EoE, Eosinophilic Esophagitis
Conditions
Brief summary
Multi-center, randomized, double blind, parallel-arm, placebo controlled trial to determine whether mepolizumab is more effective than placebo for improving symptoms of dysphagia and decreasing esophageal eosinophil counts in adults and adolescents with active eosinophilic esophagitis (EoE) after an initial 3 month treatment course, and will also assess the impact of an additional 3 months of treatment.
Detailed description
This is a multi-center, randomized, double blind, parallel-arm, placebo controlled trial of mepolizumab. After the first 3 month blinded phase, there will be a second 3 month blinded phase where all patients receive active medication, but the dose will be lower in the subjects initially randomized to the placebo arm. In the first arm, subjects will receive mepolizumab 300 mg SQ monthly for 3 months. In the second arm, subjects will receive a placebo SQ injection monthly for 3 months. Both groups will have the injection administered under direct observation in a Clinical & Translational Research Center (CTRC) or other clinic to ensure proper administration and compliance. Each visit will also provide an opportunity for symptom questionnaires to be completed and for blood samples to be drawn. After 3 months (the time point where the primary outcome is assessed), all subjects initially randomized to active treatment will continue with mepolizumab dosing 300 mg SQ monthly, and will remain blinded. All subjects initially randomized to placebo will receive mepolizumab 100mg SQ monthly, and will remain blinded. Of note, no dietary changes, changes in baseline Proton Pump Inhibitor (PPI) medication dose, changes in inhaled or intranasal steroid doses, or administration or oral, topical/swallowed, or systemic steroids will be allowed during the study period. Subjects will undergo endoscopy after the first blinded phase (at 3 months) and after the second blinded phase (after 6 months).
Interventions
Mepolizumab 300 mg subcutaneous injection
Mepolizumab 100 mg subcutaneous injection
OTHERPlacebo
Saline subcutaneous injection
Sponsors
GlaxoSmithKline
University of Utah
Northwestern University
MNGI Digestive Health, P.A.
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 16-75 * Diagnosis of EoE (eosinophilic esophagitis) as per consensus guidelines (including PPI non-response)\* * Active eosinophilia on esophageal biopsy, with a peak count of least 15 EOS/hpf (eosinophils per high power field) from at least one esophageal level. * Biopsies from the stomach and duodenum that have ruled out alternative etiologies in all children and in adults with abnormal endoscopic findings or when other gastric or small intestinal conditions are clinical possibilities. If these samples have been obtained during a previous endoscopic evaluation and in the judgement of the site-Investigator the patient has not had a clinically significant change that would merit repeat gastric/duodenal biopsies, then prior normal gastric and duodenal biopsies are acceptable to exclude alternate etiologies. * Active symptoms of dysphagia with more than 3 episodes of dysphagia over a period of 2 weeks during the screening period, and an Eosinophilic Esophagitis Symptom Activity Index (EEsAI; see below for details) score of ≥ 27 at baseline. * Able to read, comprehend, and sign consent form. * Have maintained a stable diet for 6 weeks prior to enrollment. * Able to maintain a stable diet throughout the duration of the study period. * Female subjects of childbearing potential who have had their first menses agree to use a highly effective method of birth control during the study and for 30 days after the last dose of study drug. Female subjects with reproductive potential who are using systemic contraceptives (e.g., oral contraceptives, injectable contraceptives, implantable/insertable hormonal contraceptive products, or transdermal patches) to prevent pregnancy must have stable use for ≥28 days prior to screening. * PPI non-response is defined as \>15 eos/hpf after at least 6 weeks of high dose administration (40mg total per day or higher) of any approved PPI medication or documented evidence of intolerance or allergy to PPIs. The length of the PPI trial period or documented intolerance/allergy will be determined according to the local clinical standard of care.
