A Study of Benralizumab in Patients With Eosinophilic Esophagitis

Study Overview
=================
Brief Summary
-----------------
The aim of this Phase 3 study is to investigate the use of benralizumab as a treatment for patients with EoE. The effect of doses of benralizumab on EoE histologic signs and symptoms will be assessed over a 52-week treatment period (including a 24-week double-blind placebo-controlled treatment period and a 28-week open-label treatment period). It is proposed that benralizumab will deplete eosinophils from GI tissue(s), improve the symptoms of dysphagia, and improve endoscopy scores as well as other markers of disease activity. Upon completion of the initial 52-week treatment period, patients will be offered an additional Open Label Extension period of at least 1 year, with benralizumab treatment and ongoing study assessments.

Official Title
-----------------
A Multicenter, Randomized, Double-blind, Parallel-group, Placebo Controlled Study to Investigate the Use of Benralizumab for Eosinophilic Esophagitis

Conditions
-----------------
Eosinophilic Esophagitis

Intervention / Treatment
-----------------
* Biological: Benralizumab
* Biological: Matching placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients 12 to 65 years of age, inclusive, at the time of signing the informed consent or assent (if applicable) form. Documented previous diagnosis of EoE by endoscopy. Must be symptomatic at Visit 1 (screening) and Visit 2 (randomization): A patient reported an average of at least 2 days per week with an episode of dysphagia over the 4 weeks prior to Visit 1 AND An average of at least 2 days per week with an episode of dysphagia (Daily DSQ ≥2) between Visit 1 and Visit 2, and at least 2 days per week with an episode of dysphagia (Daily DSQ ≥2) in each of the 2 weeks immediately prior to randomization May be on background medications for EoE and related treatments during the study as long as the background medications have been stable for at least 4 weeks (8 weeks for PPI) prior to the screening and there is agreement not to change type of background medication or dosage during the run-in period and for the first 52 weeks of the study unless a change is medically indicated. Negative serum pregnancy test for female patients of childbearing potential at Visit1. Women of childbearing potential must agree to use a highly effective form of birth control (confirmed by the Investigator) from randomization throughout the study duration and within 12 weeks after last dose if IP. Exclusion Criteria: Other GI disorders such as active Helicobacter pylori infection, history of achalasia, esophageal varices, Crohn's disease, ulcerative colitis, inflammatory bowel disease, or celiac disease. Esophageal stricture that prevents the easy passage of a standard endoscope or any critical esophageal stricture that requires dilation during the run-in period. Esophageal dilation performed within 8 weeks prior to screening and prior esophageal surgery that would impact the assessments for EoE Use of a feeding tube, or having a pattern of not eating solid food daily during the run-in period. Hypereosinophilic syndrome, defined by multiple organ involvement and persistent blood eosinophil count >1500 eos/μL. EGPA vasculitis. Eosinophilic gastritis, gastroenteritis, enteritis, or colitis documented by biopsy. Current malignancy, or history of malignancy with some specific exceptions. History of anaphylaxis to any biologic therapy or vaccine. Current active liver disease: Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen [HBsAg] or hepatitis C antibody), or other stable chronic liver disease are acceptable if patient otherwise meets eligibility criteria. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3 times the upper limit of normal (ULN), confirmed by repeated testing during the run-in period. Helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent or assent (if applicable) is obtained that has not been treated with or has failed to respond to standard of care therapy. History of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test. Concomitant use of immunosuppressive medication. Initiation or change of a food-elimination diet regimen or reintroduction of a previously eliminated food group in the 6 weeks prior to start of the run-in period. Currently pregnant, breastfeeding, or lactating women.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab<br>Benralizumab active solution will be administered SC to patients by healthcare professionals in this clinical study using an accessorized prefilled syringe (APFS) | Biological: Benralizumab<br>* Solution for injection in a single accessorized prefilled syringe (APFS) will be administered subcutaneously (SC), 1 mL fill volume<br>|
