Eosinophilic Esophagitis
Conditions
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.
Interventions
DRUGOral Viscous Budesonide
Oral Viscous Budesonide - 1 mg/4 mL, 4 mL of slurry twice daily
DRUGFluticasone MDI
Fluticasone multi-dose inhaler - 4 puffs twice daily (880 mcg, twice daily)
DRUGPlacebo slurry
Slurry of sucralose - 4 mL twice daily
DRUGPlacebo inhaler
Placebo inhaler - 4 puffs twice daily
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post-Treatment Maximum Eosinophil Count (Aim 1) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-treatment Symptom Severity (Aim 1) | 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) | 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) | 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. |
| Post-treatment Endoscopic Severity (Aim 1) | 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. |
| Mean Endoscopic Severity Score at Recurrence (Aim 2) | 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) | 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 |
| Number of Subjects With Histologic Recurrence, Defined as ≥15 Eosinophils Per High-power Field, at Follow-up Endoscopy. | 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. |
| Percentage of Participants With Histologic Response of <15 Eos/Hpf | 8 weeks | Percentage with histologic response, with response defined as \<15 eos/hpf, will be compared between groups |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Oral Viscous Budesonide: Oral Viscous Budesonide - 1mg/4 mL, 4 mL of slurry twice daily
Placebo inhaler: Placebo inhaler - 4 puffs twice daily | 65 |
| 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.
Fluticasone MDI: Fluticasone multi-dose inhaler - 4 puffs twice daily (880 mcg, twice daily)
Placebo slurry: Slurry of sucralose - 4 mL twice daily | 64 |
| Total | 129 |
Baseline characteristics
| Characteristic | Oral Viscous Budesonide (OVB) | Total | Active Fluticasone MDI |
|---|---|---|---|
| Age, Continuous | 36.2 years STANDARD_DEVIATION 19.1 | 38.6 years STANDARD_DEVIATION 14.9 | 39.0 years STANDARD_DEVIATION 14.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 63 Participants | 126 Participants | 63 Participants |
| Region of Enrollment United States | 65 Participants | 129 Participants | 64 Participants |
| Sex: Female, Male Female | 25 Participants | 45 Participants | 20 Participants |
| Sex: Female, Male Male | 40 Participants | 84 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 64 |
| other Total, other adverse events | 10 / 65 | 15 / 64 |
| serious Total, serious adverse events | 0 / 65 | 1 / 64 |
Outcome results
Primary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Viscous Budesonide (OVB) | Post-treatment Dysphagia Score (Aim 1) | 4.8 score on a scale | Standard Deviation 7.3 |
| Active Fluticasone MDI | Post-treatment Dysphagia Score (Aim 1) | 4.2 score on a scale | Standard Deviation 7.5 |
Comparison: The mean DSQ scores will be compared between the OVB and MDI groups using a two-sample t-test.p-value: 0.7t-test, 2 sided
Primary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Viscous Budesonide (OVB) | Post-Treatment Maximum Eosinophil Count (Aim 1) | 14.7 eosinophils per high-power field | Standard Deviation 29 |
| Active Fluticasone MDI | Post-Treatment Maximum Eosinophil Count (Aim 1) | 20.9 eosinophils per high-power field | Standard Deviation 34.3 |
Comparison: The mean post-treatment maximum eosinophil count will be compared between the OVB and MDI groups using a two-sample t-test.p-value: 0.31t-test, 2 sided
Secondary
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.
Time frame: Symptom recurrence or 1 year after completing the initial 8 week treatment
Population: This population reflects only those patients who achieved histologic remission (\<15 eosinophils per high-power field) after the blinded phase, entered the observation phase, and had endoscopic and histologic outcome data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Viscous Budesonide (OVB) | Mean Endoscopic Severity Score at Recurrence (Aim 2) | 4.8 score on a scale | Standard Deviation 1.7 |
| Active Fluticasone MDI | Mean Endoscopic Severity Score at Recurrence (Aim 2) | 4.3 score on a scale | Standard Deviation 2 |
p-value: <0.001t-test, 2 sided
Secondary
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
Time frame: Symptom recurrence or 1 year after completing the initial 8 week treatment
Population: This population reflects only those patients who achieved histologic remission (\<15 eosinophils per high-power field) after the blinded phase, entered the observation phase, and had endoscopic and histologic outcome data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Viscous Budesonide (OVB) | Mean Peak Eosinophil Count (Aim 2) | 71.8 eosinophils per high-power field | Standard Deviation 52.9 |
| Active Fluticasone MDI | Mean Peak Eosinophil Count (Aim 2) | 35.0 eosinophils per high-power field | Standard Deviation 29.4 |
p-value: <0.001t-test, 2 sided
Secondary
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.
Time frame: Symptom recurrence or 1 year after completing the initial 8 week treatment
Population: This population reflects only those patients who achieved histologic remission (\<15 eosinophils per high-power field) after the blinded phase, entered the observation phase, and had symptom outcome data.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Oral Viscous Budesonide (OVB) | Median Number of Days Until Symptom Recurrence (Aim 2) | 263 Days | Standard Error 42 |
| Active Fluticasone MDI | Median Number of Days Until Symptom Recurrence (Aim 2) | 224 Days | Standard Error 66.3 |
95% CI: [0.52, 2.08]
Secondary
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.
Time frame: Symptom recurrence or 1 year after completing the initial 8 week treatment
Population: This population reflects only those patients who achieved histologic remission (\<15 eosinophils per high-power field) after the blinded phase, entered the observation phase, and had endoscopic and histologic data available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Viscous Budesonide (OVB) | Number of Subjects With Histologic Recurrence, Defined as ≥15 Eosinophils Per High-power Field, at Follow-up Endoscopy. | 22 Participants |
| Active Fluticasone MDI | Number of Subjects With Histologic Recurrence, Defined as ≥15 Eosinophils Per High-power Field, at Follow-up Endoscopy. | 17 Participants |
p-value: <0.001Chi-squared
Secondary
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
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Viscous Budesonide (OVB) | Percentage of Participants With Histologic Response of <15 Eos/Hpf | 71 Percent responders |
| Active Fluticasone MDI | Percentage of Participants With Histologic Response of <15 Eos/Hpf | 64 Percent responders |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Viscous Budesonide (OVB) | Post-treatment Endoscopic Severity (Aim 1) | 2.1 score on a scale | Standard Deviation 1.7 |
| Active Fluticasone MDI | Post-treatment Endoscopic Severity (Aim 1) | 2.8 score on a scale | Standard Deviation 2.2 |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Viscous Budesonide (OVB) | Post-treatment Medication Compliance (Aim 1) | 87 Percentage of medication used |
| Active Fluticasone MDI | Post-treatment Medication Compliance (Aim 1) | 85 Percentage of medication used |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Viscous Budesonide (OVB) | Post-treatment Symptom Severity (Aim 1) | 22.1 score on a scale | Standard Deviation 18.9 |
| Active Fluticasone MDI | Post-treatment Symptom Severity (Aim 1) | 28.0 score on a scale | Standard Deviation 20.4 |