Exclusion criteria
* Esophageal dilation within 8 weeks of the screening endoscopy. * Inability to pass a standard upper endoscope (8-10mm) due to esophageal narrowing or stricturing. * Swallowed/topical steroids for EoE within 4 weeks of the screening endoscopy, or a course of systemic corticosteroids within 8 weeks of the screening endoscopy. * Not having maintained a stable diet for at least 6 weeks preceding the screening endoscopy. * Initiation, discontinuation, or change of dose regimen of PPIs; leukotriene inhibitors; or nasal, inhaled, and/or orally administered topical corticosteroids for any condition (such as gastroesophageal reflux disease, asthma, or allergic rhinitis) within the 8 weeks prior to the qualifying esophagogastroduodenoscopy (EGD). * Presence of concomitant eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE), eosinophilic colitis (EC), Crohn's disease, ulcerative colitis, or celiac disease. * History of malignancy within 5 years prior to screening, except completely treated in situ carcinoma of the cervix and completely treated non-metastatic squamous or basal cell carcinoma of the skin. * History of achalasia. * Prior esophageal surgery. * History of bleeding disorder or esophageal varices. * Active parasitic infection or suspicion of an active parasitic infection, which, in the opinion of the site-Investigator, has not been previously evaluated or treated. Subjects presenting with signs of active parasitic infection or suspicion of active parasitic infection as assessed by current diarrhea and/or blood or mucus in stool will be referred to their clinical physician for further testing to rule out parasitic infection. * Any other active infections judged at the discretion of the site-Investigator. * Any other medical or psychological condition that, in the opinion of the site-investigator, may present an unreasonable risk to the study patient as a result of his/her participation in this clinical trial, may make patient's participation unreliable, or may interfere with study assessments. The specific justification for patients excluded under this criterion will be noted in study documents. * Patient or his/her immediate family is a member of the investigational team. * Pregnancy or breastfeeding. * Women of children bearing potential who are not on highly-effective contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Dysphagia Score | Baseline, Month 3 Post-Treatment | Dysphagia will be assessed by the Eosinophilic Esophagitis Symptom Activity Index (EEsAI) which measures dysphagia frequency, dysphagia severity, and food avoidance/modification behaviors. EEsAI scores range from 0 to 100, with higher scores indicating more severe symptoms. A decrease of ≥ 20 points is felt to be a meaningful clinical response and scores ≤ 20 representing clinical remission. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With a Clinical Response (EEsAI Score Decrease of ≥ 20 Points) | After 3 months of treatment | The EEsAI measures dysphagia frequency, dysphagia severity, and food avoidance/modification behaviors. EEsAI scores range from 0 to 100, with higher scores indicating more severe symptoms. A decrease of ≥ 20 points is felt to be a meaningful clinical response and scores ≤ 20 representing clinical remission. |
| Absolute Peak Eosinophil Count | After 3 months of treatment | Absolute peak eosinophil (EOS) count (measured in EOS/hpf) after 3 months of treatment. |
| Percent of Participants With a Clinical Remission (EEsAI Score of ≤ 20 Points) | After 3 months of treatment | The EEsAI measures dysphagia frequency, dysphagia severity, and food avoidance/modification behaviors. EEsAI scores range from 0 to 100, with higher scores indicating more severe symptoms. A decrease of ≥ 20 points is felt to be a meaningful clinical response and scores ≤ 20 representing clinical remission. |
| Mean Change in Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) | Baseline, 3 months post-treatment | Mean change in severity of endoscopic findings as measured by the EoE (Eosinophilic Esophagitis) Endoscopic Reference Score (EREFS). The EREFS, measures features of EoE including esophageal edema, rings, exudate, furrows, and strictures. The instrument grades edema as absent (0) or present (1); furrows as absent (0), mild (1), or severe (2); rings as absent (0), mild (1, subtle circumferential ridges), moderate (2, distinct rings) and severe (3, rings that impair passage of a standard adult diagnostic endoscope); exudates as absent (0), mild (1, less than 10% of the esophageal surface area) or severe (2, greater or equal to 10% of the esophageal surface area); and strictures as absent (0) or present (1) with an estimation of the minimal luminal diameter. Higher scores indicate more severe disease (range 0 - 9). |
| Mean Change in the Straumann Dysphagia Instrument (SDI) Score | Baseline, 3 months post-treatment | The Straumann Dysphagia Instrument (SDI) is a direct measure of dysphagia frequency and severity which is completed by participants and reported over the previous week. The score ranges from 0-9, with higher scores indicating more severe dysphagia. |
| Number of Participants With Histologic Response as Assessed by Eosinophils Per High Powered Field | After 3 months of treatment | Number of participants with a histologic response as assessed by having \<15, ≤ 6, and ≤ 1 Eosinophils per high powered field (EOS/hpf). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mepolizumab 300 mg Subjects will receive Mepolizumab 300 mg subcutaneously (SQ) monthly for 6 months
Mepolizumab 300 mg: Mepolizumab 300 mg subcutaneous injection | 32 |
| Placebo, Followed by Mepolizumab 100 mg Subjects will receive placebo subcutaneously (SQ) monthly for 3 months, followed by Mepolizumab 100 mg subcutaneously (SQ) monthly for 3 months. Mepolizumab will be administered with 2 SQ injections of placebo and 1 SQ injection of Mepolizumab 100 mg to maintain blinding.