| Placebo Comparator: Placebo<br>Placebo solution will be administered SC to patients by healthcare professionals in this clinical study using an accessorized prefilled syringe (APFS) | Biological: Matching placebo<br>* Matching placebo solution for injection in APFS, 1 mL fill volume. Placebo solution will be administered subcutaneously (SC), 1 mL fill volume<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With a Histologic Response, Defined as a Peak Esophageal Intraepithelial Eosinophil Count ≤ 6 Eos/Hpf. | Percentage of patients with a histologic response at Week 24 and Week 52. A histologic response is defined as a peak esophageal intraepithelial eosinophil count <= 6 eos/hpf across all available esophageal levels. Subjects with no biopsy data at Week 24 or with intercurrent events prior to Week 24 such as changes to background medications or additional new therapies for EoE are considered non-responders. The number analyzed represents the number of participants in the treatment group that could have made it to the timepoint by the data cut off. | Week 24, Week 52 | 
| Changes From Baseline in Dysphagia Symptom Questionnaire (DSQ) | The Dysphagia Symptom Questionnaire (DSQ) captures the presence and severity of dysphagia symptoms in the past day in a 4-item questionnaire. The DSQ score is calculated over 14-day periods and ranges from 0 to 84, with a lower score indicating less severe dysphagia. At least 8 days with evaluable daily score in 14-day period are required; otherwise the DSQ score for the period is set to missing. The number analyzed represents the number of participants with data at that visit (including patients with imputed values post intercurrent events). | Week 24, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Tissue Eosinophils | Percent change from baseline in tissue eosinophils (eos) at Week 24 and Week 52. The number analyzed represents the number of participants with data at that visit (including imputed values). | Week 24, Week 52 | 
| Change From Baseline in Eosinophilic Esophagitis-Histology Scoring System (EoE-HSS) Total Grade Score at Week 24 | EoE-HSS Grade and Stage Scores evaluate eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity (grade) and extent (stage) of abnormalities will be scored using a 4-point scale (0 normal; 3 maximum change). Total grade score (TGS): mean of the grade score ratios per region. Grade score ratio per region is the sum of all available feature grade scores divided by the maximum possible score. The maximum possible total grade score is 1. The number analyzed represents the number of participants with data at that visit (including imputed values). | Week 24 | 
| Change From Baseline in Eosinophilic Esophagitis-Histology Scoring System (EoE-HSS) Total Stage Score at Week 24 | EoE-HSS Grade and Stage Scores evaluate eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity (grade) and extent (stage) of abnormalities will be scored using a 4-point scale (0 normal; 3 maximum change). Total stage score (TSS): mean of the stage score ratios per region. Stage score ratio per region is the sum of all available feature stage scores divided by the maximum possible score. The maximum possible total stage score is 1. The number analyzed represents the number of participants with data at that visit (including imputed values). | Week 24 | 
| Changes From Baseline in Centrally-read Endoscopic Reference Score (EREFS) | EREFS is a scoring system for assessing the presence and severity of the major endoscopic signs of EoE.The score ranges from 0 (normal) to 9 (severe disease). EREFS total score (TS): The worst score for each individual component from the proximal and distal scores were summed to form the EREFS total score (TS). The number analyzed represents the number of participants with data at that visit (including patients with imputed values post intercurrent events). | Week 24, Week 52 | 
| Treatment Responder Rate at Week 24, Defined as a Composite of Histological Response (≤6eos/Hpf) and Clinically Meaningful Improvement From Baseline in Dysphagia Symptom Questionnaire (DSQ) (30% Improvement) at Week 24 | Percentage of participants with a treatment response at Week 24. A treatment response is defined as composite of histologic response and clinically meaningful improvement (30% reduction) from baseline in DSQ score. Participants with missing data at Week 24 or with intercurrent events prior to Week 24 are considered non-responders. | Week 24 | 
| Centrally-read Biopsies for Additional Histopathology Including Tissue Eosinophil Counts at Week 24 | Esophagogastroduodenoscopy biopsies were collected at week 24 and sent to the central lab for slide preparation and for central, blinded pathology review of tissue eosinophil counts and histopathology. Centralized slide assessments and scoring from an independent physician review was performed for all biopsies. | Week 24 | 
| Dysphagia-free Days as Captured by the Dysphagia Symptom Questionnaire (DSQ) | Dysphagia free days is a count ranging from 0-28. Higher counts indicate better outcomes. The number analyzed represents the number of participants with data at that visit. | Week 24, Week 52 | 
| Frequency of Dysphagia Episodes as Captured by the Eosinophilic Esophagitis Daily Dysphagia Diary (EoE-3D) | EoE-3D is a daily diary focused on the patient experience of EoE. Dysphagia episode frequency is summarized as the total number of dysphagia episodes occurring over each 28-day period following randomization, scaled up to 28 days based on missing days. Requires at least 8 days of evaluable data in each 14-day period within each 28-day period; otherwise the period is set to missing. The number analyzed represents the number of participants with data at that visit. | Week 24, Week 52 | 
| Changes From Baseline in Dysphagia Associated Pain, Discomfort, and Overall Severity as Captured by the Eosinophilic Esophagitis Daily Dysphagia Diary (EoE-3D) at Week 24 | In the Eosinophilic Esophagitis Daily Dysphagia Diary (EoE-3D), patients report on whether they experienced episodes of difficulty swallowing in the past 24 hours and if so, how many. Patients respond to 3 questions on the pain, discomfort, and overall severity of the event using a numeric rating scale (0 [no] to 10 [worst]). This is repeated for each episode reported. Each category score is calculated as the sum of daily average values in the 14-day period divided by the number of days with available episodes of difficulty swallowing episodes during the same 14-day period (each of the three final scores range from 0 to 10, with higher values indicating a worse outcome in that category). Requires at least 8 days of evaluable data during the period; otherwise, the mean scores are set to missing. Days with 0 episodes of difficulty swallowing count as evaluable. In case all 14 days with 0 episode of difficulty swallowing, the score is set to missing. | Week 24 | 
| Changes From Baseline in Dysphagia Associated Pain, Discomfort, and Overall Severity as Captured by the Eosinophilic Esophagitis Daily Dysphagia Diary (EoE-3D) at Week 52 | In the Eosinophilic Esophagitis Daily Dysphagia Diary (EoE-3D), patients report on whether they experienced episodes of difficulty swallowing in the past 24 hours and if so, how many. Patients respond to 3 questions on the pain, discomfort, and overall severity of the event using a numeric rating scale (0 [no] to 10 [worst]). This is repeated for each episode reported. Each category score is calculated as the sum of daily average values in the 14-day period divided by the number of days with available episodes of difficulty swallowing episodes during the same 14-day period (each of the three final scores range from 0 to 10, with higher values indicating a worse outcome in that category). Requires at least 8 days of evaluable data during the period; otherwise, the mean scores are set to missing. Days with 0 episodes of difficulty swallowing count as evaluable. In case all 14 days with 0 episode of difficulty swallowing, the score is set to missing. | Week 52 | 
| Changes From Baseline in Abdominal Pain and Nausea as Captured by the Daily Diary at Week 24 | In the Eosinophilic Esophagitis Daily Dysphagia Diary (EoE-3D), respondents are asked to report the severity of abdominal pain and the severity of nausea at their worst over the past 24 hours using an 11-point numeric rating scale (0 [no] to 10 [worst]). Abdominal pain severity and nausea severity will be summarized individually as 14-day mean scores. Each 14-day mean score will be calculated as the sum of daily numerical rating scale score responses divided by the number of days with evaluable data in the same 14-day period. Calculation of the 14-day means will require at least 8 out of 14 days of evaluable data; otherwise, the mean score will be set to missing. The number analyzed represents the number of participants with data at that visit (including participants with imputed values post intercurrent events). | Week 24 | 
| Changes From Baseline in Abdominal Pain and Nausea as Captured by the Daily Diary at Week 52 | In the Eosinophilic Esophagitis Daily Dysphagia Diary (EoE-3D), respondents are asked to report the severity of abdominal pain and the severity of nausea at their worst over the past 24 hours using an 11-point numeric rating scale (0 [no] to 10 [worst]). Abdominal pain severity and nausea severity will be summarized individually as 14-day mean scores. Each 14-day mean score will be calculated as the sum of daily numerical rating scale score responses divided by the number of days with evaluable data in the same 14-day period. Calculation of the 14-day means will require at least 8 out of 14 days of evaluable data; otherwise, the mean score will be set to missing. The number analyzed represents the number of participants with data at that visit (including participants with imputed values post intercurrent events). | Week 52 | 
| Changes From Baseline in the Pediatric Eosinophilic Esophagitis Symptom Severity Module (PEESS) | The Pediatric Eosinophilic Esophagitis Symptom Severity Module, Version 2, Children and Teens Report (PEESS) is an 18-item assessment of EoE symptom severity and frequency validated for use in patients age 8 to 18 years. The recall period is one month. The first 18 questions alternate between a question about a given symptom's frequency (never=0, almost never=1, sometimes=2, often=3, almost always=4) and a question about the symptom's severity (face rating scale with drawings representing: not bad at all=0, a little bad=1, kind of bad=2, bad=3, very bad=4). The remaining two questions ask about frequency of eating less food than others and frequency of needing more time to eat than others. The overall score ranges from 0 to 80, with higher scores representing more severe and frequent EoE symptoms. The number analyzed represents the number of participants with data at that visit. | Week 24, Week 52 | 
| Changes From Baseline in Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EOE-QoL-A) at Week 24 | The Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QoL-A) is a 30-item assessment developed specifically to measure health-related quality of life in patients with EoE. Responses are on a 5-point scale: Not at all = 4, Slightly = 3, Moderately = 2, Quite a Bit = 1, Extremely = 0. The assessment has 5 domains: eating/diet impact, social impact, emotional impact, disease anxiety and swallowing anxiety. Domain scores are calculated as follows: Eating/Diet Impact (range 0 to 40): sum of Q2, Q9, Q16, Q24, Q25, Q26, Q27, Q28, Q29, Q30 Social Impact (range 0 to 16): sum of Q14, Q17, Q19, Q22 Emotional Impact (range 0 to 32): sum of Q1, Q5, Q6, Q7, Q11, Q13, Q21, Q23 Disease Anxiety (range 0 to 20): sum of Q4, Q10, Q12, Q15, Q18, Swallowing Anxiety (range 0 to 12): sum of Q3, Q8, Q20 The total score (range 0 to 120) is calculated as the sum of all responses. Lower scores indicate a greater degree of impairment. Higher scores indicate a better quality of life. | Week 24 | 
| Changes From Baseline in Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EOE-QoL-A) at Week 52 | The Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QoL-A) is a 30-item assessment developed specifically to measure health-related quality of life in patients with EoE. Responses are on a 5-point scale: Not at all = 4, Slightly = 3, Moderately = 2, Quite a Bit = 1, Extremely = 0. The assessment has 5 domains: eating/diet impact, social impact, emotional impact, disease anxiety and swallowing anxiety. Domain scores are calculated as follows: Eating/Diet Impact (range 0 to 40): sum of Q2, Q9, Q16, Q24, Q25, Q26, Q27, Q28, Q29, Q30 Social Impact (range 0 to 16): sum of Q14, Q17, Q19, Q22 Emotional Impact (range 0 to 32): sum of Q1, Q5, Q6, Q7, Q11, Q13, Q21, Q23 Disease Anxiety (range 0 to 20): sum of Q4, Q10, Q12, Q15, Q18, Swallowing Anxiety (range 0 to 12): sum of Q3, Q8, Q20 The total score (range 0 to 120) is calculated as the sum of all responses. Lower scores indicate a greater degree of impairment. Higher scores indicate a better quality of life. | Week 52 | 
