Efficacy and Safety of Tezepelumab in Patients With Eosinophilic Esophagitis

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled multicenter, phase 3 study to evaluate the efficacy and safety of tezepelumab administered subcutaneously (SC) using an accessorized pre-filled syringe (APFS) versus placebo in adult and adolescent patients with eosinophilic esophagitis (EoE).

Detailed Description
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The study consists of a screening period of 2 to 8 weeks and a 52-week randomized double-blind placebo-controlled treatment period. After completion of the treatment period, participants will be eligible to participate in an optional active treatment extension period (lasting for 24 weeks), followed by a 12-week off-treatment safety follow-up period. Participants who will not participate in the extension period will participate in a 12-week off-treatment safety follow-up period following completion of the 52-week treatment period. This study will randomize approximately 360 participants. The participants will be randomized at 1:1:1 ratio to the 3 treatment arms.

Official Title
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A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase 3 Efficacy and Safety Study of Tezepelumab in Patients With Eosinophilic Esophagitis (CROSSING).

Conditions
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Eosinophilic Esophagitis

Intervention / Treatment
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* Biological: Tezepelumab
* Biological: Tezepelumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 12 to 80 years of age inclusive, at the time of signing the informed consent/assent. Weight ≥ 40 kg at Visit 1 Established diagnosis of EoE with a previous EGD and esophageal biopsy confirming a diagnosis of EoE. Participants who have symptomatic EoE as defined by a history of on average at least 2 episodes of dysphagia (any severity of food going down slowly or being stuck in the throat) per week in the 4 weeks prior to Visit 1. Must remain on a stabilized diet for at least 8 weeks prior to Visit 1 and during the course of the study (stable diet is defined as no initiation of single or multiple elimination diets or reintroduction of previously eliminated food groups). May be on any background PPI and/or STC, during the course of the study, as long as background medications have been stable for at least 8 weeks prior to the screening/run-in period (Visit 1) and there is agreement not to change background medication or dosage unless medically indicated, during the screening/run-in and treatment period. Participants currently on leukotriene inhibitors and/or steroid treatments for asthma or allergies that are inhaled or administered intranasally, must report a stable dose for at least 4 weeks prior to the screening/run-in period (Visit 1). If a medication for EoE (for example PPI and/or STC) is discontinued prior to the screening/run-in, there should be a washout period of at least 8 weeks prior to Visit 1. Discontinuation of any marketed biologic (monoclonal or polyclonal antibody) should have a washout period of 4 months or 5 half-lives prior to Visit 1, whichever is longer. Participants should have previously documented standard of care treatment, which could include PPI and/or STC and/or diet. Exclusion Criteria: Other gastrointestinal disorders such as active Helicobacter pylori infection, history of achalasia, esophageal varices, Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, eosinophilic enteritis, colitis, diverticulitis, irritable bowel syndrome, or other clinically significant gastrointestinal conditions as per Investigator discretion. Esophageal stricture that prevents the easy passage of a standard endoscope or any critical esophageal stricture that requires dilation at screening. Use of a feeding tube, or having a pattern of not eating solid food >3 days of week. Solid food is defined as food that requires chewing before swallowing. Hypereosinophilic syndrome EGPA vasculitis Esophageal dilation performed within 8 weeks prior to screening.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized in a 1:1:1 ratio to receive either low dose of tezepelumab, high dose of tezepelumab, or placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tezepelumab Low Dose<br>Tezepelumab subcutaneous injections, in accessorised pre-filled syringes | Biological: Tezepelumab<br>* Tezepelumab subcutaneous injection<br>|
| Experimental: Tezepelumab High Dose<br>Tezepelumab subcutaneous injections, in accessorised pre-filled syringes | Biological: Tezepelumab<br>* Tezepelumab subcutaneous injection<br>|
| Placebo Comparator: Placebo<br>Placebo subcutaneous injections, in accessorised pre-filled syringes | Other: Placebo<br>* Placebo subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histologic response of peak esophageal eosinophil per HPF count of ≤ 6 across all available esophageal levels | Peak esophageal eosinophil count per HPF determined by histological analysis of 2-4 biopsies from each of the proximal, mid, and distal esophagus. | Week 24 | 
| Change from baseline in DSQ (Dysphagia Symptom Questionnaire) score | 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. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in EoE EREFS (Endoscopic reference score ) | The EoE EREFS is a scoring system for assessing the presence and severity of the major endoscopic signs of EoE, including esophageal edema, rings, exudates, furrows, and stricture. EoE endoscopic appearances will be analyzed by the EoE-EREFS, a scoring system for inflammatory and fibrostenotic features of the disease. Proximal and distal esophageal areas will be scored, with the score for each region ranging from 0 to 9, and the overall score ranging from 0 to 18. Higher scores indicate more extensive disease. | Week 24, Week 52 | 
| Change from baseline in EoE-HSS (Histologic scoring system) grade score | EoE HSS is a histology scoring system for esophageal biopsies that evaluates 8 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 are scored using a 4-point scale (0 normal; 3 maximum change). | Week 24 | 
| Change from baseline in EoE-HSS (Histologic scoring system) stage score | EoE HSS is a histology scoring system for esophageal biopsies that evaluates 8 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 are scored using a 4-point scale (0 normal; 3 maximum change). | Week 24 | 
| Histologic response of peak esophageal eosinophil per HPF count of ≤ 6 across all available esophageal levels | The peak esophageal eosinophil count is based on 2-4 esophageal biopsies from 2-3 locations. | Week 52 | 
| Change from baseline in DSQ (Dysphagia Symptom Questionnaire) score | 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. | Week 52 | 
| Response of achieving clinico-histological remission | Achieving pre-determined histologic and symptomatic remission thresholds. | Week 24, Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Esophagitis, Eosinophilic Esophagitis, Eosinophilic