Brief Summary
The primary objectives of the study by study part are:
Part A:
To determine the treatment effect of dupilumab compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures and to inform/confirm the final sample size determination for Part B.
Part B:
To demonstrate the efficacy of dupilumab treatment compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures.
Part C:
To assess the safety and efficacy of dupilumab treatment in adult and adolescent patients with EoE after up to 52 weeks of treatment as assessed by histological and clinical measures.
The secondary objectives of the study are:
* To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up to 52 weeks in adult and adolescent patients with EoE
* To explore the relationship between dupilumab concentration and responses in adult and adolescent patients with EoE, using descriptive analyses
* To evaluate the effects of dupilumab on transcriptomic signatures associated with EoE and type 2 inflammation
* To demonstrate the efficacy of dupilumab treatment compared to placebo after 24 weeks and 52 weeks of treatment in adult and adolescent patients with EoE who have previously received swallowed topical corticosteroids
Part A:
To determine the treatment effect of dupilumab compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures and to inform/confirm the final sample size determination for Part B.
Part B:
To demonstrate the efficacy of dupilumab treatment compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures.
Part C:
To assess the safety and efficacy of dupilumab treatment in adult and adolescent patients with EoE after up to 52 weeks of treatment as assessed by histological and clinical measures.
The secondary objectives of the study are:
* To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up to 52 weeks in adult and adolescent patients with EoE
* To explore the relationship between dupilumab concentration and responses in adult and adolescent patients with EoE, using descriptive analyses
* To evaluate the effects of dupilumab on transcriptomic signatures associated with EoE and type 2 inflammation
* To demonstrate the efficacy of dupilumab treatment compared to placebo after 24 weeks and 52 weeks of treatment in adult and adolescent patients with EoE who have previously received swallowed topical corticosteroids
Brief Title
Study to Determine the Efficacy and Safety of Dupilumab in Adult and Adolescent Patients With Eosinophilic Esophagitis (EoE)
Categories
Completion Date
Completion Date Type
Actual
Conditions
Eosinophilic Esophagitis
Eligibility Criteria
Key Inclusion Criteria (Parts A \& B):
* A documented diagnosis of EoE by endoscopic biopsy
* Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial eosinophilic infiltration
* History (by patient report) of an average of at least 2 episodes of dysphagia (with intake of solids) per week in the 4 weeks prior to screening
Key Exclusion Criteria (Parts A \& B):
* Body weight ≤40 kg
* Prior participation in a dupilumab clinical trial, or past or current treatment with dupilumab
* Initiation or change of a food-elimination diet regimen or re-introduction of a previously eliminated food group in the 6 weeks prior to screening.
* Other causes of esophageal eosinophilia or the following conditions: hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
* Active Helicobacter pylori infection
* History of achalasia, Crohn's disease, ulcerative colitis, celiac disease, and prior esophageal surgery
* Any esophageal stricture unable to be passed with a standard, diagnostic, 9 to10 mm upper endoscope or any critical esophageal stricture that requires dilation at screening
* History of bleeding disorders or esophageal varices
* Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study
Key Exclusion Criteria (Part C):
* Participants who, during Part A or Part B, developed a serious adverse event (SAE) and/or adverse event (AE) deemed related to study drug, which in the opinion of the investigator could indicate that continued treatment with study drug may present an unreasonable risk for the participant
* Participants who became pregnant during Part A or Part B
* Participants who are prematurely discontinued from study drug due to an AE (patients who are prematurely discontinued from study drug due to lack of efficacy are eligible to enter Part C)
* Patients who did not undergo endoscopy with biopsies prior to receiving rescue treatment
Note: Other inclusion/ exclusion criteria apply
* A documented diagnosis of EoE by endoscopic biopsy
* Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial eosinophilic infiltration
* History (by patient report) of an average of at least 2 episodes of dysphagia (with intake of solids) per week in the 4 weeks prior to screening
Key Exclusion Criteria (Parts A \& B):
* Body weight ≤40 kg
* Prior participation in a dupilumab clinical trial, or past or current treatment with dupilumab
* Initiation or change of a food-elimination diet regimen or re-introduction of a previously eliminated food group in the 6 weeks prior to screening.
* Other causes of esophageal eosinophilia or the following conditions: hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
* Active Helicobacter pylori infection
* History of achalasia, Crohn's disease, ulcerative colitis, celiac disease, and prior esophageal surgery
* Any esophageal stricture unable to be passed with a standard, diagnostic, 9 to10 mm upper endoscope or any critical esophageal stricture that requires dilation at screening
* History of bleeding disorders or esophageal varices
* Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study
Key Exclusion Criteria (Part C):
* Participants who, during Part A or Part B, developed a serious adverse event (SAE) and/or adverse event (AE) deemed related to study drug, which in the opinion of the investigator could indicate that continued treatment with study drug may present an unreasonable risk for the participant
* Participants who became pregnant during Part A or Part B
* Participants who are prematurely discontinued from study drug due to an AE (patients who are prematurely discontinued from study drug due to lack of efficacy are eligible to enter Part C)
* Patients who did not undergo endoscopy with biopsies prior to receiving rescue treatment
Note: Other inclusion/ exclusion criteria apply
Inclusion Criteria
Inclusion Criteria (Parts A \& B):
* A documented diagnosis of EoE by endoscopic biopsy
* Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial eosinophilic infiltration
* History (by patient report) of an average of at least 2 episodes of dysphagia (with intake of solids) per week in the 4 weeks prior to screening
inclusion/
* A documented diagnosis of EoE by endoscopic biopsy
* Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial eosinophilic infiltration
* History (by patient report) of an average of at least 2 episodes of dysphagia (with intake of solids) per week in the 4 weeks prior to screening
inclusion/
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
12 Years
NCT Id
NCT03633617
Org Class
Industry
Org Full Name
Regeneron Pharmaceuticals
Org Study Id
R668-EE-1774
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 3, Randomized, 3-Part Study to Investigate the Efficacy and Safety of Dupilumab in Adult and Adolescent Patients With Eosinophilic Esophagitis (EoE)
Primary Outcomes
Outcome Description
Esophageal intraepithelial eosinophil count obtained by esophageal endoscopy with biopsies (all 3 esophageal regions: proximal, mid, and distal).
Outcome Measure
Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤6 Eosinophils Per High-power Field (Eos/Hpf) in All Three Regions at Week 24
Outcome Time Frame
At week 24
Outcome Description
The DSQ is used to measure the frequency and intensity of dysphagia. DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia.
Outcome Measure
Absolute Change From Baseline in Dysphagia Symptom Questionnaire (DSQ) Total Score at Week 24
Outcome Time Frame
Baseline and week 24
Secondary Ids
Secondary Id
2018-000844-25
Secondary Outcomes
Outcome Description
Esophageal intraepithelial eosinophil count obtained by esophageal endoscopy with biopsies (all 3 esophageal regions: proximal, mid, and distal). A greater esophageal intraepithelial eosinophil count from baseline indicates worsening disease.
Outcome Time Frame
Baseline and week 24
Outcome Measure
Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count (Eos/Hpf) in All Three Regions at Week 24
Outcome Description
The DSQ is used to measure the frequency and intensity of dysphagia. DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia.
Outcome Time Frame
Baseline and week 24
Outcome Measure
Percent Change From Baseline in DSQ Total Score at Week 24
Outcome Description
Severity (grade) and extent (stage) of esophageal abnormalities were scored by blinded, central pathologists using a 4-point scale (0 normal; 3 maximum change) for eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells and lamina propria fibrosis (absent/present). Higher score indicates greater severity and extent of histological abnormalities.
Outcome Time Frame
Baseline and week 24
Outcome Measure
Absolute Change From Baseline in Eosinophilic Esophagitis Histology Scoring System (EoEHSS) Mean Grade Score at Week 24
Outcome Description
Severity (grade) and extent (stage) of esophageal abnormalities were scored by blinded, central pathologists using a 4-point scale (0 normal; 3 maximum change) for eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells and lamina propria fibrosis (absent/present). Higher score indicates greater severity and extent of histological abnormalities.
Outcome Time Frame
Baseline and week 24
Outcome Measure
Absolute Change From Baseline in EoEHSS Mean Stage Score at Week 24
Outcome Description
EoE esophageal characteristics analyzed based on the EoE-EREFS, a scoring system for inflammatory and remodeling features of disease. The overall total score ranges from 0 to 18 with higher number indicating worse disease.
Outcome Time Frame
Baseline and week 24
Outcome Measure
Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 24
Outcome Description
Esophageal intraepithelial eosinophil count obtained by esophageal endoscopy with biopsies (all 3 esophageal regions: proximal, mid, and distal).
Outcome Time Frame
At week 24
Outcome Measure
Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eos/Hpf in All Three Regions at Week 24
Outcome Description
NES reflects the degree to which the activity level of a set of disease 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. An NES of 0 indicates no change from baseline, a negative score reflects a reduction in the disease score (more like normal) and a positive score reflects worsening (more active disease).
