Clinical trial NCT04394351: Study to Investigate the Efficacy and Safety of Dupilumab in Pediatric Patients With Active Eosinophilic Esophagitis (EoE)
Official title: A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of Dupilumab in Pediatric Patients With Active Eosinophilic Esophagitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Eosinophilic Esophagitis (EoE)
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Sanofi
First posted: 2020-05-19
Enrollment: 102
Sex: ALL
Minimum age (years): 1
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Eligibility 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

Primary outcomes:
measure: Part A: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of Less Than or Equal to (≤) 6 Eosinophils/High Power Field (Eos/Hpf) at Week 16
timeFrame: At Week 16
Secondary outcomes:
measure: Part A: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 16
timeFrame: At Week 16
measure: Part A: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Eosinophilic Esophagitis (EoE) Diagnostic Panel (EDP) at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Change From Baseline in the Proportion of Days With 1 or More EoE Signs as Measured by Pediatric EoE Sign/Symptom Questionnaire - Caregiver Version (PESQ-C) at Week 16 (for Participants Aged ≥1 to <12 Years)
timeFrame: Baseline, Week 16
measure: Part A: Number of Sign-free Days During the 14-day Period Preceding Week 16 as Measured by the PESQ-C (for Participants Aged ≥1 to <12 Years)
timeFrame: Week 16
measure: Part A: Change From Baseline in the Proportion of Total Segments Within a Day (Night, Morning, Afternoon, Evening) With 1 or More EoE Signs as Measured by the PESQ-C at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Change From Baseline in the Proportion of Days With 1 or More EoE Signs by Pediatric EoE Sign/Symptom Questionnaire - Participant Version (PESQ-P) (for Participants Aged ≥8 to <12 Years) at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Number of Symptom-free Days During the 14-day Period Preceding Week 16 as Measured by the PESQ-P (for Participants Aged ≥8 to <12 Years)
timeFrame: Week 16
measure: Part A: Change From Baseline in the Proportion of Total Segments Within a Day (Night, Morning, Afternoon, Evening) With 1 or More EoE Signs as Measured by the PESQ-P (for Participants Aged ≥8 to <12 Years) at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Change From Baseline in Total Score as Measured by the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) Version 2.0 Caregiver Version (PEESSv2.0-C) at Week 16
timeFrame: Baseline, Week 16
measure: Part A: Concentration of Functional Dupilumab in Serum at Baseline, Week 4 and 16
timeFrame: Baseline, Week 4 and 16
measure: Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤6 Eosinophils/High Power Field at Week 52
timeFrame: At Week 52
measure: Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 52
timeFrame: At Week 52
measure: Part B: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Change From Baseline in the Proportion of Days With 1 or More EoE Signs Measured by Pediatric EoE Sign/Symptom Questionnaire - Caregiver Version (PESQ-C) at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Number of Sign-free Days During the 14-day Period Preceding Week 52 as Measured by the PESQ-C (for Participants Aged ≥1 to <12 Years)
timeFrame: Week 52
measure: Part B: Change From Baseline in the Proportion of Total Segments Within a Day (Night, Morning, Afternoon, Evening) With 1 or More EoE Signs as Measured by the PESQ-C at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Change From Baseline in the Proportion of Days With 1 or More EoE Signs by Pediatric EoE Sign/Symptom Questionnaire - Participant Version (PESQ-P) (for Participants Aged ≥8 to <12 Years) at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Number of Symptom-free Days During the 14-day Period Preceding Week 52 as Measured by the PESQ-P (for Participants Aged ≥8 to <12 Years)
timeFrame: Week 52
measure: Part B: Change From Baseline in the Proportion of Total Segments Within a Day (Night, Morning, Afternoon, Evening) With 1 or More EoE Signs as Measured by the PESQ-P (for Participants Aged ≥8 to <12 Years) at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the EoE Diagnostic Panel (EDP) at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Change From Baseline in Body Weight for Age Percentile at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Change From Baseline in Body Mass Index (BMI) for Age Z-score for Participants ≥2 Years of Age at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Change From Baseline in Weight for Age Z-score at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Change From Baseline in Body Weight From Height Z-score at Week 52
timeFrame: Baseline, Week 52
measure: Part B: Concentration of Functional Dupilumab in Serum at Week 32 and 52
timeFrame: Week 32 and 52
measure: Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Adverse Events of Special Interest (AESIs) and TEAEs Leading to Permanent Discontinuation of Study Drug
timeFrame: From Baseline up to Week 16 in Part A
measure: Part B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Adverse Events of Special Interest (AESIs) and TEAEs Leading to Permanent Discontinuation of Study Drug
timeFrame: From Week 16 up to Week 52 in Part B
measure: Part A: Number of Participants With Positive Treatment-emergent Antidrug Antibodies (ADA) Response
