Eosinophilic Esophagitis (EoE), Eosinophilic Gastrointestinal Disorders (EGIDs)
Conditions
Brief summary
The purpose of this interventional study is to test and compare the effectiveness of two elimination diets-the 1-food elimination diet (1FED, milk only) and the 6-food elimination diet (6FED, milk, egg, wheat, soy, tree nut/peanuts, and fish/shellfish). The study will also test the effectiveness of swallowed glucocorticoid therapy in some of the study participants for whom diet therapy was not effective.
Detailed description
This study will consist of two phases, plus a screening period. During the screening period, subject eligibility for the study will be determined. During Phase 1, qualified participants will be randomly assigned to one of two elimination diet therapies--the 1FED or the 6FED. Participants will remain on the assigned dietary therapy for 6 weeks. At the end of 6 weeks of therapy, esophageal biopsies from participant's standard of care (i.e. normal, routine care) endoscopy will be evaluated to determine disease status. Participants whose EoE is in remission (i.e. \<15 eos/hpf) will be done with the study. Participants whose EoE is still active (i.e. ≥15 eos/hpf) will have the option to continue into Phase 2 of the study. During Phase 2, participants who were on 1FED in Phase 1 will receive 6FED therapy for 6 weeks, and participants who were on 6FED during Phase 1 will receive swallowed glucocorticoid (SGC) therapy for 6 weeks. At the end of 6 weeks of therapy, esophageal biopsies from participant's standard of care (i.e. normal, routine care) endoscopy will be evaluated to determine disease status.
Interventions
OTHER1 Food Elimination Diet Therapy
OTHER6 Food Elimination Diet Therapy
OTHER6 Food Elimination Diet (after 1FED failure)
DRUGFluticasone Propionate, 880 mcg twice daily (after 6FED failure)
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Allergy and Infectious Diseases (NIAID)
Office of Rare Diseases (ORD)
National Center for Advancing Translational Sciences (NCATS)
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Have diagnosis of EoE (based on consensus criteria) * Have histologically confirmed active disease \>15 eosinophils/hpf in either distal or proximal esophagus within 12 weeks of screening visit * Symptomatic (have experienced symptoms within the last month prior to enrollment) * Proton pump inhibitor (PPI) confirmation * Have a negative urine pregnancy test at screening if of childbearing potential
Exclusion criteria
* Have been treated with topical swallowed steroids within the last 2 months or systemic steroids within the last 3 months * Have pathological eosinophilia in segments of the GI tract other than the esophagus determined by local review * Have been diagnosed with a GI malabsorption disorder (i.e., Inflammatory bowel disease, Crohn's disease) or Celiac disease * Are currently on dietary therapy strictly avoiding milk or on a 6FED * Have concurrent H pylori gastritis or parasitic infection * Have history of anaphylaxis to milk (with current avoidance of milk) * Have previously failed strict dietary therapy clearly documented with one of these regimens or topical steroid treatment (i.e. have achieved histological remission of \<15 eos/hpf after having been on fluticasone or \>1mg budesonide per day). * Use of investigational drugs within 4 weeks (one month) prior to enrollment * Are concurrently receiving any of the prohibited medications for the study * On immunotherapy for pollen (if not on maintenance therapy) or immunoglobulin-E (IgE) -mediated food allergy * Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants in Histologic Remission (<15 Eos/Hpf) | 6 weeks after starting treatment | Percent of participants in histologic remission in 1FED versus 6FED groups. Remission is defined as esophageal peak eosinophil count \< 15 eosinophils per high powered field (eos/hpf) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants Following SGC in Histologic Remission in Phase 2 | 6 weeks after starting treatment | Percent of participants who failed 6FED in Phase 1 in histologic remission after following swallowed glucocorticoids (SGC) in Phase 2. Remission is defined as esophageal peak eosinophil count \< 15 eos/hpf |
| Percent of Participants Following 6FED in Histologic Remission in Phase 2 | 6 weeks after starting treatment | Percent of participants who failed 1FED in Phase 1 in histologic remission after following 6FED in Phase 2. Remission is defined as esophageal peak eosinophil count \< 15 eos/hpf |
| Percent of Participants in Complete and Partial Histologic Remission | 6 weeks after starting treatment | Percent of participants in complete and partial histologic remission in 1FED versus 6FED groups. Complete remission is defined as esophageal peak eosinophil count ≤ 1 eosinophils per high powered field (eos/hpf). Partial remission is defined as esophageal peak eosinophil count of 2 - 14 eos/hpf. |