Outcome Time Frame
Baseline and week 24
Outcome Measure
Normalized Enrichment Score (NES) for the Relative Change From Baseline in the EoE Diagnostic Panel (EDP) at Week 24
Outcome Description
NES reflects the degree to which the activity level of a set of disease 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. An NES of 0 indicates no change from baseline, a negative score reflects a reduction in the disease score (more like normal) and a positive score reflects worsening (more active disease).
Outcome Time Frame
Baseline and week 24
Outcome Measure
NES for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 24
Outcome Description
Esophageal intraepithelial eosinophil count obtained by esophageal endoscopy with biopsies (all 3 esophageal regions: proximal, mid, and distal).
Outcome Time Frame
At week 24
Outcome Measure
Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤1 Eos/Hpf in All Three Regions at Week 24
Outcome Description
The EoE-IQ measures impact of EoE on emotional, social, work \& school, \& sleep aspects. Participants were asked to respond to 11 questions based on experience living with EoE during past 7 days. Response to each item is on a 5-point scale (1=Not at all \[impacted\] 2=A little, 3=Somewhat, 4=Quite a bit, 5=Extremely \[impacted\]). The average score is the sum of non-missing responses divided by the number of items with non-missing responses. The average score can range from 1 to 5; a higher score is indicative of a more negative impact.
Outcome Time Frame
Baseline and week 24
Outcome Measure
Absolute Change From Baseline in Health-related Quality of Life (QoL) Average Score as Measured by EoE Impact Questionnaire (EoE-IQ) at Week 24
Outcome Description
The EoE-SQ asks about symptoms that participants with EoE may have (chest pain, stomach pain, burning feeling in chest, food or liquid coming back up into throat, throwing up) during the past 7 days. Response to the severity of each symptom based on the worst experience in the past 7 days is on a scale of 0 to 10 (higher is worse). The EoE-SQ severity score is calculated as the sum of the severity scores from questions 1 to 3 (chest pain, stomach pain, burning feeling in chest), which could range from 0 to 30; a higher score is indicative of more severe symptoms.
Outcome Time Frame
Baseline and week 24
Outcome Measure
Absolute Change From Baseline in Severity of EoE Symptoms Other Than Dysphagia as Measured by EoE Symptom Questionnaire (EoE-SQ) at Week 24
Outcome Description
The EoE-SQ asks about symptoms that participants with EoE may have (chest pain, stomach pain, burning feeling in chest, food or liquid coming back up into throat, throwing up) during the past 7 days. Response to the frequency of each symptom is on a 5-point scale (1 = 'Never', 2 = 'One day', 3 = ' 2-6 days', 4 = 'Once a day', 5 = 'More than once a day'). The EoE-SQ frequency score is calculated as the sum of the frequency scores from the 5 items which could range from 5 to 25; a higher score is indicative of higher frequency of symptoms.
Outcome Time Frame
Baseline and week 24
Outcome Measure
Absolute Change From Baseline in Frequency of EoE Symptoms Other Than Dysphagia as Measured by EoE-SQ at Week 24
Outcome Time Frame
At week 24
Outcome Measure
Percentage of Participants Who Received Rescue Treatment During the Placebo-controlled, Double-blind Treatment Period at Week 24
Outcome Time Frame
At week 24
Outcome Measure
Absolute Change From Baseline in Esophageal Distensibility Plateau Measured by Functional Lumen Imaging, if Collected, at Week 24
Outcome Description
Esophageal intraepithelial eosinophil count obtained by esophageal endoscopy with biopsies (all 3 esophageal regions: proximal, mid, and distal).
Outcome Time Frame
At week 52
Outcome Measure
Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤6 Eosinophils Per High-power Field (Eos/Hpf) in All Three Regions at Week 52
Outcome Description
The DSQ is used to measure the frequency and intensity of dysphagia. DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia.
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
Absolute Change in Dysphagia Symptom Questionnaire (DSQ) Total Score at Week 52
Outcome Description
The DSQ is used to measure the frequency and intensity of dysphagia. DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia.
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
Percent Change in DSQ Total Score at Week 52
Outcome Description
EoE esophageal characteristics analyzed based on the EoE-EREFS, a scoring system for inflammatory and remodeling features of disease. The overall total score ranges from 0 to 18 with higher number indicating worse disease.
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
Absolute Change in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 52
Outcome Description
Esophageal intraepithelial eosinophil count obtained by esophageal endoscopy with biopsies (all 3 esophageal regions: proximal, mid, and distal). A greater esophageal intraepithelial eosinophil count from baseline indicates worsening disease.
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
Percent Change in Peak Esophageal Intraepithelial Eosinophil Count (Eos/Hpf) in All Three Regions at Week 52
Outcome Description
Severity (grade) and extent (stage) of esophageal abnormalities were scored by blinded, central pathologists using a 4-point scale (0 normal; 3 maximum change) for eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells and lamina propria fibrosis (absent/present). Higher score indicates greater severity and extent of histological abnormalities.
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
Absolute Change in EoE Histology Scoring System (EoEHSS) Mean Grade Score at Week 52
Outcome Description
Severity (grade) and extent (stage) of esophageal abnormalities were scored by blinded, central pathologists using a 4-point scale (0 normal; 3 maximum change) for eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells and lamina propria fibrosis (absent/present). Higher score indicates greater severity and extent of histological abnormalities.
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
Absolute Change in EoEHSS Mean Stage Score at Week 52
Outcome Description
Esophageal intraepithelial eosinophil count obtained by esophageal endoscopy with biopsies (all 3 esophageal regions: proximal, mid, and distal).
Outcome Time Frame
At week 52
Outcome Measure
Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eos/Hpf in All Three Regions at Week 52
Outcome Description
Esophageal intraepithelial eosinophil count obtained by esophageal endoscopy with biopsies (all 3 esophageal regions: proximal, mid, and distal).
Outcome Time Frame
At week 52
Outcome Measure
Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤1 Eos/Hpf in All Three Regions at Week 52
Outcome Description
The EoE-IQ measures impact of EoE on emotional, social, work \& school, \& sleep aspects. Participants were asked to respond to 11 questions based on experience living with EoE during past 7 days. Response to each item is on a 5-point scale (1=Not at all \[impacted\] 2=A little, 3=Somewhat, 4=Quite a bit, 5=Extremely \[impacted\]). The average score is the sum of non-missing responses divided by the number of items with non-missing responses. The average score can range from 1 to 5; a higher score is indicative of a more negative impact.
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
Absolute Change in Health-related QOL as Measured by EoE-IQ at Week 52
Outcome Description
The EoE-SQ asks about symptoms that participants with EoE may have (chest pain, stomach pain, burning feeling in chest, food or liquid coming back up into throat, throwing up) during the past 7 days. Response to the severity of each symptom based on the worst experience in the past 7 days is on a scale of 0 to 10 (higher is worse). The EoE-SQ severity score is calculated as the sum of the severity scores from questions 1 to 3 (chest pain, stomach pain, burning feeling in chest), which could range from 0 to 30; a higher score is indicative of more severe symptoms.
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
Absolute Change From Baseline in Severity of EoE Symptoms Other Than Dysphagia as Measured by EoE-SQ at Week 52
Outcome Description
The EoE-SQ asks about symptoms that participants with EoE may have (chest pain, stomach pain, burning feeling in chest, food or liquid coming back up into throat, throwing up) during the past 7 days. Response to the frequency of each symptom is on a 5-point scale (1 = 'Never', 2 = 'One day', 3 = ' 2-6 days', 4 = 'Once a day', 5 = 'More than once a day'). The EoE-SQ frequency score is calculated as the sum of the frequency scores from the 5 items which could range from 5 to 25; a higher score is indicative of higher frequency of symptoms.
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
Absolute Change From Baseline in Frequency of EoE Symptoms Other Than Dysphagia as Measured by EoE-SQ at Week 52
Outcome Time Frame
Baseline (of Part C) to week 28
Outcome Measure
Percentage of Participants Who Received Rescue Medication During the 28-week Extended Active Treatment Period
Outcome Description
NES reflects the degree to which the activity level of a set of disease 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. An NES of 0 indicates no change from baseline, a negative score reflects a reduction in the disease score (more like normal) and a positive score reflects worsening (more active disease).
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
NES for the Relative Change From Baseline in EoE Diagnostic Panel (EDP) at Week 52
Outcome Description
NES reflects the degree to which the activity level of a set of disease 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. An NES of 0 indicates no change from baseline, a negative score reflects a reduction in the disease score (more like normal) and a positive score reflects worsening (more active disease).
Outcome Time Frame
Baseline (of previous study part) and week 52
Outcome Measure
NES for the Relative Change in the Type 2 Inflammation Signature (T2INF) at Week 52
Outcome Time Frame
Baseline (of Part C) up to week 52
Outcome Measure
Concentration of Functional Dupilumab in Serum at Week 52
Outcome Description
Number of treatment-emergent ADA responses to dupilumab reported.
Outcome Time Frame
Baseline (of previous study part) up to week 52
Outcome Measure
Incidence of Treatment-emergent Anti-drug Antibody (ADA) Response
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
12
Investigators
Investigator Type
Principal Investigator
Investigator Name
Jenny Shliozberg
Investigator Email
jshliozb@montefiore.org
Investigator Phone
jshliozb