Mepolizumab 100 mg: Mepolizumab 100 mg subcutaneous injection
Placebo: Saline subcutaneous injection | 34 |
| Total | 66 |
Baseline characteristics
| Characteristic | Total | Mepolizumab 300 mg | Placebo, Followed by Mepolizumab 100 mg |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 66 Participants | 32 Participants | 34 Participants |
| Age, Continuous | 35.5 years STANDARD_DEVIATION 11.1 | 38.1 years STANDARD_DEVIATION 12 | 33.1 years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 31 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| 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 | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 63 Participants | 30 Participants | 33 Participants |
| Region of Enrollment United States | 66 Participants | 32 Participants | 34 Participants |
| Sex: Female, Male Female | 27 Participants | 11 Participants | 16 Participants |
| Sex: Female, Male Male | 39 Participants | 21 Participants | 18 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 / 32 | 0 / 34 | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 13 / 32 | 19 / 34 | 12 / 28 | 18 / 28 |
| serious Total, serious adverse events | 2 / 32 | 0 / 34 | 2 / 28 | 0 / 28 |
Outcome results
Primary
Mean Change in Dysphagia Score
Dysphagia will be assessed by the Eosinophilic Esophagitis Symptom Activity Index (EEsAI) which measures dysphagia frequency, dysphagia severity, and food avoidance/modification behaviors. EEsAI scores range from 0 to 100, with higher scores indicating more severe symptoms. A decrease of ≥ 20 points is felt to be a meaningful clinical response and scores ≤ 20 representing clinical remission.
Time frame: Baseline, Month 3 Post-Treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mepolizumab 300 mg | Mean Change in Dysphagia Score | 15.4 score on a scale | Standard Deviation 18.1 |
| Placebo, Followed by Mepolizumab 100 mg | Mean Change in Dysphagia Score | 8.3 score on a scale | Standard Deviation 18 |
p-value: 0.14ANCOVA
Secondary
Absolute Peak Eosinophil Count
Absolute peak eosinophil (EOS) count (measured in EOS/hpf) after 3 months of treatment.
Time frame: After 3 months of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mepolizumab 300 mg | Absolute Peak Eosinophil Count | 35.7 eosinophils per high power field | Standard Deviation 43 |
| Placebo, Followed by Mepolizumab 100 mg | Absolute Peak Eosinophil Count | 163 eosinophils per high power field | Standard Deviation 133.1 |
p-value: <0.001t-test, 2 sided
Secondary
Mean Change in Eosinophilic Esophagitis Endoscopic Reference Score (EREFS)
Mean change in severity of endoscopic findings as measured by the EoE (Eosinophilic Esophagitis) Endoscopic Reference Score (EREFS). The EREFS, measures features of EoE including esophageal edema, rings, exudate, furrows, and strictures. The instrument grades edema as absent (0) or present (1); furrows as absent (0), mild (1), or severe (2); rings as absent (0), mild (1, subtle circumferential ridges), moderate (2, distinct rings) and severe (3, rings that impair passage of a standard adult diagnostic endoscope); exudates as absent (0), mild (1, less than 10% of the esophageal surface area) or severe (2, greater or equal to 10% of the esophageal surface area); and strictures as absent (0) or present (1) with an estimation of the minimal luminal diameter. Higher scores indicate more severe disease (range 0 - 9).