| Change From Baseline in Total Histology Scoring System | 6 weeks after starting treatment | The histology scoring system (HSS) measures the severity (grade) and extent (stage) of eight histologic abnormalities in the esophagus including eosinophilic inflammation, eosinophilic abscess, eosinophilic surface layering, surface epithelial alteration, dilated intercellular spaces, basal zone hyperplasia, dyskeratotic epithelial cells, and lamina propria fibrosis. Total score is the sum of grade and stage scores from the esophageal biopsy (distal, mid, or proximal) with the highest score (worst abnormalities) divided by the maximum possible score for the biopsy. Total scores range from 0 - 2 (higher scores indicate more severe and/or extensive abnormalities). Histology scores were obtained at baseline and 6 weeks. Change in total histology scoring system (HSS) is defined as total HSS score at 6 weeks minus total HSS score at baseline. Changes in scores are compared between 1FED and 6FED. A reduction (negative change) in score indicates improvement. |
| Change From Baseline in Total Endoscopic Reference Score | 6 weeks after starting treatment | The endoscopic reference score (EREFS) utilizes standardized criteria for the presence and degree of 5 major endoscopic features (edema, fixed rings, exudates, furrows, strictures). Total score is the sum of the five feature scores from the distal and proximal esophagus. Total scores range from 0 - 18 (higher scores indicate worsening features). Endoscopic features were assessed at baseline and 6 weeks. Change in total endoscopic reference score is defined as total score at 6 weeks minus total score at baseline. Changes in scores are compared between 1FED and 6FED. A reduction (negative change) in score indicates improvement. |
| Change From Baseline in Peak Eosinophil Count | 6 weeks after starting treatment | Peak eosinophil counts were obtained at baseline and 6 weeks. The maximum (highest) peak eosinophil count among distal, mid, and proximal esophageal biopsies was obtained. Change in peak eosinophil count is defined as peak count at 6 weeks minus peak count at baseline. Changes in peak count are compared between 1FED and 6FED. A reduction (negative change) in peak count indicates improvement. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from eosinophilic esophagitis specialty clinics (10 sites) in the USA between May 20, 2016 and March 2019
Pre-assignment details
143 participants screened, 14 excluded (8 did not meet inclusion criteria, 1 met exclusion criteria, 5 withdrew during screening), and 129 randomized
Participants by arm
| Arm | Count |
|---|---|
| 1-Food Elimination Diet (1FED) Participants eliminate milk from the diet in Phase 1
1 Food Elimination Diet Therapy | 67 |
| 6-Food Elimination Diet (6FED) Participants eliminate milk, egg, wheat, soy, nuts, fish from the diet in Phase 1
6 Food Elimination Diet Therapy | 62 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase 1 | Withdrawal by Subject | 2 | 3 | 0 | 0 |
| Phase 2 | Adverse Event | 0 | 0 | 0 | 1 |
| Phase 2 | Physician Decision | 0 | 0 | 0 | 1 |
| Phase 2 | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | 1-Food Elimination Diet (1FED) | 6-Food Elimination Diet (6FED) | Total |
|---|---|---|---|
| Age, Continuous | 36.4 years STANDARD_DEVIATION 10.2 | 37.8 years STANDARD_DEVIATION 10.4 | 37.0 years STANDARD_DEVIATION 10.3 |
| Endoscopic Reference Score | 7.0 score on a scale | 6.5 score on a scale | 7.0 score on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants | 61 Participants | 126 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Histology scoring system | 0.83 score on a scale STANDARD_DEVIATION 0.26 | 0.81 score on a scale STANDARD_DEVIATION 0.25 | 0.82 score on a scale STANDARD_DEVIATION 0.26 |
| Peak Eosinophil Count | 56 eosinophils per high power field | 38 eosinophils per high power field | 44 eosinophils per high power field |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 63 Participants | 61 Participants | 124 Participants |
| Region of Enrollment United States | 67 participants | 62 participants | 129 participants |
| Sex: Female, Male Female | 30 Participants | 29 Participants | 59 Participants |
| Sex: Female, Male Male | 37 Participants | 33 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 67 | 0 / 62 | 0 / 21 | 0 / 11 |
| other Total, other adverse events | 1 / 67 | 2 / 62 | 0 / 21 | 4 / 11 |
| serious Total, serious adverse events | 0 / 67 | 0 / 62 | 0 / 21 | 1 / 11 |
Outcome results
Primary
Percent of Participants in Histologic Remission (<15 Eos/Hpf)
Percent of participants in histologic remission in 1FED versus 6FED groups. Remission is defined as esophageal peak eosinophil count \< 15 eosinophils per high powered field (eos/hpf)
Time frame: 6 weeks after starting treatment
Population: Intent to treat analysis including participants who had at least one clinical observation post randomization. Participants whose histologic remission could not be determined were imputed as treatment failures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1-Food Elimination Diet (1FED) | Percent of Participants in Histologic Remission (<15 Eos/Hpf) | 34.3 percentage of participants |
| 6-Food Elimination Diet (6FED) | Percent of Participants in Histologic Remission (<15 Eos/Hpf) | 40.3 percentage of participants |
p-value: 0.58Fisher Exact
Secondary
Change From Baseline in Peak Eosinophil Count
Peak eosinophil counts were obtained at baseline and 6 weeks. The maximum (highest) peak eosinophil count among distal, mid, and proximal esophageal biopsies was obtained. Change in peak eosinophil count is defined as peak count at 6 weeks minus peak count at baseline. Changes in peak count are compared between 1FED and 6FED. A reduction (negative change) in peak count indicates improvement.
