • Alexander E.S.
      • et al.
      Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.
      The DSQ was completed daily during this study; data related to pain with swallowing are not presented here. Question 1 of the DSQ asks patients whether they had eaten solid food on that day; if the patient answers “yes,” they proceed to answer questions 2 and 3. Scores for question 2 (frequency of dysphagia) and question 3 (severity of dysphagia) were summed and divided by the number of days for which the diary had been completed and were multiplied by 14 days, as reported elsewhere.
      • Dellon E.S.
      • Katzka D.A.
      • Collins M.H.
      • et al.
      Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.
      ,
      • Collins M.H.
      • Martin L.J.
      • Alexander E.S.
      • et al.
      Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.
      The DSQ score was calculated by summing the scores from questions 2 and 3 from each reported daily diary with nonmissing data, and dividing this by the number of reported daily diaries with nonmissing data in the selected 14-day period. For each 14-day period, at least 8 reported diaries were needed to calculate a DSQ combined score. If fewer than 8 reported diaries were available within the 14-day period, the most recent 8 reported diaries in a consecutive 14-day period were used to calculate the DSQ combined score. Such 14-day periods could not be shifted for more than 7 days when calculating the DSQ score at the baseline visit and could not be shifted for more than 14 days before the final treatment evaluation. DSQ scores could range from 0 to 84.
      • Dellon E.S.
      • Katzka D.A.
      • Collins M.H.
      • et al.
      Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.
      ,
      • Collins M.H.
      • Martin L.J.
      • Alexander E.S.
      • et al.
      Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.
      Upper endoscopy was performed at screening and after 12 weeks of therapy. The validated EoE Endoscopic Reference Score (EREFS) was used to quantify the severity of endoscopic features (exudates, 0–2; rings, 0–3; edema, 0–2; furrows, 0–2; and strictures, 0–1) for proximal and distal esophageal levels.
      • Hudgens S.
      • Evans C.
      • Philips E.
      • et al.
      Psychometric validation of the Dysphagia Symptom Questionnaire in patients with eosinophilic esophagitis treated with oral budesonide suspension.
      EREFS for each level could range from 0 to 10 (total scores could thus range from 0 to 20).
      • Dellon E.S.
      • Katzka D.A.
      • Collins M.H.
      • et al.
      Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.
      The EoEHSS was used to assess the severity (grade) and extent (stage) of 8 histopathologic features (eosinophilic inflammation, basal zone hyperplasia, eosinophilic abscess, eosinophilic surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis). Features are scored for grade and stage (0–3 points for each feature, with higher scores indicative of greater severity) and summed to generate a total grade and stage score for each biopsy.
      • 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.
      A total score ratio was then calculated to normalize scores by accounting for missing features.
      • Collins M.H.
      • Dellon E.S.
      • Katzka D.A.
      • et al.
      Budesonide oral suspension significantly improves eosinophilic esophagitis histology scoring system results: analyses from a 12-week, phase 2, randomized, placebo-controlled trial.
      EoEHSS grade and stage scores were generated for proximal, middle, and distal regions of the esophagus.
      The DSQ, EREFS, and EoEHSS tools have all been previously validated.
      • Collins M.H.
      • Martin L.J.
      • Alexander E.S.
      • et al.
      Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.
      • Hudgens S.
      • Evans C.
      • Philips E.
      • et al.
      Psychometric validation of the Dysphagia Symptom Questionnaire in patients with eosinophilic esophagitis treated with oral budesonide suspension.
      • 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.

       Safety Assessments

      Safety assessments included monitoring of adverse events, physical examinations, measurement of vital signs (temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), body weight and height (stadiometry for patients 11–17 years of age) assessments, dual-energy x-ray absorptiometry scans for bone mineral density (for patients 11–17 years of age), clinical laboratory tests (hematology, chemistry, urinalysis, and serum pregnancy test, if appropriate), and adrenocorticotropic hormone (ACTH) stimulation tests. Data relating to bone mineral density will not be reported here but will be provided along with the 36-week, double-blind, placebo-controlled extension trial for BOS (ORBIT2/SHP621-302/NCT02736409).
      • Dellon E.S.
      • Liacouras C.A.
      • Molina-Infante J.
      • et al.
      Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference.
      Serial blood samples for pharmacokinetic analysis were obtained from patients (≥18 years of age) as part of an optional study procedure at a single visit during the double-blind treatment phase (pharmacokinetic set; data not reported here).
      All adverse event data (including treatment-emergent adverse events [TEAEs]) were collected from the time informed consent was given until the end of the defined follow-up period. This included events occurring during the screening phase of the study, regardless of whether or not study treatment was administered. The severity and relationship of adverse events to the study treatment were also assessed. TEAEs were defined as adverse events that started or deteriorated on or after the first dose of double-blind study treatment and through the safety follow-up period, or 31 days after the last dose of study treatment for patients who did not have a safety follow-up visit.
      ACTH stimulation tests were performed at baseline and at week 12 of therapy. For these tests, blood samples were taken 30 and 60 minutes after the administration of synthetic ACTH (250 μg intramuscularly/intravenously), with the peak defined as the higher value from the 2 time points. In addition, fasting unstimulated morning cortisol levels were determined from blood samples collected between 6 am and 9 am at baseline and at each visit. An abnormal shift was defined as a peak ACTH-stimulated cortisol level ≤18 μg/dL at the end of treatment.

       Statistical Analyses

      Based on the results of the previous phase 2 trial,
      • Dellon E.S.
      • Gibbs W.B.
      • Fritchie K.J.
      • et al.
      Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease.
      randomization of at least 228 patients (BOS, n = 152; placebo, n = 76) was planned, allowing for a ~5% dropout rate. This would yield 90% power at the significance level of .05 (2-sided) to detect a 24% difference in symptom response and 99% power to detect a 37% difference in stringent histologic response at the significance level of .0499 (2-sided) using a 2-group chi-square test. The overall study power for co-primary efficacy endpoints was estimated to be at least 85%. The protocol was subsequently amended to increase enrollment in SHP621-301 and to ensure adequate enrollment into the extension trial (ORBIT2/SHP621-302/NCT02736409).
      A planned interim analysis assessed the appropriateness of assumptions for each of the co-primary efficacy endpoints used in the sample size determinations, and a minimal fraction of α (0.0001) was spent by using the conditional power approach under certain conditions.
      A hierarchical testing procedure was used to control the type I error the multiple endpoints tested at α = 0.0499. Efficacy endpoints were tested in the following order: co-primary endpoints of stringent histologic response and dysphagia symptom response, and change in DSQ score from baseline to week 12 of therapy.
      • Mehta C.R.
      • Pocock S.J.
      Adaptive increase in sample size when interim results are promising: a practical guide with examples.

      Supplementary Results

       Baseline Characteristics (Full Analysis Set)

      During the double-blind treatment phase, the mean ± SD compliance with treatment administration of BOS 2.0 mg twice daily and placebo was 87.1 ± 17.0% and 85.8 ± 15.7%, respectively.

       Patient Disposition (Per-Protocol Set)

      The per-protocol set comprised 259 patients without major protocol deviations (BOS, n = 175; placebo, n = 84). Major protocol deviations included inclusion criteria violation (n = 17 [BOS, n = 10; placebo, n = 7]), exclusion criteria violation (n = 9 [BOS, n = 8; placebo, n = 1]), and use of prohibited concomitant medications (n = 1 in the BOS group). A further 34 patients who had <70% or >130% compliance with either BOS or placebo treatment (ie, patients who took less or more study drug than intended) were also considered to have major protocol deviations. Some patients had multiple major protocol deviations but were counted only once per category.