Time frame: Baseline, 3 months post-treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mepolizumab 300 mg | Mean Change in Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) | 1 score on a scale | Standard Deviation 1.1 |
| Placebo, Followed by Mepolizumab 100 mg | Mean Change in Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) | 0.4 score on a scale | Standard Deviation 1.3 |
p-value: 0.03ANCOVA
Secondary
Mean Change in the Straumann Dysphagia Instrument (SDI) Score
The Straumann Dysphagia Instrument (SDI) is a direct measure of dysphagia frequency and severity which is completed by participants and reported over the previous week. The score ranges from 0-9, with higher scores indicating more severe dysphagia.
Time frame: Baseline, 3 months post-treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mepolizumab 300 mg | Mean Change in the Straumann Dysphagia Instrument (SDI) Score | 2.4 score on a scale | Standard Deviation 1.7 |
| Placebo, Followed by Mepolizumab 100 mg | Mean Change in the Straumann Dysphagia Instrument (SDI) Score | 2.7 score on a scale | Standard Deviation 2.2 |
p-value: 0.44ANCOVA
Secondary
Number of Participants With Histologic Response as Assessed by Eosinophils Per High Powered Field
Number of participants with a histologic response as assessed by having \<15, ≤ 6, and ≤ 1 Eosinophils per high powered field (EOS/hpf).
Time frame: After 3 months of treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mepolizumab 300 mg | Number of Participants With Histologic Response as Assessed by Eosinophils Per High Powered Field | <15 eos/hpf | 13 Participants |
| Mepolizumab 300 mg | Number of Participants With Histologic Response as Assessed by Eosinophils Per High Powered Field | ≤6 eos/hpf | 7 Participants |
| Mepolizumab 300 mg | Number of Participants With Histologic Response as Assessed by Eosinophils Per High Powered Field | ≤1 eos/hpf | 3 Participants |
| Placebo, Followed by Mepolizumab 100 mg | Number of Participants With Histologic Response as Assessed by Eosinophils Per High Powered Field | <15 eos/hpf | 1 Participants |
| Placebo, Followed by Mepolizumab 100 mg | Number of Participants With Histologic Response as Assessed by Eosinophils Per High Powered Field | ≤6 eos/hpf | 1 Participants |
| Placebo, Followed by Mepolizumab 100 mg | Number of Participants With Histologic Response as Assessed by Eosinophils Per High Powered Field | ≤1 eos/hpf | 1 Participants |
Comparison: \<15 eos/hpfp-value: <0.001Chi-squared
Comparison: ≤6 eos/hpfp-value: 0.02Chi-squared
Comparison: ≤1 eos/hpfp-value: 0.27Chi-squared
Secondary
Percent of Participants With a Clinical Remission (EEsAI Score of ≤ 20 Points)
The EEsAI measures dysphagia frequency, dysphagia severity, and food avoidance/modification behaviors. EEsAI scores range from 0 to 100, with higher scores indicating more severe symptoms. A decrease of ≥ 20 points is felt to be a meaningful clinical response and scores ≤ 20 representing clinical remission.
Time frame: After 3 months of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mepolizumab 300 mg | Percent of Participants With a Clinical Remission (EEsAI Score of ≤ 20 Points) | 6.45 percent of participants |
| Placebo, Followed by Mepolizumab 100 mg | Percent of Participants With a Clinical Remission (EEsAI Score of ≤ 20 Points) | 6.06 percent of participants |
p-value: 0.95Chi-squared
Secondary
Percent of Participants With a Clinical Response (EEsAI Score Decrease of ≥ 20 Points)
The EEsAI measures dysphagia frequency, dysphagia severity, and food avoidance/modification behaviors. EEsAI scores range from 0 to 100, with higher scores indicating more severe symptoms. A decrease of ≥ 20 points is felt to be a meaningful clinical response and scores ≤ 20 representing clinical remission.
Time frame: After 3 months of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mepolizumab 300 mg | Percent of Participants With a Clinical Response (EEsAI Score Decrease of ≥ 20 Points) | 35.48 percent of participants |
| Placebo, Followed by Mepolizumab 100 mg | Percent of Participants With a Clinical Response (EEsAI Score Decrease of ≥ 20 Points) | 21.21 percent of participants |
p-value: 0.2Chi-squared