Study to Investigate the Efficacy and Safety of Dupilumab in Pediatric Patients With Active Eosinophilic Esophagitis (EoE)

Study Overview
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Brief Summary
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The Primary objective is to demonstrate the efficacy of dupilumab treatment compared with placebo in pediatric patients with active eosinophilic esophagitis (EoE) based on histologic improvement meeting validated histologic criteria. The Secondary objectives are: To demonstrate the efficacy of dupilumab compared to placebo in pediatric patients with active EoE after 16 weeks of treatment as assessed by endoscopic visual measurements of disease activity using the Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-EREFS) and histologic abnormalities as measured by the EoE Histology Scoring System (EoE-HSS) To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up to 16 weeks in pediatric patients with active EoE To evaluate the effects of dupilumab on transcriptomic signatures associated with EoE and type 2 inflammation To study the effects of dupilumab on the type 2 inflammation gene expression signature To evaluate the concentration-time profile of functional dupilumab in serum in this population To assess efficacy of long-term (up to 160 weeks) dupilumab treatment To assess the impact of dupilumab treatment on changes in weight and growth during the extended active period and open-label extension period of the study To assess safety, tolerability, and immunogenicity of long-term (up to 160 weeks) dupilumab treatment To evaluate the impact of dupilumab treatment on EoE signs and symptoms

Detailed Description
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This is a 3-part study: Part A: Double-blind 16-week treatment period Part B: 36-week extended active treatment period Part C: Up to108 weeks open-label extension period

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of Dupilumab in Pediatric Patients With Active Eosinophilic Esophagitis

Conditions
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Eosinophilic Esophagitis (EoE)

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: A documented diagnosis of eosinophilic esophagitis (EoE) Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial eosinophilic infiltration Key Exclusion Criteria: Body weight <5 kg or ≥60 kg at screening Other causes of esophageal eosinophilia Active Helicobacter pylori History of Crohn's disease, ulcerative colitis, celiac disease, or prior esophageal surgery Any esophageal stricture unable to be passed with a standard, diagnostic, upper endoscope or any critical esophageal stricture that requires dilation at screening Treatment with swallowed topical corticosteroids within 8 weeks prior to baseline standard of care endoscopy History of bleeding disorders or esophageal varices that, in the opinion of the investigator, would put the patient at undue risk for significant complications from an endoscopy procedure Active parasitic infection or suspected parasitic infection Known or suspected immunodeficiency disorder Key Exclusion for Patients Re-Entering the Study (for Entry into Part C, as defined in protocol): Patients who are ≥12 years old, weigh ≥40 kg (or minimum weight for which dupilumab is approved for EoE), and dupilumab is commercially available for the treatment of EoE in their country Patients who, during their previous participation in this clinical trial, developed an SAE and/or AE deemed related to dupilumab, which in the opinion of the investigator or of the medical monitor could indicate that continued treatment with dupilumab may present an unreasonable risk for the patient Patients who did not undergo endoscopy with biopsies at week 16 and/or week 52 or prior to receiving rescue treatment Note: If the endoscopy with biopsies could not occur due to COVID-19 restrictions and rescue treatment was needed to be initiated without delay, these patients will be eligible to participate in Part C Patients who became pregnant during their previous participation in this dupilumab clinical trial Patients who, during their previous participation in this trial, were prematurely withdrawn because of a protocol violation, poor compliance, or inability to complete required study assessments NOTE: Other protocol defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 11 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - High Dose<br>Part A consists of a 16-week double-blind treatment period. Patients will be randomized to receive dupilumab or placebo subcutaneous (SC) administration at tiered dosing regimens based on body weight | Drug: Dupilumab<br>* Single-use, prefilled syringe<br>* Other names: •SAR231893;Drug: Matching Placebo<br>* Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance<br>|
| Experimental: Part A - Low Dose<br>Part A consists of a 16-week double-blind treatment period. Patients will be randomized to receive dupilumab or placebo subcutaneous (SC) administration at tiered dosing regimens based on body weight | Drug: Dupilumab<br>* Single-use, prefilled syringe<br>* Other names: •SAR231893;Drug: Matching Placebo<br>* Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance<br>|
| Experimental: Part B - High Dose<br>Part B consists of a 36-week extended active treatment period. All patients to receive subcutaneous (SC) administration at tiered dosing regimens based on body weight | Drug: Dupilumab<br>* Single-use, prefilled syringe<br>* Other names: •SAR231893;Drug: Matching Placebo<br>* Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance<br>|
| Experimental: Part B - Low Dose<br>Part B consists of a 36-week extended active treatment period. All patients to receive subcutaneous (SC) administration at tiered dosing regimens based on body weight | Drug: Dupilumab<br>* Single-use, prefilled syringe<br>* Other names: •SAR231893;Drug: Matching Placebo<br>* Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance<br>|
| Experimental: Part C - High Dose<br>Part C consists of up to 108-week open-label extension period. All patients will receive higher exposure dupilumab subcutaneous (SC) administration at tiered dosing regimens based on body weight. No matching placebo administered in Part C. | Drug: Dupilumab<br>* Single-use, prefilled syringe<br>* Other names: •SAR231893;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving peak esophageal intraepithelial eosinophil count ≤6 eos/hpf (400×) |  | At Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf | Part A | At Week 16 | 
| Proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf | Part B | At Week 52 | 
| Proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf | Part C | At Week 100 | 
| Proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf | Part C | At Week 160 | 
| Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) | Part A | Baseline to Week 16 | 
| Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) | Part B | Baseline to Week 52 | 
| Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) | Part C | Baseline to Week 100 | 
| Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) | Part C | Baseline to Week 160 | 
| Absolute change in mean eosinophilic esophagitis (EoE) Histology Scoring System (EoE-HSS) | Part A The EoEHSS assesses the severity (grade) and extent (stage) of abnormalities using a 4-point scale (0 normal; 3 maximum change). | Baseline to Week 16 | 
| Absolute change in mean EoE-HSS | Part B The EoEHSS as stated above. | Baseline to Week 52 | 
| Absolute change in mean EoE-HSS | Part C The EoEHSS as stated above. | Baseline to Week 100 | 
| Absolute change in mean EoE-HSS | Part C The EoEHSS as stated above. | Baseline to Week 160 | 
| Absolute change in Eosinophilic Esophagitis-Endoscopic Reference (EoE EREFS) | Part A EoE esophageal characteristics will be analyzed based on the EoE-EREFS, a scoring system for inflammatory and remodeling features of disease using both overall scores and scores for each individual characteristic. The proximal and distal esophageal regions will be scored separately; The score for each region ranges from 0 to 9 and the overall score ranges from 0 to 18. | Baseline to Week 16 | 
| Absolute change in EoE-EREFS | Part B EoE esophageal characteristics will be analyzed based on the EoE-EREFS, as stated above. | Baseline to Week 52 | 
| Absolute change in EoE-EREFS | Part C EoE esophageal characteristics will be analyzed based on the EoE-EREFS, as stated above. | Baseline to Week 100 | 
| Absolute change in EoE-EREFS | Part C EoE esophageal characteristics will be analyzed based on the EoE-EREFS, as stated above. | Baseline to Week 160 | 
| Change in the type 2 inflammation transcriptional signature | Part A | Baseline at Week 16 | 
| Change in the type 2 inflammation transcriptional signature | Part B | Baseline at Week 52 | 
| Change in the proportion of days with 1 or more EoE signs as measured by the Pediatric EoE Sign/Symptom Questionnaire- Caregiver version (PESQ-C) | Part A: For patients aged ≥1 to <12 years The PESQ-C is an observer-reported outcome measure intended to be completed independently by caregivers. The PESQ-C will measure occurrence of signs of EoE and will be completed once daily via an electronic diary. Data from a 14-day period preceding the baseline visit and a 14-day period preceding the week 16 visit will be used to calculate the proportion of days or total time segments within a day (night, morning, afternoon, evening) with 1 or more EoE signs. | Baseline to Week 16 | 
| Change in the proportion of days with 1 or more EoE signs as measured by the PESQ-C | Part B: For patients aged ≥1 to <12 years The PESQ-C as stated above. | Baseline to Week 52 | 
| Number of sign-free days during the 14-day period preceding week 16 as measured by the PESQ-C | Part A: For patients aged ≥1 to <12 years The PESQ-C as stated above. | Up to Week 16 | 
| Number of sign-free days during the 14-day period preceding week 52 as measured by the PESQ-C | Part B: For patients aged ≥1 to <12 years The PESQ-C as stated above. | Up to Week 52 | 
| Change in the proportion of total segments within a day with 1 or more EoE signs as measured by the PESQ-C | Part A: For patients aged ≥1 to <12 years The PESQ-C as stated above. | Baseline to Week 16 | 
| Change in the proportion of total segments within a day with 1 or more EoE signs as measured by the PESQ-C | Part B: For patients aged ≥1 to <12 years The PESQ-C as stated above. | Baseline to Week 52 | 
| Change in the proportion of days with 1 or more EoE symptoms as measured by the Pediatric EoE Sign/Symptom Questionnaire- Patient version (PESQ-P) | Part A: For patients aged ≥8 to <12 years The PESQ-P is a patient-reported outcome measure intended to be completed independently by EoE patients. The PESQ-P will measure occurrence and severity of EoE symptoms and will be completed once daily via an electronic diary. Data from a 14-day period preceding the baseline visit and a 14-day period preceding the week 16 visit will be used to calculate the proportion of days or total time segments within a day (night, morning, afternoon, evening) with 1 or more EoE symptoms. | Baseline to Week 16 | 
| Change in the proportion of days with 1 or more EoE symptoms as measured by the PESQ-P | Part B: For patients aged ≥8 to <12 years The PESQ-P as stated above. | Baseline to Week 52 | 
| Number of symptom-free days during the 14-day period preceding week 16 as measured by the PESQ-P | Part A: For patients aged ≥8 to <12 years The PESQ-P as stated above. | Up to Week 16 | 
| Number of symptom-free days during the 14-day period preceding week 52 as measured by the PESQ-P | Part B: For patients aged ≥8 to <12 years The PESQ-P as stated above. | Up to Week 52 | 
| Change in the proportion of total segments within a day with 1 or more EoE symptoms as measured by the PESQ-P | Part A: For patients aged ≥8 to <12 years The PESQ-P as stated above. | Baseline to Week 16 | 
| Change in the proportion of total segments within a day with 1 or more EoE symptoms as measured by the PESQ-P | Part B: For patients aged ≥8 to <12 years The PESQ-P as stated above. | Baseline to Week 52 | 
| Change in total score as measured by the PEESSv2.0-caregiver version questionnaire | Part A: For patients aged ≥1 to <12 years The PEESSv2.0-caregiver version assesses the frequency and severity of EoE symptoms among pediatric patients (Franciosi, 2011). The PEESSv2.0 consists of 20 items and has a one-month recall period. The total score ranges from 0 to 100; higher scores indicate greater symptom burden of among pediatric EoE patients | Baseline to Week 16 | 
| Change in total score as measured by the PEESSv2.0- caregiver version questionnaire | Part C The PEESSv2.0-caregiver version as stated above. | Baseline to Week 160 | 
| Normalized Enrichment Scores (NES) for the relative change in the EoE diagnostic panel (EDP) transcriptome signature | Part A NES reflects the degree to which the activity level of a set of transcripts is overrepresented at the extremes (top or bottom) of the entire ranked list of transcripts within a sample and is normalized by accounting for the number of transcripts in the set (Barbie, 2009)(Subramanian, 2005). NES scores will be calculated for each transcriptome signature for each sample for statistical analyses. | Baseline to Week 16 | 
| NES for the relative change in the EDP transcriptome signature | Part B NES as stated above. | Baseline to Week 52 | 
| NES for the relative change in the EDP transcriptome signature | Part C NES as stated above. | Baseline to Week 100 | 
| NES for the relative change in the EDP transcriptome signature | Part C NES as stated above. | Baseline to Week 160 | 
| NES for the relative change in the type 2 inflammation transcriptome signature | Part A NES as stated above. | Baseline to Week 16 | 
| NES for the relative change in the type 2 inflammation transcriptome signature | Part B NES as stated above. | Baseline to Week 52 | 
| NES for the relative change in the type 2 inflammation transcriptome signature | Part C NES as stated above. | Baseline to Week 100 | 
| Change in body weight for age percentile | Part B | Baseline at Week 52 | 
| Change in body weight for age percentile | Part C | Baseline up to Week 160 | 
| Change in body mass index for age z-score | Part B: For patients ≥2 years of age | Baseline to Week 52 | 
| Change in body mass index for age z-score | Part C: For patients ≥2 years of age | Baseline to up to Week 160 | 
| Change in weight for age z-score | Part B | Baseline to Week 52 | 
| Change in weight for age z-score | Part C | Baseline up to Week 160 | 
| Change in weight for height z-score | Part B | Baseline to Week 52 | 
| Change in weight for height z-score | Part C | Baseline up to Week 160 | 
| Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (400×) | Part C | At Week 100 | 
| Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (400×) | Part C | At Week 160 | 
| Proportion of patients (with food elimination diet regimens at baseline) that have a re-introduction of a previously eliminated food group | Part C | Baseline by Week 100 | 
| Proportion of patients (with food elimination diet regimens at baseline) that have a re-introduction of a previously eliminated food group | Part C | Baseline by Week 160 | 
| Incidence of treatment-emergent adverse events (TEAEs) | Part A | Up to Week 16 | 
| Incidence of TEAEs | Part B | Up to Week 52 | 
| Incidence of TEAEs | Part C | Up to Week 160 | 
| Incidence of treatment-emergent serious adverse events (SAEs) | Part A | Up to Week 16 | 
| Incidence of treatment-emergent SAEs | Part B | Up to Week 52 | 
| Incidence of treatment-emergent SAEs | Part C | Up to Week 160 | 
| Incidence of treatment-emergent adverse events of special interest (AESIs) | Part A | Up to Week 16 | 
| Incidence of treatment-emergent AESIs | Part B | Up to Week 52 | 
| Incidence of treatment-emergent AESIs | Part C | Up to Week 160 | 
| Incidence of TEAEs leading to permanent discontinuation of study treatment | Part A | Up to Week 16 | 
| Incidence of TEAEs leading to permanent discontinuation of study treatment | Part B | Up to Week 52 | 
| Incidence of TEAEs leading to permanent discontinuation of study treatment | Part C | Up to Week 160 | 
| Incidence of treatment-emergent Anti-drug antibody (ADA) responses and titer | Part A | Up to Week 16 | 
| Incidence of treatment-emergent ADA responses and titer | Part B | Up to Week 52 | 
| Incidence of treatment-emergent ADA responses and titer | Part C | Up to Week 160 | 
| Concentration of functional dupilumab in serum |  | Baseline to end of study, Up to Week 160 |