Study of Dupilumab in Adult Participants With Active Eosinophilic Esophagitis (EoE)

Study Overview
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Brief Summary
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The primary objective of the study is to assess the clinical efficacy of repeat subcutaneous (SC) doses of dupilumab, compared with placebo, to relieve symptoms in adult participants with active, moderate to severe Eosinophilic Esophagitis (EoE). The secondary objectives of the study are: To assess the safety, tolerability, and immunogenicity of SC doses of dupilumab in adult participants with active, moderate to severe EoE To assess the effect of dupilumab on esophageal eosinophilic infiltration To evaluate the pharmacokinetics (PK) of dupilumab in adult participants with EoE

Official Title
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A Randomized, Double-Blind, Parallel, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of Dupilumab in Adult Patients With Active Eosinophilic Esophagitis

Conditions
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Eosinophilic Esophagitis

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Documented diagnosis of EoE by endoscopy prior to or at screening History of on average at least 2 episodes of dysphagia (with intake of solids off anti-inflammatory therapy) per week in the 4 weeks prior to screening and on average at least 2 episodes of documented dysphagia per week in the weeks between screening and baseline; dysphagia is defined as trouble swallowing solid food, or having solid food stick, by participant report Must remain on a stabilized diet for at least 6 weeks prior to screening 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 Documented history of or presence of any of the following: allergic disease (e.g, allergic asthma, allergic rhinitis, atopic dermatitis (AD), or food allergies), peripheral eosinophil counts ≥0.25 GI/L, or serum total Immunoglobulin E (IgE) ≥100 kU/L Key Exclusion Criteria: Prior participation in a dupilumab (anti-IL-4R) clinical trial Other causes of esophageal eosinophilia or the following diseases: hypereosinophilic syndromes, Churg-Strauss vasculitis, and eosinophilic gastroenteritis History of achalasia, active Helicobacter pylori infection, Crohn's disease, ulcerative colitis, celiac disease, and prior esophageal surgery prior to screening Any esophageal stricture unable to be passed with a standard, diagnostic, adult (9 to10 mm) upper endoscope or any critical esophageal stricture that requires dilation at screening History of bleeding disorders or esophageal varices Use of chronic aspirin, nonsteroidal agents, or anti-coagulants within 2 weeks prior to screening. Participants should not stop these agents solely to become eligible for entry into this study Treatment with an investigational drug within 2 months or within 5 half-lives (if known), whichever is longer, prior to screening Use of systemic corticosteroids within 3 months or swallowed topical corticosteroids within 3 months prior to screening Use of inhaled (pulmonary or nasal) topical corticosteroids within 3 months prior to screening and during the study, except stable dose for at least 3 months prior to screening biopsy, which cannot be changed during the study Treatment with oral immunotherapy (OIT) within 6 months prior to screening Allergen immunotherapy unless on stable dose for at least 1 year prior to screening Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study Note: The list of inclusion/ exclusion criteria provided above is not intended to contain all considerations relevant to a participant's potential participation in this clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab 300 mg QW<br>Participants received SC dupilumab 300 mg during the 12-week double-blind treatment phase. Participants received 2 injections (300-mg initial dose, followed by a 300-mg loading dose) on day 1, followed by weekly injections. | Drug: Dupilumab<br> <br> * Other names: REGN668(SAR231893);|
| Experimental: Placebo<br>Participants received matching placebo once weekly (qw) during the 12-week double-blind treatment phase. Participants received 2 injections on day 1, followed by weekly injections. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Straumann Dysphagia Instrument (SDI) Patient Reported Outcome (PRO) Total Score at Week 10 | The SDI is a PRO used to determine frequency/ intensity of dysphagia (recall period 1-wk). Frequency of dysphagia events is graded on a 5-pt scale: 0=none, 1=1x/wk, 2=several/wk, 3=1x/day, 4=several/day; intensity is graded on a 6-pt scale: 0=swallowing unrestricted, 1=slight sensation of resistance, 2=slight retching with delay, 3=short period of obstruction necessitating intervention, 4=longer-lasting period of obstruction removable by vomiting, 5=long-lasting complete obstruction requiring endoscopic intervention. Total score ranges from 0-9 (higher score indicates worsening symptoms). | Baseline, Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Straumann Dysphagia Instrument (SDI) Patient Reported Outcome (PRO) Total Score at Week 10 | The SDI is a PRO used to determine frequency/ intensity of dysphagia (recall period 1-wk). Frequency of dysphagia events is graded on a 5-pt scale: 0=none, 1=1x/wk, 2=several/wk, 3=1x/day, 4=several/day; intensity is graded on a 6-pt scale: 0=swallowing unrestricted, 1=slight sensation of resistance, 2=slight retching with delay, 3=short period of obstruction necessitating intervention, 4=longer-lasting period of obstruction removable by vomiting, 5=long-lasting complete obstruction requiring endoscopic intervention. Total score ranges from 0-9 (higher score indicates worsening symptoms). | Baseline, Week 10 | 
| Absolute Change From Baseline in Straumann Dysphagia Instrument (SDI) Patient Reported Outcome (PRO) Total Score at Week 12 | The SDI is a PRO used to determine frequency/intensity of dysphagia (recall period 1-wk). Frequency of dysphagia events is graded on a 5-pt scale: 0=none, 1=1x/wk, 2=several/wk, 3=1x/day, 4=several/day; intensity is graded on a 6-pt scale: 0=swallowing unrestricted, 1=slight sensation of resistance, 2=slight retching with delay, 3=short period of obstruction necessitating intervention, 4=longer-lasting period of obstruction removable by vomiting, 5=long-lasting complete obstruction requiring endoscopic intervention. Total score ranges from 0-9 (higher score indicates worsening symptoms). | Baseline, Week 12 | 
| Percent Change From Baseline in Straumann Dysphagia Instrument (SDI) Patient Reported Outcome (PRO) Total Score at Week 12 | The SDI is a PRO used to determine frequency/ intensity of dysphagia (recall period 1-wk). Frequency of dysphagia events is graded on a 5-pt scale: 0=none, 1=1x/wk, 2=several/wk, 3=1x/day, 4=several/day; intensity is graded on a 6-pt scale: 0=swallowing unrestricted, 1=slight sensation of resistance, 2=slight retching with delay, 3=short period of obstruction necessitating intervention, 4=longer-lasting period of obstruction removable by vomiting, 5=long-lasting complete obstruction requiring endoscopic intervention. Total score ranges from 0-9 (higher score indicates worsening symptoms). | Baseline, Week 12 | 
| Percentage of Participants Achieving a Reduction of ≥ 3 Points in Straumann Dysphagia Instrument (SDI) Patient Reported Outcome (PRO) Total Score From Baseline at Week 10 | The SDI is a PRO used to determine frequency/ intensity of dysphagia (recall period 1-wk). Frequency of dysphagia events is graded on a 5-pt scale: 0=none, 1=1x/wk, 2=several/wk, 3=1x/day, 4=several/day; intensity is graded on a 6-pt scale: 0=swallowing unrestricted, 1=slight sensation of resistance, 2=slight retching with delay, 3=short period of obstruction necessitating intervention, 4=longer-lasting period of obstruction removable by vomiting, 5=long-lasting complete obstruction requiring endoscopic intervention. Total score ranges from 0-9 (higher score indicates worsening symptoms). | Baseline, Week 10 | 
| Percentage of Participants Achieving a Reduction of ≥ 3 Points in Straumann Dysphagia Instrument (SDI) Patient Reported Outcome (PRO) Total Score From Baseline at Week 12 | The SDI is a PRO used to determine frequency/ intensity of dysphagia (recall period 1-wk). Frequency of dysphagia events is graded on a 5-pt scale: 0=none, 1=1x/wk, 2=several/wk, 3=1x/day, 4=several/day; intensity is graded on a 6-pt scale: 0=swallowing unrestricted, 1=slight sensation of resistance, 2=slight retching with delay, 3=short period of obstruction necessitating intervention, 4=longer-lasting period of obstruction removable by vomiting, 5=long-lasting complete obstruction requiring endoscopic intervention. Total score ranges from 0-9 (higher score indicates worsening symptoms). | Baseline, Week 12 | 
| Percent Change From Baseline in Weekly Reported Eosinophilic Esophagitis Activity Index (EEsAI) Patient Reported Outcome (PRO) Score at Week 10 | The EEsAI PRO questionnaire includes items related to the intensity and frequency of dysphagia, the influence of specific food groups on dysphagia symptoms, and other symptoms independent of eating or drinking (ie, heartburn, acid regurgitation, and chest pain). The total EEsAI PRO score ranges from 0 to 100 (higher score indicates worsening symptoms). The EEsAI PRO utilizes 24-hour and 1-week recall periods. | Baseline, Week 10 | 
| Absolute Change From Baseline in Weekly Reported Eosinophilic Esophagitis Activity Index (EEsAI) Patient Reported Outcome (PRO) Score at Week 10 | The EEsAI PRO questionnaire includes items related to the intensity and frequency of dysphagia, the influence of specific food groups on dysphagia symptoms, and other symptoms independent of eating or drinking (ie, heartburn, acid regurgitation, and chest pain). The total EEsAI PRO score ranges from 0 to 100 (higher score indicates worsening symptoms). The EEsAI PRO utilizes 24-hour and 1-week recall periods. | Baseline, Week 10 | 
| Percent Change From Baseline in Weekly Reported Eosinophilic Esophagitis Activity Index (EEsAI) Patient Reported Outcome (PRO) Score at Week 12 | The EEsAI PRO questionnaire includes items related to the intensity and frequency of dysphagia, the influence of specific food groups on dysphagia symptoms, and other symptoms independent of eating or drinking (ie, heartburn, acid regurgitation, and chest pain). The total EEsAI PRO score ranges from 0 to 100 (higher score indicates worsening symptoms). The EEsAI PRO utilizes 24-hour and 1-week recall periods. | Baseline, Week 12 | 
| Absolute Change From Baseline in Weekly Reported Eosinophilic Esophagitis Activity Index (EEsAI) Patient Reported Outcome (PRO) Score at Week 12 | The EEsAI PRO questionnaire includes items related to the intensity and frequency of dysphagia, the influence of specific food groups on dysphagia symptoms, and other symptoms independent of eating or drinking (ie, heartburn, acid regurgitation, and chest pain). The total EEsAI PRO score ranges from 0 to 100 (higher score indicates worsening symptoms). The EEsAI PRO utilizes 24-hour and 1-week recall periods. | Baseline, Week 12 | 
| Percentage of Participants Achieving ≥ 40% Improvement in Weekly Reported Eosinophilic Esophagitis Activity Index (EEsAI) Patient Reported Outcome (PRO) Score From Baseline at Week 10 | The EEsAI PRO questionnaire includes items related to the intensity and frequency of dysphagia, the influence of specific food groups on dysphagia symptoms, and other symptoms independent of eating or drinking (ie, heartburn, acid regurgitation, and chest pain). The total EEsAI PRO score ranges from 0 to 100 (higher score indicates worsening symptoms). The EEsAI PRO utilizes 24-hour and 1-week recall periods. | Baseline, Week 10 | 
| Percentage of Participants Achieving ≥ 40% Improvement in Weekly Reported Eosinophilic Esophagitis Activity Index (EEsAI) Patient Reported Outcome (PRO) Score From Baseline at Week 12 | The EEsAI PRO questionnaire includes items related to the intensity and frequency of dysphagia, the influence of specific food groups on dysphagia symptoms, and other symptoms independent of eating or drinking (ie, heartburn, acid regurgitation, and chest pain). The total EEsAI PRO score ranges from 0 to 100 (higher score indicates worsening symptoms). The EEsAI PRO utilizes 24-hour and 1-week recall periods. | Baseline, Week 12 | 
| Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophils of 3 Esophageal Regions at Week 12 | Peak eosinophils/high power field (eos/hpf) was determined by counting eosinophils in the most inflamed areas of each esophageal region sampled at each time point and calculating the change in the peak count at each site. | Baseline, Week 12 | 
| Absolute Change From Baseline in Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-EREFS) by Feature at Week 12 | The EoE-EREFS includes a total of 6 major items related to the presence/ severity of esophageal features. Specific features scored by the investigator include rings (absent[0], mild[1], moderate[2], severe[3], not applicable); stricture (yes[1], no[0], not applicable); diameter of the stricture (if applicable; measurement not scored); exudates (absent[0], mild [1], severe[2]); furrows (absent[0], present[1]); edema (absent[0], present[1]). The total score of the 5 scored items ranges from 0 to 8 (higher score indicates worsening symptoms). | Baseline, Week 12 | 
| Change From Baseline in Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QOL-A) Score at Week 12 | The EoE-QOL-A questionnaire includes 30 items related to 5 established domains (eating/diet impact, social impact, emotional impact, disease anxiety, and swallowing anxiety) of daily life experiences. The EoE-QOL-A has a 1-week recall period. The items are graded on a 5-point scale: 1 (Not at All), 2 (Slightly), 3 (Moderately), 4 (Quite a bit), and 5 (Extremely). The EoE-QOL-A score is the average obtained by dividing the total score by the number of questions (for participants without disease, 120/30 = 4). Total scores range from 1 to 5 (higher scores indicate worsening symptoms). | Baseline, Week 12 | 
| Percentage of Participants With Use of Rescue Medication or Procedure (e.g., Esophageal Dilation) Through Week 12 |  | Baseline through Week 12 | 
| Percent of Participants With Treatment-Emergent Adverse Events (TEAEs) During the Study | Treatment-emergent adverse events (TEAEs) were defined as adverse events (AEs) that developed or worsened or became serious during the on-treatment period (time from the first dose of study drug up to the end of study (Week 28). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-participant hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs. | Baseline through Week 28 |