| Change From Baseline in Short Form 36-item Health Survey (Version 2, Acute Recall) (SF-36v2) at Week 24 | The Short Form 36-item Health Survey, version 2, acute recall (SF-36v2) is a 36-item, self-report survey of functional health and well-being, with a 1-week recall period. There are 8 domain scores: Physical Functioning (PF), Role Limitations due to Physical Health (RP), Bodily Pain (BP), General Health Perceptions (GH), Vitality (VT), Social Functioning (SF), Role Limitations due to Emotional Problems (RE), and Mental Health (MH). Psychometrically-based physical and mental health component summary scores (PCS and MCS, respectively) were computed from subscale scores to give a broader metric of physical and mental health-related quality of life. All scores range from 0-100, with higher scores meaning better outcomes. The number analyzed represents the number of participants with data at that visit (including participants with imputed values post intercurrent events). | Week 24 | 
| Change From Baseline in Short Form 36-item Health Survey (Version 2, Acute Recall) (SF-36v2) at Week 52 | The Short Form 36-item Health Survey, version 2, acute recall (SF-36v2) is a 36-item, self-report survey of functional health and well-being, with a 1-week recall period. There are 8 domain scores: Physical Functioning (PF), Role Limitations due to Physical Health (RP), Bodily Pain (BP), General Health Perceptions (GH), Vitality (VT), Social Functioning (SF), Role Limitations due to Emotional Problems (RE), and Mental Health (MH). Psychometrically-based physical and mental health component summary scores (PCS and MCS, respectively) were computed from subscale scores to give a broader metric of physical and mental health-related quality of life. All scores range from 0-100, with higher scores meaning better outcomes. The number analyzed represents the number of participants with data at that visit (including participants with imputed values post intercurrent events). | Week 52 | 
| Percent of Patients With Relevant Concomitant Procedures and Healthcare Resource Utilization at Week 24 and Week 52. | Percent of patients with any relevant concomitant procedures or healthcare resource utilization for Eosinophilic esophagitis (EoE) or an EoE-related episode (e.g., an intervention for food impaction or stricture requiring dilatation) since last healthcare resource utilization assessment during the previous scheduled visit. Assessed at Week 24 and Week 52. | Week 24, Week 52 | 
| Patient Reported Overall Severity of Disease as Measured by Patient Global Impression of Severity (PGI-S) at Week 24 | Patient Global Impression of Severity (PGI-S) is an assessment of the patient's perceived disease severity. The answer options are no symptoms, very mild, mild, moderate, severe, and very severe. The number analyzed represents the participants with evaluable PGI-S results at that timepoint. | Week 24 | 
| Patient Reported Overall Severity of Disease as Measured by Patient Global Impression of Severity (PGI-S) at Week 52 | Patient Global Impression of Severity (PGI-S) is an assessment of the patient's perceived disease severity. The answer options are no symptoms, very mild, mild, moderate, severe, and very severe. The number analyzed represents the participants with evaluable PGI-S results at that timepoint. | Week 52 | 
| Patient Reported Change in Health Status Since Baseline as Measured by Patient Global Impression of Change (PGI-C) at Week 24 | Patient Global Impression of Change (PGI-C) measures the patient's overall impression of response to treatment since the initial dose. The answer options are much better, moderately better, a little better, about the same/no change, a little worse, moderately worse, and much worse. The number analyzed represents the participants with evaluable PGI-C results at that timepoint. | Week 24 | 
| Patient Reported Change in Health Status Since Baseline as Measured by Patient Global Impression of Change (PGI-C) at Week 52 | Patient Global Impression of Change (PGI-C) measures the patient's overall impression of response to treatment since the initial dose. The answer options are much better, moderately better, a little better, about the same/no change, a little worse, moderately worse, and much worse. The number analyzed represents the participants with evaluable PGI-C results at that timepoint. | Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Eosinophilic Esophagitis, EoE, Benralizumab