Budesonide Versus Fluticasone for Treatment of Eosinophilic Esophagitis

Study Overview
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Brief Summary
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Purpose: To determine whether oral viscous budesonide (OVB) or fluticasone metered dose inhaler (MDI) most effectively treats EoE by improving histologic findings and symptoms, which medication provides a more durable treatment response, and whether biomarkers can predict treatment response. Participants: A total of up to 200 16-80 year old patients with a new diagnosis of eosinophilic esophagitis (EoE) who are referred for upper endoscopy will be consented with a target of 122 randomized. Procedures: This will be a prospective, randomized, double-blind, double-dummy, clinical trial comparing OVB to fluticasone MDI for treatment of EoE. This overall study design will generate data for all three Aims

Detailed Description
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This will be a prospective, randomized, double-blind, double-dummy, clinical trial comparing oral viscous budesonide (OVB) to fluticasone metered dose inhaler (MDI) for treatment of EoE. A total of 122 subjects aged 16-80 years old will be randomized in a 1:1 fashion to one of two active treatment arms: OVB + placebo inhaler or fluticasone MDI + placebo slurry. In the first arm, subjects will be treated with OVB at a dose of 1 mg twice daily, and they will also be instructed to use a placebo inhaler identical to the fluticasone MDI, with instructions to swallow 4 puffs twice daily. The OVB is a slurry equivalent to what is used clinically: 1 mg/4 mL aqueous budesonide mixed with 10 g of sucralose. Rather than asking the subjects to mix the slurry on their own and risk inconsistent formulations, the University of North Carolina (UNC) investigational drug pharmacy (IDP) will provide pre-mixed OVB to all patients. The IDP will also provide placebo inhalers to all patients. The dose for OVB has been chosen because it is the most commonly studied dose, including one prior study led by this Principal Investigator, so we can accurately estimate response rates. In the second arm, subjects will be treated with fluticasone MDI at a dose of 880 mcg twice daily (4 puffs of a 220 mcg inhaler twice daily), and they will also be instructed to take 4 mL twice daily of a placebo slurry of sucralose identical in consistency and taste to the OVB. The UNC investigational drug pharmacy (IDP) will provide the fluticasone MDIs and pre-mixed placebo slurries to all patients. The dose for fluticasone MDI has been chosen because this is the most commonly used dose in adolescents and adults with EoE, so effect estimates are also available. For both arms, the slurry will be administered first, the MDI will be administered 15 minutes later, and patients will take nothing by mouth for an additional 30 minutes. Subjects will receive 8 weeks of treatment and will then be monitored for up to 52 weeks for recurrence of symptoms.

Official Title
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Budesonide Versus Fluticasone for Treatment of Eosinophilic Esophagitis

Conditions
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Eosinophilic Esophagitis

Intervention / Treatment
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* Drug: Oral Viscous Budesonide
* Drug: Fluticasone MDI
* Drug: Placebo slurry
* Drug: Placebo inhaler


Participation Criteria
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Eligibility Criteria
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Inclusion criteria are as follows: Age: 16 - 80 years Subject is having a clinically indicated endoscopy for suspicious EoE and has been on twice daily (BID) proton pump inhibitor (PPI) for at least 8 weeks OR New diagnosis of EoE as per consensus guidelines. Cases must have symptoms of dysphagia, persistent esophageal eosinophilia (≥ 15 eosinophils in at least one high-power field) after 8 weeks of treatment with a twice daily proton-pump inhibitor, and other competing causes of esophageal eosinophilia excluded. Exclusion criteria are as follows: Medical instability that precludes safely performing upper endoscopy Ongoing or recent symptoms of intestinal bleeding (throwing up blood, passing blood in the stool) Concomitant eosinophilic gastroenteritis Esophageal narrowing or stricturing that will not allow a standard 9 mm upper endoscopy scope to pass Cancer in the esophagus, stomach, or intestine Previous esophageal surgery Esophageal varices (dilated blood vessels in the esophagus) Current use of blood thinners like Plavix or Coumadin that are not stopped prior to endoscopy procedures Any corticosteroid exposure within the 4 weeks prior to their baseline endoscopic exam. Exclusionary corticosteroid exposure is defined as any swallowed topical steroids for EoE or systemic steroids for any condition within the four weeks prior to the baseline endoscopy. Corticosteroids used for asthma or intranasal corticosteroids are not an exclusion and are allowable. Pregnancy Inability to read or understand English

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oral Viscous Budesonide (OVB)<br>Subjects will be treated with OVB at a dose of 1 mg twice daily, and they will also be instructed to use a placebo inhaler identical to the fluticasone MDI, with instructions to swallow 4 puffs twice daily. | Drug: Oral Viscous Budesonide<br>* Oral Viscous Budesonide - 1 mg/4 mL, 4 mL of slurry twice daily<br>* Other names: Pulmicort;Drug: Placebo inhaler<br>* Placebo inhaler - 4 puffs twice daily<br>* Other names: Placebo;|
| Active Comparator: Active Fluticasone MDI<br>Subjects will be treated with fluticasone MDI at a dose of 880 mcg twice daily (4 puffs of a 220 mcg inhaler twice daily), and they will also be instructed to take 4 mL twice daily of a placebo slurry of sucralose identical in consistency and taste to the OVB. | Drug: Fluticasone MDI<br>* Fluticasone multi-dose inhaler - 4 puffs twice daily (880 mcg, twice daily)<br>* Other names: Flovent;Drug: Placebo slurry<br>* Slurry of sucralose - 4 mL twice daily<br>* Other names: Sucralose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-Treatment Maximum Eosinophil Count (Aim 1) | To determine whether viscous budesonide is more effective than fluticasone MDI for improving post-treatment maximum esophageal eosinophil counts (measured in eosinophils per high powered field (eos/hpf)) in patients with eosinophilic esophagitis (EoE). The mean post-treatment maximum eosinophil count will be compared between the OVB and MDI groups using a two-sample t-test. | 8 weeks | 
| Post-treatment Dysphagia Score (Aim 1) | To determine whether viscous budesonide is more effective than fluticasone MDI for improving dysphagia (measured by the Daily Symptoms Questionnaire (DSQ)) in patients with EoE. The mean DSQ scores will be compared between the OVB and MDI groups using a two-sample t-test. The DSQ is a dysphagia severity score which ranges from 0-84, with higher numbers indicating more severe symptoms. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-treatment Endoscopic Severity (Aim 1) | Endoscopic severity will be quantified using the EoE Endoscopic Reference Score (EREFS) and compared between the two treatment arms. EREFS is a validated endoscopic severity score of key EoE endoscopic features (exudates, rings, edema, furrows, and strictures), and ranges from 0-9 with higher scores indicating higher endoscopic severity. | 8 weeks | 
| Percentage of Participants With Histologic Response of <15 Eos/Hpf | Percentage with histologic response, with response defined as <15 eos/hpf, will be compared between groups | 8 weeks | 
| Post-treatment Symptom Severity (Aim 1) | Post-treatment symptoms severity will be assessed with the EoE Symptom Activity Index (EEsAI), a validated dysphagia severity measure. The EEsAI ranges from 0-100, with higher scores indicating more severe symptoms; symptom remission is defined by a score <20. | 8 weeks | 
| Post-treatment Medication Compliance (Aim 1) | Medication compliance as measured by the percentage of medication appropriately used in each arm. For the slurry, this percentage is calculated after measuring the residual volume. For the inhaler, this percentage is calculated after measured using the residual weight. | 8 weeks | 
| Median Number of Days Until Symptom Recurrence (Aim 2) | To test whether OVB results in less symptomatic recurrence than fluticasone MDI, the median number of days until symptom occurrence will be quantified between treatment end (week 8) and recurrent symptoms or study end (week 60) as the time of interest. Hazard ratio will be calculated using Cox proportional modeling. | Symptom recurrence or 1 year after completing the initial 8 week treatment | 
| Number of Subjects With Histologic Recurrence, Defined as ≥15 Eosinophils Per High-power Field, at Follow-up Endoscopy. | To test whether OVB results in less histologic recurrence than fluticasone MDI, the number of subjects with ≥15 eosinophils per high-power field at follow-up endoscopy in each group will be compared using chi-square. | Symptom recurrence or 1 year after completing the initial 8 week treatment | 
| Mean Endoscopic Severity Score at Recurrence (Aim 2) | Measurement of endoscopic severity, using the EoE Endoscopic Reference Score (EREFS) measure, at the time of recurrence. EREFS is a validated endoscopic severity score of key EoE endoscopic features (exudates, rings, edema, furrows, and strictures), and ranges from 0-9 with higher scores indicating higher endoscopic severity. | Symptom recurrence or 1 year after completing the initial 8 week treatment | 
| Mean Peak Eosinophil Count (Aim 2) | This will assess the mean peak level of esophageal eosinophilia on biopsy (measured in peak eosinophil count - eos/hpf) at the time of recurrence | Symptom recurrence or 1 year after completing the initial 8 week treatment |