Time frame: 6 weeks after starting treatment
Population: Intent to treat analysis including participants who had at least one clinical observation post randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1-Food Elimination Diet (1FED) | Change From Baseline in Peak Eosinophil Count | -18 eosinophils per high power field |
| 6-Food Elimination Diet (6FED) | Change From Baseline in Peak Eosinophil Count | -22 eosinophils per high power field |
p-value: 0.9Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Total Endoscopic Reference Score
The endoscopic reference score (EREFS) utilizes standardized criteria for the presence and degree of 5 major endoscopic features (edema, fixed rings, exudates, furrows, strictures). Total score is the sum of the five feature scores from the distal and proximal esophagus. Total scores range from 0 - 18 (higher scores indicate worsening features). Endoscopic features were assessed at baseline and 6 weeks. Change in total endoscopic reference score is defined as total score at 6 weeks minus total score at baseline. Changes in scores are compared between 1FED and 6FED. A reduction (negative change) in score indicates improvement.
Time frame: 6 weeks after starting treatment
Population: Intent to treat analysis including participants who had at least one clinical observation post randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1-Food Elimination Diet (1FED) | Change From Baseline in Total Endoscopic Reference Score | -1.0 score on a scale |
| 6-Food Elimination Diet (6FED) | Change From Baseline in Total Endoscopic Reference Score | -2.0 score on a scale |
p-value: 0.71Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Total Histology Scoring System
The histology scoring system (HSS) measures the severity (grade) and extent (stage) of eight histologic abnormalities in the esophagus including eosinophilic inflammation, eosinophilic abscess, eosinophilic surface layering, surface epithelial alteration, dilated intercellular spaces, basal zone hyperplasia, dyskeratotic epithelial cells, and lamina propria fibrosis. Total score is the sum of grade and stage scores from the esophageal biopsy (distal, mid, or proximal) with the highest score (worst abnormalities) divided by the maximum possible score for the biopsy. Total scores range from 0 - 2 (higher scores indicate more severe and/or extensive abnormalities). Histology scores were obtained at baseline and 6 weeks. Change in total histology scoring system (HSS) is defined as total HSS score at 6 weeks minus total HSS score at baseline. Changes in scores are compared between 1FED and 6FED. A reduction (negative change) in score indicates improvement.
Time frame: 6 weeks after starting treatment
Population: Intent to treat analysis including participants who had at least one clinical observation post randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1-Food Elimination Diet (1FED) | Change From Baseline in Total Histology Scoring System | -0.15 score on a scale | Standard Deviation 0.39 |
| 6-Food Elimination Diet (6FED) | Change From Baseline in Total Histology Scoring System | -0.23 score on a scale | Standard Deviation 0.34 |
p-value: 0.22t-test, 2 sided
Secondary
Percent of Participants Following 6FED in Histologic Remission in Phase 2
Percent of participants who failed 1FED in Phase 1 in histologic remission after following 6FED in Phase 2. Remission is defined as esophageal peak eosinophil count \< 15 eos/hpf
Time frame: 6 weeks after starting treatment
Population: Intent to treat analysis including participants who had at least one clinical observation in Phase 2. Participants whose histologic remission could not be determined were imputed as treatment failures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1-Food Elimination Diet (1FED) | Percent of Participants Following 6FED in Histologic Remission in Phase 2 | 42.9 percentage of participants |
Secondary
Percent of Participants Following SGC in Histologic Remission in Phase 2
Percent of participants who failed 6FED in Phase 1 in histologic remission after following swallowed glucocorticoids (SGC) in Phase 2. Remission is defined as esophageal peak eosinophil count \< 15 eos/hpf
Time frame: 6 weeks after starting treatment
Population: Intent to treat analysis including participants who had at least one clinical observation in Phase 2. Participants whose histologic remission could not be determined were imputed as treatment failures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1-Food Elimination Diet (1FED) | Percent of Participants Following SGC in Histologic Remission in Phase 2 | 81.8 percentage of participants |
Secondary
Percent of Participants in Complete and Partial Histologic Remission
Percent of participants in complete and partial histologic remission in 1FED versus 6FED groups. Complete remission is defined as esophageal peak eosinophil count ≤ 1 eosinophils per high powered field (eos/hpf). Partial remission is defined as esophageal peak eosinophil count of 2 - 14 eos/hpf.
Time frame: 6 weeks after starting treatment
Population: Intent to treat analysis including participants who had at least one clinical observation post randomization. Participants whose histologic remission could not be determined were imputed as treatment failures.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1-Food Elimination Diet (1FED) | Percent of Participants in Complete and Partial Histologic Remission | Complete remission (≤ 1eos/hpf) | 6.0 percentage of participants |
| 1-Food Elimination Diet (1FED) | Percent of Participants in Complete and Partial Histologic Remission | Partial remission (2 - 14 eos/hpf) | 28.4 percentage of participants |
| 6-Food Elimination Diet (6FED) | Percent of Participants in Complete and Partial Histologic Remission | Complete remission (≤ 1eos/hpf) | 21.0 percentage of participants |
| 6-Food Elimination Diet (6FED) | Percent of Participants in Complete and Partial Histologic Remission | Partial remission (2 - 14 eos/hpf) | 19.4 percentage of participants |
p-value: 0.06Fisher Exact