       Co-primary Efficacy Endpoint Outcomes (Per-Protocol Set)

      Significantly more BOS-treated patients than placebo-treated patients achieved a stringent histologic response or dysphagia symptom response after 12 weeks (BOS vs placebo: stringent histologic responders, 53.1% vs 1.2%; Δ52% [95% confidence interval (CI), 41.8%–59.5%]; P < .001 [after adjustment with the Cochran–Mantel–Haenszel test]; symptomatic responders, 52.0% [n = 91 of 175] vs 36.9% [n = 31 of 84]; Δ14% [95% CI, 1.5%–26.6%]; P = .028) (Supplemental Figure 2A and B). A description regarding Supplemental Figure 3 can be found in the main text.

       Safety Outcomes

       TEAEs leading to study discontinuation

      One patient discontinued the study due to an inability to pass the endoscope completely through the esophagus at follow-up endoscopy. This was deemed related to EoE and unrelated to the study drug (BOS). This patient had previously undergone esophageal dilation. The other 3 patients discontinuing the study were receiving placebo and reported a total of 4 TEAEs (mouth ulceration in 1 patient [1 event], dizziness and headache in 1 patient [2 events], and mood swings in 1 patient [1 event]), all of which were related to the study treatment and resolved following discontinuation of placebo.

       TEAEs of Candidiasis

      Potential local effects of corticosteroid use that may be related to local Candida infection were observed more frequently in BOS-treated patients than in placebo-treated patients: esophageal candidiasis (3.8% vs 1.9%), oral candidiasis (3.8% vs 0.0%), and oropharyngeal candidiasis (0.5% vs 0.0%). All of these TEAEs were mild or moderate in severity and the majority of them resolved/were resolving without interruption or withdrawal of study treatment. One BOS-treated patient with esophageal candidiasis had treatment withdrawn; 1 BOS-treated patient with oral candidiasis had treatment interrupted. Of these TEAEs, none were considered serious. All patients received concomitant antifungal therapy.

       Adrenal Function Abnormality

      Of the 5 BOS-treated patients with TEAEs of adrenal suppression or insufficiency, 4 had treatment-emergent abnormal ACTH stimulation test results. One patient had moderate suppression of ACTH-stimulated and unstimulated cortisol production (unstimulated cortisol: baseline, 16.2 μg/dL, week 4 of therapy, 0.5 μg/dL; week 8 of therapy, 0.5 μg/dL; week 12 of therapy, 0.5 μg/dL), which after further exploration was deemed as associated with increased budesonide plasma concentrations and exposure (these assessments were conducted for patients included in the pharmacokinetic set). The ACTH-stimulated cortisol response of this patient was transient and returned to normal after completion of the study and a hydrocortisone taper; this patient completed the 12-week double-blind treatment period. This event was temporally associated with a TEAE of fatigue, which was believed to be possibly related to BOS; it resolved shortly before completion of therapy (the affected individual was 1 of 5 patients reporting a TEAE of fatigue [BOS, n = 4; placebo, n = 1]).
      Two patients had mild suppression of ACTH-stimulated cortisol; 1 TEAE was determined to be definitely related to BOS therapy and resulted in discontinuation of treatment, after which it resolved. (The patient was also receiving concomitant intranasal fluticasone propionate for environmental allergies.) The other patient with mild suppression had a normal peak ACTH-stimulated cortisol level at baseline (29.6 μg/dL), which was abnormal at week 12 of therapy (16.8 μg/dL); this was determined to be probably related to study drug. One patient had borderline suppression of ACTH-stimulated cortisol production (peak ACTH-stimulated cortisol level of 19.7 μg/dL at week 12 of therapy); this TEAE was found to be unrelated to BOS therapy and resolved after completion of the study.
      One patient had a pretreatment abnormal peak ACTH-stimulated cortisol level at baseline (17.5 μg/dL), which was normal at week 12 of therapy (22.9 μg/dL).
      Supplementary Table 1DSQ Scores (Key Secondary Efficacy Endpoint), EREFS, Maximum Peak Eosinophil Counts, and EoEHSS Grade and Stage Score Ratios (Secondary Efficacy Endpoints) at Baseline and After 12 Weeks of Therapy (Full Analysis Set)
      EndpointBOS 2.0 mg twice dailyPlaceboDifference (95% CI) and/or

      P value
      P values reported for other secondary endpoints are nominal.
      DSQ score (0–84)
      Absolute and percentage distribution-based MIDs for DSQ score have been reported (7.4% and 8.9%, respectively). Absolute and percentage anchor-based MCIDs and CIDs have been reported (MCID, −6.5% and −27.4%, respectively; CID, −13.5% and −55.4%, respectively).13
       Baseline, mean (SD)n = 211

      30.3 (13.9)
      n = 105

      30.4 (13.1)
       Week 12 of therapy, mean (SD)n = 198

      19.5 (17.0)
      n = 89

      22.6 (17.5)
       Change from baseline, LS mean (SEM)n = 197

      −13.0 (1.2)
      n = 89

      −9.1 (1.5)
      −3.9 (−7.1 to −0.8)

      P = .015
      Total EREFS (0–20)
       Baseline, mean (SD)n = 213

      7.6 (3.6)
      n = 105

      8.2 (3.3)
       Week 12 of therapy, mean (SD)n = 202

      4.2 (3.3)
      n = 93

      6.2 (3.7)
       Change from baseline, LS mean (SEM)n = 202

      −4.0 (0.3)
      n = 93

      −2.2 (0.4)
      −1.8 (−2.6 to −1.1)

      P < .001
      Maximum peak eosinophil count, eos/hpf
       Baseline, mean (SD)n = 213

      74.5 (39.2)
      n = 104

      76.6 (45.0)
       Week 12 of therapy, mean (SD)n = 201

      21.9 (34.6)
      n = 92

      69.9 (38.4)
       Change from baseline, LS mean (SEM)n = 201

      −55.2 (3.4)
      n = 92

      −7.6 (4.3)
      −47.6 (−56.4 to −38.8)

      P < .001
      EoEHSS grade (0–1)
      The EoEHSS scores presented here are ratios, and hence range from 0 to 1.
       Baseline, mean (SD)n = 213

      0.4 (0.1)
      n = 104

      0.4 (0.1)
       Week 12 of therapy, mean (SD)n = 201

      0.1 (0.1)
      n = 92

      0.3 (0.1)
       Change from baseline, LS mean (SEM)n = 201

      −0.22 (0.01)
      n = 92

      −0.03 (0.02)
      −0.19 (−0.22 to −0.16)

      P < .001
      EoEHSS stage (0–1)
      The EoEHSS scores presented here are ratios, and hence range from 0 to 1.
       Baseline, mean (SD)n = 213

      0.3 (0.1)
      n = 104

      0.3 (0.1)
       Week 12 of therapy, mean (SD)n = 201

      0.1 (0.1)
      n = 92

      0.3 (0.1)
       Change from baseline, LS mean (SEM)n = 201

      −0.2 (0.01)
      n = 92

      −0.0 (0.02)
      −0.20 (−0.20 to −0.20)

      P < .001
      NOTE. The full analysis set included all randomized patients who received at least 1 dose of study treatment during the double-blind phase.
      BOS, budesonide oral suspension; CI, confidence interval; CID, clinically important difference; DSQ, Dysphagia Symptom Questionnaire; EoE, eosinophilic esophagitis; EoEHSS, Eosinophilic Esophagitis Histology Scoring System; eos/hpf, eosinophils per high-power field; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; LS, least-squares; MCID, minimal clinically important difference; MID, minimally important difference.
      a P values reported for other secondary endpoints are nominal.
      b Absolute and percentage distribution-based MIDs for DSQ score have been reported (7.4% and 8.9%, respectively). Absolute and percentage anchor-based MCIDs and CIDs have been reported (MCID, −6.5% and −27.4%, respectively; CID, −13.5% and −55.4%, respectively).
      • Collins M.H.
      • Martin L.J.
      • Alexander E.S.
      • et al.
      Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.
      c The EoEHSS scores presented here are ratios, and hence range from 0 to 1.
      Supplementary Table 2Shift in Cortisol Levels Following Stimulation with Synthetic ACTH (250 μg) from Baseline to Week 12 of Therapy (Safety Set)
      Cortisol level at week 12 of therapy Post-ACTH injectionBOS 2.0 mg Twice Daily (n = 196)Placebo (n = 84)
      Baseline cortisol level post-ACTH injectionBaseline crtisol level post-ACTH injection
      ≤18 μg/dL>18 μg/dLTotal≤18 μg/dL>18 μg/dLTotal
      ≤18 μg/dL2 (1.0)16 (8.2)18 (9.2)0 (0.0)3 (3.6)3 (3.6)
      >18 μg/dL5 (2.6)173 (88.3)178 (90.8)2 (2.4)79 (94.0)81 (96.4)
      Total7 (3.6)189 (96.4)196 (100.0)2 (2.4)82 (97.6)84 (100.0)
      NOTE. Values are n (%). Data show the proportion of patients at baseline and at week 12 with cortisol levels ≤18 μg/dL or >18 μg/dL following stimulation with synthetic ACTH (250 μg) stratified by treatment group. The safety set included all patients who received at least 1 dose of study treatment during the double-blind phase.
      ACTH, adrenocorticotropic hormone; BOS, budesonide oral suspension.
      Figure thumbnail fx2
      Supplementary Figure 1Study design and patient flow. b.i.d., twice daily; BOS, budesonide oral suspension; EGD, esophagogastroduodenoscopy.
      Figure thumbnail fx3
      Supplementary Figure 2Co-primary efficacy endpoints: prespecified sensitivity analysis (per-protocol set [the per-protocol set included all patients in the full analysis set excluding those with major protocol deviations]): (A) Proportion of patients achieving a stringent histologic response (a stringent histologic response was defined as ≤6 eosinophils per high-power field) after 12 weeks of therapy; (B) proportion of patients achieving a dysphagia symptom response (a dysphagia symptom response was defined as ≥30% reduction in Dysphagia Symptom Questionnaire score) after 12 weeks of therapy. b.i.d., twice daily; BOS, budesonide oral suspension; CI, confidence interval.
      Figure thumbnail fx4
      Supplementary Figure 3Secondary efficacy endpoints by esophageal region (full analysis set [the full analysis set included all randomized patients who received at least 1 dose of study treatment during the double-blind phase]): (A) change in Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) (proximal and distal; prespecified) from baseline to week 12 of therapy; (B) change in peak eosinophil count (proximal, middle, and distal; prespecified; histologic assessments—proximal: budesonide oral suspension [BOS], n = 201 and placebo, n = 92; middle: BOS, n = 199 and placebo, n = 92; distal: BOS, n = 201 and placebo, n = 91) from baseline to week 12 of therapy; (C) Change in Eosinophilic Esophagitis Histology Scoring System (EoEHSS) grade total score ratio (proximal, middle, and distal; post hoc) from baseline to week 12 of therapy; (D) change in EoEHSS stage total score ratio (proximal, middle, and distal; post hoc) from baseline to week 12 of therapy. b.i.d., twice daily; CI, confidence interval; EoE, eosinophilic esophagitis; eos/hpf, eosinophils per high-power field; LS, least-squares.

      References

        • Dellon E.S.
        • Liacouras C.A.
        • Molina-Infante J.
        • et al.
        Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference.
        Gastroenterology. 2018; 155: 1022-1033
        • Lucendo A.J.
        • Molina-Infante J.
        • Arias A.
        • et al.
        Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
        United European Gastroenterol J. 2017; 5: 335-358
        • Dellon E.S.
        • Gibbs W.B.
        • Fritchie K.J.
        • et al.
        Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease.
        Clin Gastroenterol Hepatol. 2009; 7: 1305-1313
        • Hirano I.
        • Aceves S.S.
        Clinical implications and pathogenesis of esophageal remodeling in eosinophilic esophagitis.
        Gastroenterol Clin North Am. 2014; 43: 297-316
        • Hirano I.
        • Chan E.S.
        • Rank M.A.
        • et al.
        AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters clinical guidelines for the management of eosinophilic esophagitis.
        Gastroenterology. 2020; 158: 1776-1786
        • Hirano I.
        • Spechler S.
        • Furuta G.
        • et al.
        AGA white paper: drug development for eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2017; 15: 1173-1183
        • Schupack D.A.
        • Ravi K.
        • Geno D.M.
        • et al.
        Effect of maintenance therapy for eosinophilic esophagitis on need for recurrent dilation.
        Dig Dis Sci. 2021; 66: 503-510
        • Kuchen T.
        • Straumann A.
        • Safroneeva E.
        • et al.
        Swallowed topical corticosteroids reduce the risk for long-lasting bolus impactions in eosinophilic esophagitis.
        Allergy. 2014; 69: 1248-1254
        • Kim J.P.
        • Weingart G.
        • Hiramoto B.
        • et al.
        Clinical outcomes of adults with eosinophilic esophagitis with severe stricture.
        Gastrointest Endosc. 2020; 92: 44-53
        • Runge T.M.
        • Eluri S.
        • Cotton C.C.
        • et al.
        Outcomes of esophageal dilation in eosinophilic esophagitis: safety, efficacy, and persistence of the fibrostenotic phenotype.
        Am J Gastroenterol. 2016; 111: 206-213
        • 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
        • Dellon E.S.
        • Katzka D.A.
        • Collins M.H.
        • et al.
        Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.
        Gastroenterology. 2017; 152: 776-786
        • Hudgens S.
        • Evans C.
        • Philips E.
        • et al.
        Psychometric validation of the Dysphagia Symptom Questionnaire in patients with eosinophilic esophagitis treated with oral budesonide suspension.
        J Patient Rep Outcomes. 2017; 1: 3
        • 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
        • 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: 1526-1537
        • 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
        • van Rhijn B.D.
        • Verheij J.
        • van den Bergh Weerman M.A.
        • et al.
        Histological response to fluticasone propionate in patients with eosinophilic esophagitis is associated with improved functional esophageal mucosal integrity.
        Am J Gastroenterol. 2015; 110: 1289-1297
        • 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
        • Ma C.
        • van Rhijn B.D.
        • Jairath V.
        • et al.
        Heterogeneity in clinical, endoscopic, and histologic outcome measures and placebo response rates in clinical trials of eosinophilic esophagitis: a systematic review.
        Clin Gastroenterol Hepatol. 2018; 16: 1714-1729
        • Lucendo A.J.
        • Miehlke S.
        • Schlag C.
        • et al.
        Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial.
        Gastroenterology. 2019; 157: 74-86
        • European Medicines Agency
        EPAR summary for the public. Jorveza (budesonide).
        (Available from:)
        • Eluri S.
        • Selitsky S.R.
        • Perjar I.
        • et al.
        Clinical and molecular factors associated with histologic response to topical steroid treatment in patients with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2019; 17: 1081-1088
        • 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
        • Harer K.N.
        • Enders F.T.
        • Lim K.G.
        • et al.
        An allergic phenotype and the use of steroid inhalers predict eosinophilic oesophagitis in patients with asthma.
        Aliment Pharmacol Ther. 2013; 37: 107-113
        • Hirano I.
        • Dellon E.S.
        • Collins M.H.
        • et al.
        Clinical features at baseline cannot predict symptom response to placebo in patients with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2019; 17: 2126-2128.e1
        • Elsenbruch S.
        • Enck P.
        Placebo effects and their determinants in gastrointestinal disorders.
        Nat Rev Gastroenterol Hepatol. 2015; 12: 472-485
        • 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
        • Dellon E.S.
        • Gonsalves N.
        • Hirano I.
        • et al.
        ACG Clinical Guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE).
        Am J Gastroenterol. 2013; 108: 679-692
        • Eluri S.
        • Runge T.M.
        • Cotton C.C.
        • et al.
        The extremely narrow-caliber esophagus is a treatment resistant sub-phenotype of eosinophilic esophagitis.
        Gastrointest Endosc. 2016; 83: 1142-1148