timeFrame: From Baseline up to Week 16 in Part A
measure: Part A: Number of Participants With Positive Treatment-emergent Antidrug Antibodies (ADA) by Maximum Titer Category
timeFrame: From Baseline up to Week 16 in Part A
measure: Part B: Number of Participants With Positive Treatment-emergent Antidrug Antibodies (ADA) Response and Titer
timeFrame: From Week 16 up to Week 52 in Part B
measure: Part C: Proportion of Patients Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eos/Hpf
timeFrame: At Week 100
measure: Part C: Proportion of Patients Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eos/Hpf
timeFrame: At Week 160
measure: Part C: Percent Change in Peak Esophageal Intraepithelial Eosinophil Count (Eos/Hpf)
timeFrame: Baseline to Week 100
measure: Part C: Percent Change in Peak Esophageal Intraepithelial Eosinophil Count (Eos/Hpf)
timeFrame: Baseline to Week 160
measure: Part C: Absolute Change in Mean EoE-HSS
timeFrame: Baseline to Week 100
measure: Part C: Absolute Change in Mean EoE-HSS
timeFrame: Baseline to Week 160
measure: Part C: Absolute Change in EoE-EREFS
timeFrame: Baseline to Week 100
measure: Part C: Absolute Change in EoE-EREFS
timeFrame: Baseline to Week 160
measure: Part C: Change in Total Score as Measured by the PEESSv2.0- Caregiver Version Questionnaire
timeFrame: Baseline to Week 160
measure: Part C: NES for the Relative Change in the EDP Transcriptome Signature
timeFrame: Baseline to Week 100
measure: Part C: NES for the Relative Change in the EDP Transcriptome Signature
timeFrame: Baseline to Week 160
measure: Part C: NES for the Relative Change in the Type 2 Inflammation Transcriptome Signature
timeFrame: Baseline to Week 100
measure: Part C: Change in Body Weight for Age Percentile
timeFrame: Baseline up to Week 160
measure: Part C: Change in Body Mass Index for Age Z-score
timeFrame: Baseline to up to Week 160
measure: Part C: Change in Weight for Age Z-score
timeFrame: Baseline up to Week 160
measure: Part C: Change in Weight for Height Z-score
timeFrame: Baseline up to Week 160
measure: Part C: Proportion of Patients Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤6 Eos/Hpf (400×)
timeFrame: At Week 100
measure: Part C: Proportion of Patients Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤6 Eos/Hpf (400×)
timeFrame: At Week 160
measure: Part C: Proportion of Patients (With Food Elimination Diet Regimens at Baseline) That Have a Re-introduction of a Previously Eliminated Food Group
timeFrame: Baseline by Week 100
measure: Part C: Proportion of Patients (With Food Elimination Diet Regimens at Baseline) That Have a Re-introduction of a Previously Eliminated Food Group
timeFrame: Baseline by Week 160
measure: Part C: Incidence of TEAEs
timeFrame: Up to Week 160
measure: Part C: Incidence of Treatment-emergent SAEs
timeFrame: Up to Week 160
measure: Part C: Incidence of Treatment-emergent AESIs
timeFrame: Up to Week 160
measure: Part C: Incidence of TEAEs Leading to Permanent Discontinuation of Study Treatment
timeFrame: Up to Week 160
measure: Part C: Incidence of Treatment-emergent ADA Responses and Titer
timeFrame: Up to Week 160
measure: Part C: Concentration of Functional Dupilumab in Serum
timeFrame: Baseline to end of study, Up to Week 160
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Regeneron Study Site
state: Arizona
city: Little Rock
country: United States
facility: Regeneron Study Site
state: Arkansas
city: Los Angeles
country: United States
facility: Regeneron Study Site
state: California
city: San Francisco
country: United States
facility: Regeneron Study Site
state: California
city: Aurora
country: United States
facility: Regeneron Study Site
state: Colorado
city: Saint Petersburg
country: United States
facility: Regeneron Study Site
state: Florida
city: Atlanta
country: United States
facility: Regeneron Study Site
state: Georgia
city: Atlanta
country: United States
facility: Regeneron Study Site
state: Georgia
city: Chicago
country: United States
facility: Regeneron Study Site
state: Illinois
city: Indianapolis
country: United States
facility: Regeneron Study Site
state: Indiana
city: Iowa City
country: United States
facility: Regeneron Study Site
state: Iowa
city: Boston
country: United States
facility: Regeneron Study Site
state: Massachusetts
city: Boston
country: United States
facility: Regeneron Study Site
state: Massachusetts
city: Boston
country: United States
facility: Regeneron Study Site
state: Massachusetts
city: Lincoln
country: United States
facility: Regeneron Study Site
state: Nebraska
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: Chapel Hill
country: United States
facility: Regeneron Study Site
state: North Carolina
city: Cincinnati
country: United States
facility: Regeneron Study Site
state: Ohio
city: Cleveland
country: United States
facility: Regeneron Study Site
state: Ohio
city: Philadelphia
country: United States
facility: Regeneron Study Site
state: Pennsylvania
city: Dallas
country: United States
facility: Regeneron Study Site
state: Texas
city: Fort Worth
country: United States
facility: Regeneron Study Site
state: Texas
city: Houston
country: United States
facility: Regeneron Study Site
state: Texas
city: Milwaukee
country: United States
facility: Regeneron Study Site
state: Wisconsin
city: London
country: Canada
facility: Regeneron Study Site
state: Ontario
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References: