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Budesonide Versus Fluticasone for Treatment of Eosinophilic Esophagitis

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ClinicalTrials.gov Identifier: NCT02019758
Recruitment Status : Completed
First Posted : December 24, 2013
Results First Posted : April 26, 2019
Last Update Posted : April 27, 2020
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Tracking Information
First Submitted Date  ICMJE December 18, 2013
First Posted Date  ICMJE December 24, 2013
Results First Submitted Date  ICMJE April 3, 2019
Results First Posted Date  ICMJE April 26, 2019
Last Update Posted Date April 27, 2020
Actual Study Start Date  ICMJE January 1, 2015
Actual Primary Completion Date May 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 3, 2019)
  • Post-Treatment Maximum Eosinophil Count (Aim 1) [ Time Frame: 8 weeks ]
    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.
  • Post-treatment Dysphagia Score (Aim 1) [ Time Frame: 8 weeks ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 18, 2013)
  • Histologic effectiveness of viscous budesonide versus fluticasone MDI [ Time Frame: 8 weeks ]
    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 EoE. The mean post-treatment maximum eosinophil count will be compared between the OVB and MDI groups using a two-sample t-test. The pre- and post-treatment counts will also be compared within study groups using a paired t-test.
  • Symptomatic effectiveness of viscous budesonide versus fluticasone MDI [ Time Frame: 2 weeks ]
    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, and within groups using a paired t-test.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 15, 2020)
  • Post-treatment Endoscopic Severity (Aim 1) [ Time Frame: 8 weeks ]
    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.
  • Percentage of Participants With Histologic Response of <15 Eos/Hpf [ Time Frame: 8 weeks ]
    Percentage with histologic response, with response defined as <15 eos/hpf, will be compared between groups
  • Post-treatment Symptom Severity (Aim 1) [ Time Frame: 8 weeks ]
    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.
  • Post-treatment Medication Compliance (Aim 1) [ Time Frame: 8 weeks ]
    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.
  • Median Number of Days Until Symptom Recurrence (Aim 2) [ Time Frame: Symptom recurrence or 1 year after completing the initial 8 week treatment ]
    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.
  • Number of Subjects With Histologic Recurrence, Defined as ≥15 Eosinophils Per High-power Field, at Follow-up Endoscopy. [ Time Frame: Symptom recurrence or 1 year after completing the initial 8 week treatment ]
    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.
  • Mean Endoscopic Severity Score at Recurrence (Aim 2) [ Time Frame: Symptom recurrence or 1 year after completing the initial 8 week treatment ]
    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.
  • Mean Peak Eosinophil Count (Aim 2) [ Time Frame: Symptom recurrence or 1 year after completing the initial 8 week treatment ]
    This will assess the mean peak level of esophageal eosinophilia on biopsy (measured in peak eosinophil count - eos/hpf) at the time of recurrence
Original Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2013)
  • Symptom recurrence [ Time Frame: Symptom recurrence or 1 year after enrollment ]
    To test whether OVB results in less symptomatic recurrence than fluticasone MDI, survival analysis will be performed with the interval between treatment end (week 8) and recurrent symptoms or study end (week 60) as the time of interest. A Kaplan-Meier curve will be constructed comparing the time until symptom recurrence in both study groups using the log-rank test.
  • Histologic recurrence [ Time Frame: Symptom recurrence or 1 year after enrollment ]
    To test whether OVB results in less histologic recurrence than fluticasone MDI, the proportion of subjects with ≥15 eos/hpf at follow-up endoscopy in each group will be compared using chi-square.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: December 18, 2013)
  • Baseline immunohistochemical (IHC) staining and histologic response [ Time Frame: Enrollment (Day 1) ]
    To determine whether baseline immunohistochemical (IHC) staining of esophageal biopsies for major basic protein (MBP), eotaxin-3, and mast cell tryptase (MCT) is associated with histologic response in EoE patients treated with topical corticosteroid therapy. The mean baseline cellular staining for each biomarker (MBP, eotaxin-3, and MCT) will be compared between the responder and non-responder groups using a two-sample t-test.
  • Endoscopic findings of EoE [ Time Frame: 8 weeks ]
    To measure the EoE Endoscopic Reference Score (EREFS) based on esophageal findings: esophageal exudates, rings, edema, furrows, and stricture.
  • Levels of histologic response [ Time Frame: 8 weeks ]
    To measure the levels of histologic response defined as complete responders (< 5 eos/hpf), partial responders (5-14 eos/hpf) and non-responders (≥ 15 eos/hpf).
  • Medication compliance [ Time Frame: 8 weeks ]
    To measure medication compliance by residual OVB slurry left over and the actuation counter on the MDI
  • Baseline immunohistochemical (IHC) staining and other levels of histologic response [ Time Frame: Enrollment (Day 1) ]
    To determine whether baseline immunohistochemical (IHC) staining of esophageal biopsies for major basic protein (MBP), eotaxin-3, and mast cell tryptase (MCT) is associated with other levels of histologic response (partial response with 5-14 eos/hpf and non-response with ≥15 eos/hpf) in EoE patients treated with topical corticosteroid therapy.
 
Descriptive Information
Brief Title  ICMJE Budesonide Versus Fluticasone for Treatment of Eosinophilic Esophagitis
Official Title  ICMJE Budesonide Versus Fluticasone for Treatment of Eosinophilic Esophagitis
Brief Summary

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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Eosinophilic Esophagitis
Intervention  ICMJE
  • Drug: Oral Viscous Budesonide
    Oral Viscous Budesonide - 1 mg/4 mL, 4 mL of slurry twice daily
    Other Name: Pulmicort
  • Drug: Fluticasone MDI
    Fluticasone multi-dose inhaler - 4 puffs twice daily (880 mcg, twice daily)
    Other Name: Flovent
  • Drug: Placebo slurry
    Slurry of sucralose - 4 mL twice daily
    Other Name: Sucralose
  • Drug: Placebo inhaler
    Placebo inhaler - 4 puffs twice daily
    Other Name: Placebo
Study Arms  ICMJE
  • Active Comparator: Oral Viscous Budesonide (OVB)
    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.
    Interventions:
    • Drug: Oral Viscous Budesonide
    • Drug: Placebo inhaler
  • Active Comparator: Active Fluticasone MDI
    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.
    Interventions:
    • Drug: Fluticasone MDI
    • Drug: Placebo slurry
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 3, 2019)
129
Original Estimated Enrollment  ICMJE
 (submitted: December 18, 2013)
122
Actual Study Completion Date  ICMJE April 2019
Actual Primary Completion Date May 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 80 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02019758
Other Study ID Numbers  ICMJE 13-4047
R01DK101856 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of North Carolina, Chapel Hill
Study Sponsor  ICMJE University of North Carolina, Chapel Hill
Collaborators  ICMJE National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators  ICMJE
Principal Investigator: Evan S Dellon, MD, MPH University of North Carolina, Chapel Hill
PRS Account University of North Carolina, Chapel Hill
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP