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

• ClinicalTrials.gov Identifier: NCT04394351
• Recruitment Status: Active, not recruiting
• First Posted: May 19, 2020
• Last Update Posted: June 5, 2023
• Sponsor: Regeneron Pharmaceuticals
• Collaborator: Sanofi
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Eosinophilic Esophagitis (EoE)	Drug: Dupilumab; Drug: Matching Placebo	Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Detailed Description:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 102 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of Dupilumab in Pediatric Patients With Active Eosinophilic Esophagitis
• Actual Study Start Date: September 1, 2020
• Actual Primary Completion Date: June 2, 2022
• Estimated Study Completion Date: July 7, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A - High Dose; 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; Single-use, prefilled syringe; Other Names: •DUPIXENT; •REGN668; •SAR231893; Drug: Matching Placebo; Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance
Experimental: Part A - Low Dose; 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; Single-use, prefilled syringe; Other Names: •DUPIXENT; •REGN668; •SAR231893; Drug: Matching Placebo; Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance
Experimental: Part B - High Dose; 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; Single-use, prefilled syringe; Other Names: •DUPIXENT; •REGN668; •SAR231893; Drug: Matching Placebo; Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance
Experimental: Part B - Low Dose; 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; Single-use, prefilled syringe; Other Names: •DUPIXENT; •REGN668; •SAR231893; Drug: Matching Placebo; Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance
Experimental: Part C - High Dose; 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; Single-use, prefilled syringe; Other Names: •DUPIXENT; •REGN668; •SAR231893

Outcome Measures

Primary Outcome Measures :

1. Proportion of patients achieving peak esophageal intraepithelial eosinophil count ≤6 eos/hpf (400×) [ Time Frame: At Week 16 ]

Secondary Outcome Measures :

1. Proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf [ Time Frame: At Week 16 ]
   Part A
2. Proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf [ Time Frame: At Week 52 ]
   Part B
3. Proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf [ Time Frame: At Week 100 ]
   Part C
4. Proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf [ Time Frame: At Week 160 ]
   Part C
5. Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) [ Time Frame: Baseline to Week 16 ]
   Part A
6. Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) [ Time Frame: Baseline to Week 52 ]
   Part B
7. Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) [ Time Frame: Baseline to Week 100 ]
   Part C
8. Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) [ Time Frame: Baseline to Week 160 ]
   Part C
9. Absolute change in mean eosinophilic esophagitis (EoE) Histology Scoring System (EoE-HSS) [ Time Frame: Baseline to Week 16 ]

   Part A

   The EoEHSS assesses the severity (grade) and extent (stage) of abnormalities using a 4-point scale (0 normal; 3 maximum change).

10. Absolute change in mean EoE-HSS [ Time Frame: Baseline to Week 52 ]

    Part B

    The EoEHSS as stated above.

11. Absolute change in mean EoE-HSS [ Time Frame: Baseline to Week 100 ]

    Part C

    The EoEHSS as stated above.

12. Absolute change in mean EoE-HSS [ Time Frame: Baseline to Week 160 ]

    Part C

    The EoEHSS as stated above.

13. Absolute change in Eosinophilic Esophagitis-Endoscopic Reference (EoE EREFS) [ Time Frame: Baseline to Week 16 ]

    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.

14. Absolute change in EoE-EREFS [ Time Frame: Baseline to Week 52 ]

    Part B

    EoE esophageal characteristics will be analyzed based on the EoE-EREFS, as stated above.

15. Absolute change in EoE-EREFS [ Time Frame: Baseline to Week 100 ]

    Part C

    EoE esophageal characteristics will be analyzed based on the EoE-EREFS, as stated above.

16. Absolute change in EoE-EREFS [ Time Frame: Baseline to Week 160 ]

    Part C

    EoE esophageal characteristics will be analyzed based on the EoE-EREFS, as stated above.

17. Change in the type 2 inflammation transcriptional signature [ Time Frame: Baseline at Week 16 ]
    Part A
18. Change in the type 2 inflammation transcriptional signature [ Time Frame: Baseline at Week 52 ]
    Part B
19. 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) [ Time Frame: Baseline to Week 16 ]

    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.

20. Change in the proportion of days with 1 or more EoE signs as measured by the PESQ-C [ Time Frame: Baseline to Week 52 ]

    Part B: For patients aged ≥1 to <12 years

    The PESQ-C as stated above.

21. Number of sign-free days during the 14-day period preceding week 16 as measured by the PESQ-C [ Time Frame: Up to Week 16 ]

    Part A: For patients aged ≥1 to <12 years

    The PESQ-C as stated above.

22. Number of sign-free days during the 14-day period preceding week 52 as measured by the PESQ-C [ Time Frame: Up to Week 52 ]

    Part B: For patients aged ≥1 to <12 years

    The PESQ-C as stated above.

23. Change in the proportion of total segments within a day with 1 or more EoE signs as measured by the PESQ-C [ Time Frame: Baseline to Week 16 ]

    Part A: For patients aged ≥1 to <12 years

    The PESQ-C as stated above.

24. Change in the proportion of total segments within a day with 1 or more EoE signs as measured by the PESQ-C [ Time Frame: Baseline to Week 52 ]

    Part B: For patients aged ≥1 to <12 years

    The PESQ-C as stated above.

25. 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) [ Time Frame: Baseline to Week 16 ]

    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.

26. Change in the proportion of days with 1 or more EoE symptoms as measured by the PESQ-P [ Time Frame: Baseline to Week 52 ]

    Part B: For patients aged ≥8 to <12 years

    The PESQ-P as stated above.

27. Number of symptom-free days during the 14-day period preceding week 16 as measured by the PESQ-P [ Time Frame: Up to Week 16 ]

    Part A: For patients aged ≥8 to <12 years

    The PESQ-P as stated above.

28. Number of symptom-free days during the 14-day period preceding week 52 as measured by the PESQ-P [ Time Frame: Up to Week 52 ]

    Part B: For patients aged ≥8 to <12 years

    The PESQ-P as stated above.

29. Change in the proportion of total segments within a day with 1 or more EoE symptoms as measured by the PESQ-P [ Time Frame: Baseline to Week 16 ]

    Part A: For patients aged ≥8 to <12 years

    The PESQ-P as stated above.

30. Change in the proportion of total segments within a day with 1 or more EoE symptoms as measured by the PESQ-P [ Time Frame: Baseline to Week 52 ]

    Part B: For patients aged ≥8 to <12 years

    The PESQ-P as stated above.

31. Change in total score as measured by the PEESSv2.0-caregiver version questionnaire [ Time Frame: Baseline to Week 16 ]

    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

32. Change in total score as measured by the PEESSv2.0- caregiver version questionnaire [ Time Frame: Baseline to Week 160 ]

    Part C

    The PEESSv2.0-caregiver version as stated above.

33. Normalized Enrichment Scores (NES) for the relative change in the EoE diagnostic panel (EDP) transcriptome signature [ Time Frame: Baseline to Week 16 ]

    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.

34. NES for the relative change in the EDP transcriptome signature [ Time Frame: Baseline to Week 52 ]

    Part B

    NES as stated above.

35. NES for the relative change in the EDP transcriptome signature [ Time Frame: Baseline to Week 100 ]

    Part C

    NES as stated above.

36. NES for the relative change in the EDP transcriptome signature [ Time Frame: Baseline to Week 160 ]

    Part C

    NES as stated above.

37. NES for the relative change in the type 2 inflammation transcriptome signature [ Time Frame: Baseline to Week 16 ]

    Part A

    NES as stated above.

38. NES for the relative change in the type 2 inflammation transcriptome signature [ Time Frame: Baseline to Week 52 ]

    Part B

    NES as stated above.

39. NES for the relative change in the type 2 inflammation transcriptome signature [ Time Frame: Baseline to Week 100 ]

    Part C

    NES as stated above.

40. Change in body weight for age percentile [ Time Frame: Baseline at Week 52 ]
    Part B
41. Change in body weight for age percentile [ Time Frame: Baseline up to Week 160 ]
    Part C
42. Change in body mass index for age z-score [ Time Frame: Baseline to Week 52 ]
    Part B: For patients ≥2 years of age
43. Change in body mass index for age z-score [ Time Frame: Baseline to up to Week 160 ]
    Part C: For patients ≥2 years of age
44. Change in weight for age z-score [ Time Frame: Baseline to Week 52 ]
    Part B
45. Change in weight for age z-score [ Time Frame: Baseline up to Week 160 ]
    Part C
46. Change in weight for height z-score [ Time Frame: Baseline to Week 52 ]
    Part B
47. Change in weight for height z-score [ Time Frame: Baseline up to Week 160 ]
    Part C
48. Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (400×) [ Time Frame: At Week 100 ]
    Part C
49. Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (400×) [ Time Frame: At Week 160 ]
    Part C
50. Proportion of patients (with food elimination diet regimens at baseline) that have a re-introduction of a previously eliminated food group [ Time Frame: Baseline by Week 100 ]
    Part C
51. Proportion of patients (with food elimination diet regimens at baseline) that have a re-introduction of a previously eliminated food group [ Time Frame: Baseline by Week 160 ]
    Part C
52. Incidence of treatment-emergent adverse events (TEAEs) [ Time Frame: Up to Week 16 ]
    Part A
53. Incidence of TEAEs [ Time Frame: Up to Week 52 ]
    Part B
54. Incidence of TEAEs [ Time Frame: Up to Week 160 ]
    Part C
55. Incidence of treatment-emergent serious adverse events (SAEs) [ Time Frame: Up to Week 16 ]
    Part A
56. Incidence of treatment-emergent SAEs [ Time Frame: Up to Week 52 ]
    Part B
57. Incidence of treatment-emergent SAEs [ Time Frame: Up to Week 160 ]
    Part C
58. Incidence of treatment-emergent adverse events of special interest (AESIs) [ Time Frame: Up to Week 16 ]
    Part A
59. Incidence of treatment-emergent AESIs [ Time Frame: Up to Week 52 ]
    Part B
60. Incidence of treatment-emergent AESIs [ Time Frame: Up to Week 160 ]
    Part C
61. Incidence of TEAEs leading to permanent discontinuation of study treatment [ Time Frame: Up to Week 16 ]
    Part A
62. Incidence of TEAEs leading to permanent discontinuation of study treatment [ Time Frame: Up to Week 52 ]
    Part B
63. Incidence of TEAEs leading to permanent discontinuation of study treatment [ Time Frame: Up to Week 160 ]
    Part C
64. Incidence of treatment-emergent Anti-drug antibody (ADA) responses and titer [ Time Frame: Up to Week 16 ]
    Part A
65. Incidence of treatment-emergent ADA responses and titer [ Time Frame: Up to Week 52 ]
    Part B
66. Incidence of treatment-emergent ADA responses and titer [ Time Frame: Up to Week 160 ]
    Part C
67. Concentration of functional dupilumab in serum [ Time Frame: Baseline to end of study, Up to Week 160 ]

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 11 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

1. A documented diagnosis of eosinophilic esophagitis (EoE)
2. Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial eosinophilic infiltration

Key Exclusion Criteria:

1. Body weight <5 kg or ≥60 kg at screening
2. Other causes of esophageal eosinophilia
3. Active Helicobacter pylori
4. History of Crohn's disease, ulcerative colitis, celiac disease, or prior esophageal surgery
5. Any esophageal stricture unable to be passed with a standard, diagnostic, upper endoscope or any critical esophageal stricture that requires dilation at screening
6. Treatment with swallowed topical corticosteroids within 8 weeks prior to baseline standard of care endoscopy
7. 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
8. Active parasitic infection or suspected parasitic infection
9. Known or suspected immunodeficiency disorder

Key Exclusion for Patients Re-Entering the Study (for Entry into Part C, as defined in protocol):

1. 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
2. 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
3. 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
4. Patients who became pregnant during their previous participation in this dupilumab clinical trial
5. 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

Contacts and Locations

Locations

United States, Arizona

Regeneron Study Site

Phoenix, Arizona, United States, 85016

United States, Arkansas

Regeneron Study Site

Little Rock, Arkansas, United States, 72202

United States, California

Regeneron Study Site

Los Angeles, California, United States, 90027

Regeneron Study Site

San Francisco, California, United States, 94143

United States, Colorado

Regeneron Study Site

Aurora, Colorado, United States, 80045

United States, Florida

Regeneron Study Site

Saint Petersburg, Florida, United States, 33701

United States, Georgia

Regeneron Study Site

Atlanta, Georgia, United States, 30322

Regeneron Study Site

Atlanta, Georgia, United States, 30342

United States, Illinois

Regeneron Study Site

Chicago, Illinois, United States, 60611

United States, Indiana

Regeneron Study Site

Indianapolis, Indiana, United States, 46202

United States, Iowa

Regeneron Study Site

Iowa City, Iowa, United States, 52242

United States, Massachusetts

Regeneron Study Site

Boston, Massachusetts, United States, 02111

Regeneron Study Site

Boston, Massachusetts, United States, 02114

Regeneron Study Site

Boston, Massachusetts, United States, 02115

United States, Nebraska

Regeneron Study Site

Lincoln, Nebraska, United States, 68510

United States, New York

Regeneron Study Site

New York, New York, United States, 10029

Regeneron Study Site

New York, New York, United States, 10032

Regeneron Study Site

New York, New York, United States, 10065

United States, North Carolina

Regeneron Study Site

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Regeneron Study Site

Cincinnati, Ohio, United States, 45229

Regeneron Study Site

Cleveland, Ohio, United States, 44106

United States, Pennsylvania

Regeneron Study Site

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Regeneron Study Site

Dallas, Texas, United States, 75207

Regeneron Study Site

Fort Worth, Texas, United States, 76104

Regeneron Study Site

Houston, Texas, United States, 77030

United States, Wisconsin

Regeneron Study Site

Milwaukee, Wisconsin, United States, 53226

Canada, Ontario

Regeneron Study Site

London, Ontario, Canada, N6A 5W9

Sponsors and Collaborators

Regeneron Pharmaceuticals

Sanofi

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

More Information

• Responsible Party: Regeneron Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04394351
• Other Study ID Numbers: R668-EE-1877; 2019-003078-24 ( EudraCT Number )
• First Posted: May 19, 2020
• Last Update Posted: June 5, 2023
• Last Verified: June 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All Individual Patient Data that underlie publicly available results will be considered for sharing
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Individual anonymized participant data will be considered for sharing once the indication has been approved by a regulatory body, if there is legal authority to share the data and there is not a reasonable likelihood of participant re-identification.
• Access Criteria: Qualified researchers may request access to anonymized patient level data or aggregate study data when Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc) for the product and indication, has the legal authority to share the data, and has made the study results publicly available (eg, scientific publication, scientific conference, clinical trial registry).
• URL: https://vivli.org/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Esophagitis; Eosinophilic Esophagitis; Esophageal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Gastroenteritis; Eosinophilia; Leukocyte Disorders; Hematologic Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases