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

Summary
EudraCT number	2019-003078-24
Trial protocol	Outside EU/EEA
Global end of trial date	14 May 2024

Results information
Results version number	v1(current)
This version publication date	28 Nov 2024
First version publication date	28 Nov 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

R668-EE-1877

ISRCTN number

US NCT number

NCT04394351

WHO universal trial number (UTN)

Sponsor organisation name

Regeneron Pharmaceuticals, Inc.

Sponsor organisation address

777 Old Saw Mill River Road, Tarrytown, NY, United States, 10591

Public contact

Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.com

Scientific contact

Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001501-PIP02-13

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

14 May 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 May 2024

Was the trial ended prematurely?

Main objective of the trial

The Primary objective is to demonstrate the efficacy of dupilumab treatment compared with placebo in pediatric participants with active eosinophilic esophagitis (EoE) based on histologic improvement meeting validated histologic criteria.

Protection of trial subjects

It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Sep 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

United States: 101

Worldwide total number of subjects

102

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

This study consisted of 3 parts: Part A (double-blind 16-week treatment period), Part B (36-week extended active treatment period) and Part C (open-label extension period of up to 108 weeks).

Period 1 title

Part A (16 weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Carer, Data analyst, Assessor, Subject

Are arms mutually exclusive

Yes

Part A: Pooled Placebo

Arm description

Participants who received subcutaneous (SC) injection of placebo matched to higher exposure dupilumab or lower exposure dupilumab in Part A. Lower exposure dupilumab regimen were exposures approximating those in adolescents and adults receiving 300 mg dupilumab Q2W). Higher exposure dupilumab regimen were exposures approximating those in adolescents and adults receiving 300 mg dupilumab QW.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance

Part A: Dupilumab Low Dose

Arm description

Participants received subcutaneous (SC) injection of lower exposure dupilumab in Part A. Lower exposure dupilumab regimen were exposures approximating those in adolescents and adults receiving 300 mg dupilumab Q2W)

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

SAR231893

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

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

Part A: Dupilumab High Dose

Arm description

Participants received subcutaneous (SC) injection of higher exposure dupilumab in Part A. Higher exposure dupilumab regimen were exposures approximating those in adolescents and adults receiving 300 mg dupilumab QW

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

SAR231893

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

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

Number of subjects in period 1	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Started	34	31	37
Completed	33	29	37
Not completed	1	2	0
Physician decision	-	1	-
Consent withdrawn by subject	-	1	-
Adverse event, non-fatal	1	-	-

Period 2 title

Part B (36 weeks)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Data analyst, Assessor

Are arms mutually exclusive

Yes

Part B: Placebo to Dupilumab Low Dose

Arm description

Participants who received subcutaneous (SC) injection of placebo in Part A and received lower exposure dupilumab in Part B. Lower exposure dupilumab regimen were exposures approximating those in adolescents and adults receiving 300 mg dupilumab Q2W)

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

SAR231893

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

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

Part B: Placebo to Dupilumab High Dose

Arm description

Participants who received subcutaneous (SC) injection of placebo in Part A and received higher exposure dupilumab in Part B. Higher exposure dupilumab regimen were exposures approximating those in adolescents and adults receiving 300 mg dupilumab QW

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

SAR231893

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

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

Part B: Dupilumab Low Dose to Dupilumab Low Dose

Arm description

Participants received subcutaneous (SC) injection of lower exposure dupilumab in Parts A and B. Lower exposure dupilumab regimen were exposures approximating those in adolescents and adults receiving 300 mg dupilumab Q2W)

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

SAR231893

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

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

Part B: Dupilumab High Dose to Dupilumab High Dose

Arm description

Participants received subcutaneous (SC) injection of higher exposure dupilumab in Parts A and B. Higher exposure dupilumab regimen were exposures approximating those in adolescents and adults receiving 300 mg dupilumab QW.

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

SAR231893

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

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

Number of subjects in period 2 ^[1]	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Started	14	18	29	37
Completed	14	18	29	36
Not completed	0	0	0	1
Adverse event, non-fatal	-	-	-	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Part A participants transitioned to Part B

Period 3 title

Part C: Dupilumab (Up to Wk108+12Wk F/U)

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Part C: Dupilumab (Up to Wk 108+12 Wk Follow-Up)

Part C: Dupilumab

Arm description

Participants who completed Part A and B were eligible to enroll in Part C and receive Dupilumab extended active treatment

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

SAR231893

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

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.

Number of subjects in period 3 ^[2]	Part C: Dupilumab
Started	61
Completed	8
Not completed	53
Physician decision	3
Consent withdrawn by subject	16
Other	32
Protocol deviation	2

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Part B participants transitioned to Part C

Baseline characteristics

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Reporting group title

Part A: Pooled Placebo

Reporting group description

Reporting group title

Part A: Dupilumab Low Dose

Reporting group description

Reporting group title

Part A: Dupilumab High Dose

Reporting group description

Reporting group values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose	Total
Number of subjects	34	31	37	102
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age Continuous
Units: years
arithmetic mean (standard deviation)	7.2 ( 3.03 )	7.2 ( 3.07 )	6.8 ( 3.11 )	-
Sex: Female, Male
Units: participants
Female	9	6	9	24
Male	25	25	28	78
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	3	2	2	7
Not Hispanic or Latino	30	29	33	92
Unknown or Not Reported	1	0	2	3
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	0	1	1	2
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	3	4	4	11
White	30	22	32	84
More than one race	0	0	0	0
Unknown or Not Reported	0	0	0	0
Other	1	4	0	5

End points

Top of page

Reporting group title

Part A: Pooled Placebo

Reporting group description

Reporting group title

Part A: Dupilumab Low Dose

Reporting group description

Reporting group title

Part A: Dupilumab High Dose

Reporting group description

Reporting group title

Part B: Placebo to Dupilumab Low Dose

Reporting group description

Reporting group title

Part B: Placebo to Dupilumab High Dose

Reporting group description

Reporting group title

Part B: Dupilumab Low Dose to Dupilumab Low Dose

Reporting group description

Reporting group title

Part B: Dupilumab High Dose to Dupilumab High Dose

Reporting group description

Reporting group title

Part C: Dupilumab

Reporting group description

Participants who completed Part A and B were eligible to enroll in Part C and receive Dupilumab extended active treatment

Subject analysis set title

Part A: Pooled Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Part A: Dupilumab Low Dose

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Part A: Dupilumab High Dose

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Part B: Placebo to Dupilumab Low Dose

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Part B: Placebo to Dupilumab High Dose

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Part B: Dupilumab Low Dose to Dupilumab Low Dose

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Part B: Dupilumab High Dose to Dupilumab High Dose

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Part C: Dupilumab

Subject analysis set type

Per protocol

Subject analysis set description

Participants who completed Part A or B were eligible to enroll in Part C and receive Dupilumab extended active treatment

Subject analysis set title

Part C: Dupilumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received Dupilumab; Anti-Drug Antibody Analysis Set (AAS): The Part C AAS included all participants who received any amount of study drug in Part C and had at least 1 non-missing ADA result following the first dose of study drug. Analysis was based on treatment received.

Primary: 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

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End point title

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

End point description

Peak esophageal intraepithelial eosinophil count was measured from esophageal biopsies. A total of at least 9 mucosal pinch biopsies were collected from 3 esophageal regions: 3 proximal, 3 mid, and 3 distal. The peak esophageal intraepithelial eosinophil count at each visit was the maximum of the quantities of eosinophils in the most inflamed hpfs across the 3 regions. If the quantity of eosinophils was missing for 1 or 2 esophageal regions, the peak eosinophil count was the maximum of the quantities of eosinophils from the region(s) where eosinophil quantities were available. Analysis was performed on Part A FAS which included all randomized participants in Part A.

End point type

Primary

End point timeframe

At Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: percentage of participants
number (confidence interval 95%)	2.9 (0.07 to 15.33)	58.1 (39.08 to 75.45)	67.6 (50.21 to 81.99)

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

46.7

Confidence interval

level

95%

sides

2-sided

lower limit

5.47

upper limit

399.54

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

53.8

Confidence interval

level

95%

sides

2-sided

lower limit

7.37

upper limit

392.82

Secondary: Part A: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 16

Top of page

End point title

Part A: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 16

End point description

End point type

Secondary

End point timeframe

At Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: percentage of participants
number (confidence interval 95%)	2.9 (0.07 to 15.33)	67.7 (48.63 to 83.32)	83.8 (67.99 to 93.81)

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[1]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

55.3

Confidence interval

level

95%

sides

2-sided

lower limit

7.45

upper limit

410.23

Notes
[1] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

178

Confidence interval

level

95%

sides

2-sided

lower limit

18.84

upper limit

1682.4

Secondary: Part A: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 16

Top of page

End point title

Part A: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 16

End point description

Peak esophageal intraepithelial eosinophil count was measured from esophageal biopsies. A total of at least 9 mucosal pinch biopsies were collected from 3 esophageal regions: 3 proximal, 3 mid, and 3 distal. The peak esophageal intraepithelial eosinophil count at each visit was the maximum of the quantities of eosinophils in the most inflamed hpfs across the 3 regions. If the quantity of eosinophils was missing for 1 or 2 esophageal regions, the peak eosinophil count was the maximum of the quantities of eosinophils from the region(s) where eosinophil quantities were available. Least squared (LS) mean and standard error (SE) from analysis of covariance (ANCOVA) model with Baseline measurement as covariate and the treatment, baseline weight group strata as fixed factors.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: percent change
least squares mean (standard error)	20.98 ( 12.23 )	-77.93 ( 12.89 )	-86.09 ( 11.84 )

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[2]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-98.92

Confidence interval

level

95%

sides

2-sided

lower limit

-132.463

upper limit

-65.37

Notes
[2] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-107.07

Confidence interval

level

95%

sides

2-sided

lower limit

-139.249

upper limit

-74.9

Secondary: Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 16

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End point title

Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 16

End point description

EoE-HSS is a validated histologic scoring system that measures other histological abnormalities in addition to density of eosinophilic infiltration. Severity (grade) and extent (stage) of abnormalities will be scored using a 4-point scale (0 normal; 3 maximum change). Higher total score indicated greater severity & extent of histological abnormalities. For each of 3 esophageal regions (proximal, mid, and distal), the ratio of the sum of assigned score for each evaluated feature divided by maximum possible score (maximum value is 24) was calculated. The mean grade scores summed over the 3 regions was the final score used in primary analysis, the mean grade score ranged from 0 to 3, with higher score indicating more severe.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: Score on a scale
least squares mean (standard error)	0.023 ( 0.0498 )	-0.757 ( 0.0524 )	-0.879 ( 0.0481 )

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.902

Confidence interval

level

95%

sides

2-sided

lower limit

-1.0325

upper limit

-0.7714

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[3]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.78

Confidence interval

level

95%

sides

2-sided

lower limit

-0.917

upper limit

-0.644

Notes
[3] - P-value is not adjusted for multiple comparisons

Secondary: Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 16

Top of page

End point title

Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 16

End point description

EoE-HSS is a validated histologic scoring system that measures other histological abnormalities in addition to density of eosinophilic infiltration. Severity (grade) and extent (stage) of abnormalities will be scored using a 4-point scale (0 normal; 3 maximum change). Higher total score indicated greater severity & extent of histological abnormalities. For each of 3 esophageal regions (proximal, mid, and distal), the ratio of the sum of assigned score for each evaluated feature divided by maximum possible score (maximum value is 24) was calculated. The mean stage scores summed over the 3 regions was the final score used in primary analysis, the mean stage score ranged from 0 to 3, with higher score indicating more severe.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: Score on a scale
least squares mean (standard error)	0.048 ( 0.0482 )	-0.721 ( 0.0507 )	-0.835 ( 0.0466 )

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[4]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.769

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9013

upper limit

-0.6362

Notes
[4] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.883

Confidence interval

level

95%

sides

2-sided

lower limit

-1.0095

upper limit

-0.7568

Secondary: Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 16

Top of page

End point title

Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 16

End point description

A Normalized Enrichment Score (NES) is a way to generate a single numerical value to represent a complex gene expression signature. Changes in NES score represented the overall changes in the expression of that molecular phenotype. The NESs calculated for T2INF reflect the expression at Week 16 relative to Baseline of the pre-specified gene set as a way to evaluate normalization of type 2 inflammation with treatment. For each subject, an NES of 0 indicates no change from baseline, a negative score shows a reduction in disease score (more like normal) and positive score shows worsening (more active disease). NES does not have a minimum/maximum score. Analysis was performed on Part A FAS which included all randomized participants in Part A. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	21	15	24
Units: Score on a scale
median (full range (min-max))	0.340 (-1.84 to 1.65)	-1.930 (-2.00 to -1.39)	-1.895 (-2.03 to -1.61)

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[5]

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimator

Point estimate

-2.19

Confidence interval

level

95%

sides

2-sided

lower limit

-2.45

upper limit

-1.82

Notes
[5] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimator

Point estimate

-2.22

Confidence interval

level

95%

sides

2-sided

lower limit

-2.44

upper limit

-1.95

Secondary: Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Eosinophilic Esophagitis (EoE) Diagnostic Panel (EDP) at Week 16

Top of page

End point title

Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Eosinophilic Esophagitis (EoE) Diagnostic Panel (EDP) at Week 16

End point description

A Normalized Enrichment Score (NES) is a way to generate a single numerical value to represent a complex gene expression signature. Changes in NES score represented the overall changes in the expression of that molecular phenotype. The NESs calculated for the EDP reflect the expression at Week 16 relative to Baseline of a gene set that is differentially expressed between esophageal biopsies from EoE participants compared to healthy controls as a way to evaluate normalization of the molecular pathology. For each subject, an NES of 0 indicates no change from baseline, a negative score shows a reduction in disease score (more like normal) and positive score shows worsening (more active disease). NES does not have minimum/maximum score. Analysis was performed on Part A FAS which included all randomized participants in Part A. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	21	15	24
Units: Score on a scale
median (full range (min-max))	0.180 (-2.53 to 2.39)	-2.710 (-2.84 to -0.80)	-2.630 (-2.85 to -2.25)

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[6]

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimator

Point estimate

-2.7

Confidence interval

level

95%

sides

2-sided

lower limit

-3.31

upper limit

-1.62

Notes
[6] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimator

Point estimate

-2.84

Confidence interval

level

95%

sides

2-sided

lower limit

-3.35

upper limit

-1.96

Secondary: Part A: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 16

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End point title

Part A: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 16

End point description

The EoE-EREFS is a validated endoscopic scoring system for inflammatory and remodeling features of EoE including edema, rings, exudates, furrows, and stricture. The score was assessed in the proximal and distal esophageal regions with each region scored from 0 to 9 with total scores ranging from 0 to 18. Higher scores indicate worse endoscopic inflammatory and remodeling findings.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: score on a scale
least squares mean (standard error)	0.3 ( 0.45 )	-3.0 ( 0.48 )	-3.5 ( 0.42 )

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[7]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.59

upper limit

-2.1

Notes
[7] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-3.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.94

upper limit

-2.63

Secondary: 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)

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End point title

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)

End point description

PESQ-C is a novel, observer-reported outcome measure intended to be completed independently by caregivers of all pediatric EoE participants in the study. PESQ-C measures the signs of EoE observed by the caregiver, including stomach pain, heartburn, acid reflux, regurgitation, vomiting, food refusal, and trouble swallowing food. Data from a 14-day period preceding the baseline visit and a 14-day period preceding week 16 will be used to calculate the proportion of days with 1 or more EoE symptoms.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: proportion of days
least squares mean (standard error)	-0.17 ( 0.054 )	-0.18 ( 0.060 )	-0.28 ( 0.052 )

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9533 ^[8]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.155

upper limit

0.146

Notes
[8] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1526

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.244

upper limit

0.038

Secondary: 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)

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End point title

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)

End point description

PESQ-C is a novel, observer-reported outcome measure intended to be completed independently by caregivers of all pediatric EoE participants in the study. The PESQ-C measures the signs of EoE observed by the caregiver, including stomach pain, heartburn, acid reflux, regurgitation, vomiting, food refusal, and trouble swallowing food. WOCF approach was used for imputing the missing data due to rescue treatment/AE/lack of efficacy, and the multiple imputations approach was used for the missing data due to other reasons. LS mean SE derived from ANCOVA model.

End point type

Secondary

End point timeframe

Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: sign-free days
least squares mean (standard error)	8.93 ( 0.756 )	8.93 ( 0.840 )	10.38 ( 0.735 )

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9965 ^[9]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2.107

upper limit

2.117

Notes
[9] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1507 ^[10]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

1.45

Confidence interval

level

95%

sides

2-sided

lower limit

-0.527

upper limit

3.422

Notes
[10] - P-value is not adjusted for multiple comparisons

Secondary: 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

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End point title

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

End point description

PESQ-C is a novel, observer-reported outcome measure intended to be completed independently by caregivers of all pediatric EoE participants in the study. The PESQ-C measured the occurrence of signs of EoE and was completed once daily via an electronic diary. Data from a 14-day period preceding the baseline visit and a 14-day period preceding week 16 will be used to calculate the total time segments within a day (night, morning, afternoon, evening) with 1 or more EoE symptoms.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: proportion of segments
least squares mean (standard error)	-0.11 ( 0.032 )	-0.09 ( 0.036 )	-0.16 ( 0.031 )

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6361 ^[11]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.069

upper limit

0.112

Notes
[11] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2064 ^[12]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.139

upper limit

0.03

Notes
[12] - P-value is not adjusted for multiple comparisons

Secondary: 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

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End point title

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

End point description

The PESQ-P was a participant-reported outcome measure intended to be completed independently by participants ≥8 to <12 years of age. The PESQ-P measured occurrence of signs of EoE and was completed once daily via an electronic diary. Data from a 14-day period preceding the baseline visit and a 14-day period preceding week 16 will be used to calculate the proportion of days with 1 or more EoE symptoms.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	17	19	17
Units: proportion of days
least squares mean (standard error)	-0.26 ( 0.068 )	-0.16 ( 0.067 )	-0.13 ( 0.077 )

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2975 ^[13]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.088

upper limit

0.286

Notes
[13] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2086 ^[14]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.072

upper limit

0.33

Notes
[14] - P-value is not adjusted for multiple comparisons

Secondary: 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)

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End point title

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)

End point description

The PESQ-P was a participant-reported outcome measure intended to be completed independently by EoE participants ≥8 to <12 years of age. The PESQ-P measures the signs of EoE, including stomach pain, heartburn, acid reflux, regurgitation, vomiting, food refusal, and trouble swallowing food. The PESQ-P score was calculated based on the daily responses over a 14-day period (i.e., the 14 days prior to the baseline visit and the week 16 visit). The score ranges from 0 to 1. WOCF approach was used for imputing the missing data due to rescue treatment/AE/lack of efficacy, and the multiple imputations approach was used for the missing data due to other reasons. LS Mean SE from ANCOVA.

End point type

Secondary

End point timeframe

Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	17	19	17
Units: sign-free days
least squares mean (standard error)	10.49 ( 0.953 )	9.13 ( 0.936 )	8.69 ( 1.081 )

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3098 ^[15]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-1.36

Confidence interval

level

95%

sides

2-sided

lower limit

-3.972

upper limit

1.26

Notes
[15] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2085 ^[16]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.615

upper limit

1.007

Notes
[16] - P-value is not adjusted for multiple comparisons

Secondary: 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

Top of page

End point title

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

End point description

The PESQ-P was a participant-reported outcome measure intended to be completed independently by EoE participants ≥8 to <12 years of age. The PESQ-P measured the occurrence of signs of EoE and was completed once daily via an electronic diary. Data from a 14-day period preceding the baseline visit and a 14-day period preceding week 16 will be used to calculate the total time segments within a day (night, morning, afternoon, evening) with 1 or more EoE symptoms.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	17	19	17
Units: proportion of segments
least squares mean (standard error)	-0.15 ( 0.040 )	-0.08 ( 0.039 )	-0.08 ( 0.045 )

A: Dupilumab Low Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1939 ^[17]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.037

upper limit

0.181

Notes
[17] - P-value is not adjusted for multiple comparisons

A: Dupilumab High Dose vs A: Pooled Placebo

Comparison groups

Part A: Pooled Placebo v Part A: Dupilumab High Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.236 ^[18]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.046

upper limit

0.186

Notes
[18] - P-value is not adjusted for multiple comparisons

Secondary: 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

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End point title

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

End point description

The PEESSv2.0-C is a caregiver-reported outcome measure that assesses the frequency and severity of EoE symptoms among pediatric participants. The PEESSv2.0-C consists of 20 items and has a one-month recall period. Each item had a 0-4 scale, which was transformed to 0-100 as follows: 0 = 0, 1 = 25, 2 = 50, 3 = 75, 4 = 100. The mean total PEESSv2.0 score was computed as the sum of all the item scores over the number of items answered. The total PEESSv2.0-C score ranges from 0 to 100 where higher scores indicate greater symptom burden among pediatric EoE participants. Values after first rescue treatment use were set to missing (censoring). WOCF approach was used for imputing the missing data due to rescue treatment/AE/lack of efficacy, and the MI approach was used for the missing data due to other reasons. LS mean SE from ANCOVA model.

End point type

Secondary

End point timeframe

Baseline, Week 16

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	31	37
Units: score on a scale
least squares mean (standard error)	-11.83 ( 2.909 )	-10.10 ( 2.785 )	-19.86 ( 2.577 )

No statistical analyses for this end point

Secondary: Part A: Concentration of Functional Dupilumab in Serum at Baseline, Week 4 and 16

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End point title

Part A: Concentration of Functional Dupilumab in Serum at Baseline, Week 4 and 16 ^[19]

End point description

Concentration of functional dupilumab in serum at Baseline, Week 4 and 16 was reported in this outcome measure.

End point type

Secondary

End point timeframe

Baseline, Week 4 and 16

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants who received dupilumab were included in the analysis of this endpoint.

End point values	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	28	36
Units: milligrams per liter (mg/L)
arithmetic mean (standard deviation)
Baseline	0 ( 0 )	0 ( 0 )
Week 4	40.6 ( 11.2 )	75.7 ( 25.7 )
Week 16	86.0 ( 29.2 )	163 ( 60.8 )

No statistical analyses for this end point

Secondary: Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤6 Eosinophils/High Power Field at Week 52

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End point title

Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤6 Eosinophils/High Power Field at Week 52

End point description

End point type

Secondary

End point timeframe

At Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	17	29	35
Units: percentage of participants
number (not applicable)	92.9	52.9	65.5	62.9

No statistical analyses for this end point

Secondary: Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 52

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End point title

Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 52

End point description

End point type

Secondary

End point timeframe

At Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	17	29	35
Units: percentage of participants
number (not applicable)	92.9	64.7	69.0	85.7

No statistical analyses for this end point

Secondary: Part B: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 52

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End point title

Part B: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 52

End point description

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	17	29	35
Units: percent change
arithmetic mean (standard deviation)	-92.72 ( 19.229 )	-76.83 ( 41.228 )	-85.41 ( 22.851 )	-90.97 ( 14.482 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 52

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End point title

Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 52

End point description

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	17	29	35
Units: Score on a scale
arithmetic mean (standard deviation)	-0.804 ( 0.3099 )	-0.885 ( 0.2962 )	-0.773 ( 0.3374 )	-0.967 ( 0.3920 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 52

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End point title

Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 52

End point description

EoE-HSS is a validated histologic scoring system that measures other histological abnormalities in addition to density of eosinophilic infiltration. Severity (grade) and extent (stage) of abnormalities will be scored using a 4-point scale (0 normal; 3 maximum change). Higher total score indicated greater severity & extent of histological abnormalities. For each of 3 esophageal regions (proximal, mid, and distal), the ratio of the sum of assigned score for each evaluated feature divided by maximum possible score (maximum value is 24) was calculated. The mean stage scores summed over the 3 regions was the final score used in primary analysis, the mean stage score ranged from 0 to 3, with higher score indicating more severe.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	17	29	35
Units: Score on a scale
arithmetic mean (standard deviation)	-0.767 ( 0.3114 )	-0.855 ( 0.3485 )	-0.784 ( 0.3183 )	-0.892 ( 0.3181 )

No statistical analyses for this end point

Secondary: Part B: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 52

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End point title

Part B: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 52

End point description

The EoE-EREFS is a validated endoscopic scoring system for inflammatory and remodeling features of EoE including edema, rings, exudates, furrows, and stricture. The score was assessed in the proximal and distal esophageal regions with each region scored from 0 to 9 with total scores possibly ranging from 0 to 18. Higher scores indicate worse endoscopic inflammatory and remodeling findings.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	11	14	22	30
Units: score on a scale
arithmetic mean (standard deviation)	-5.82 ( 1.722 )	-3.64 ( 3.342 )	-4.50 ( 3.203 )	-4.77 ( 3.081 )

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

PESQ-C is a novel, observer-reported outcome measure intended to be completed independently by caregivers of all pediatric EoE participants in the study. Data from a 14-day period preceding the baseline visit and a 14-day period preceding week 16 will be used to calculate the proportion of days with 1 or more EoE symptoms.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	6	9	18	27
Units: proportion of days
arithmetic mean (standard deviation)	-0.20 ( 0.373 )	-0.47 ( 0.395 )	-0.49 ( 0.339 )	-0.30 ( 0.299 )

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	6	9	18	27
Units: proportion of segments
arithmetic mean (standard deviation)	-0.03 ( 0.249 )	-0.24 ( 0.221 )	-0.26 ( 0.250 )	-0.17 ( 0.187 )

No statistical analyses for this end point

Secondary: 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)

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End point title

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)

End point description

PESQ-C is a novel, observer-reported outcome measure intended to be completed independently by caregivers of all pediatric EoE participants in the study.

End point type

Secondary

End point timeframe

Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	6	9	18	27
Units: sign-free days
arithmetic mean (standard deviation)	11.58 ( 3.968 )	12.10 ( 4.652 )	11.35 ( 3.947 )	12.13 ( 4.053 )

No statistical analyses for this end point

Secondary: 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)

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End point title

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)

End point description

The PESQ-P was a participant-reported outcome measure intended to be completed independently by participants ≥8 to <12 years of age. The PESQ-P measures the signs of EoE, including stomach pain, heartburn, acid reflux, regurgitation, vomiting, food refusal, and trouble swallowing food.

End point type

Secondary

End point timeframe

Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	3	6	11	12
Units: sign-free days
arithmetic mean (standard deviation)	9.33 ( 8.083 )	11.67 ( 5.715 )	10.64 ( 4.943 )	13.63 ( 0.874 )

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	3	6	11	12
Units: proportion of days
arithmetic mean (standard deviation)	-0.33 ( 0.322 )	-0.43 ( 0.369 )	-0.42 ( 0.400 )	-0.26 ( 0.396 )

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	3	6	11	12
Units: proportion of segments
arithmetic mean (standard deviation)	-0.17 ( 0.164 )	-0.26 ( 0.269 )	-0.21 ( 0.293 )	-0.16 ( 0.284 )

No statistical analyses for this end point

Secondary: Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the EoE Diagnostic Panel (EDP) at Week 52

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End point title

Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the EoE Diagnostic Panel (EDP) at Week 52

End point description

A Normalized Enrichment Score (NES) is a way to generate a single numerical value to represent a complex gene expression signature. Changes in NES score represented the overall changes in the expression of that molecular phenotype. The NESs calculated for the EDP reflect the expression at Week 16 relative to Baseline of a gene set that is differentially expressed between esophageal biopsies from EoE participants compared to healthy controls as a way to evaluate normalization of the molecular pathology. For each subject, an NES of 0 indicates no change from baseline, a negative score shows a reduction in disease score (more like normal) and positive score shows worsening (more active disease). NES does not have minimum/maximum score.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	8	12	16	21
Units: NES
number (not applicable)	-2.715	-2.615	-2.625	-2.670

No statistical analyses for this end point

Secondary: Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 52

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End point title

Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 52

End point description

A Normalized Enrichment Score (NES) is a way to generate a single numerical value to represent a complex gene expression signature. Changes in NES score represented the overall changes in the expression of that molecular phenotype. The NESs calculated for T2INF reflect the expression at Week 16 relative to Baseline of the pre-specified gene set as a way to evaluate normalization of type 2 inflammation with treatment. For each subject, an NES of 0 indicates no change from baseline, a negative score shows a reduction in disease score (more like normal) and positive score shows worsening (more active disease). NES does not have minimum/maximum score. Analysis was performed on Part B SAF which included all participants who received at least 1 dose of Part B study drug. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	8	12	16	21
Units: Score on a scale
median (inter-quartile range (Q1-Q3))	-1.960 (-2.000 to -1.895)	-1.965 (-1.995 to -1.765)	-1.920 (-1.965 to -1.865)	-1.920 (-1.930 to -1.850)

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Body Weight for Age Percentile at Week 52

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End point title

Part B: Change From Baseline in Body Weight for Age Percentile at Week 52

End point description

Body weight for age percentile was calculated based on the growth charts from the Centers for Disease Control and Prevention (CDC) for ages 0 to 20 years (for ages 2 to <12 years) and World Health Organization (WHO) growth charts for ages 0 to <2 years (for ages 1 to <2 years). These charts included a set of smoothed percentiles along with CDC LMS (Lambda-Mu-Sigma) parameters to allow the calculation of percentiles.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	16	29	35
Units: Percentile
arithmetic mean (standard deviation)	-0.02 ( 13.893 )	5.48 ( 12.644 )	4.75 ( 11.968 )	5.96 ( 11.519 )

No statistical analyses for this end point

Secondary: Part B: Change from Baseline in Body Mass Index (BMI) for Age Z-score for Participants ≥2 Years of Age at Week 52

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End point title

Part B: Change from Baseline in Body Mass Index (BMI) for Age Z-score for Participants ≥2 Years of Age at Week 52

End point description

BMI for age z-score indicates how much higher or lower a participant’s BMI for age is relative to a reference growth chart (based on the growth charts from Centers for Disease Control and Prevention [CDC] for ages 0 to 20 years [for ages 2 to <12 years]). An increase in the mean change in BMI for age z-score (ie, increase in the standard deviation [SD] from the reference growth chart) indicates an increase in BMI for age relative to the reference.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	15	27	32
Units: z-score
arithmetic mean (standard deviation)	-0.0206 ( 0.54625 )	0.0687 ( 0.47605 )	-0.0549 ( 0.88582 )	0.0987 ( 0.72329 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Weight for Age Z-score at Week 52

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End point title

Part B: Change From Baseline in Weight for Age Z-score at Week 52

End point description

Weight for age z-score indicates how much higher or lower a participant’s weight for age is relative to a reference growth chart (based on the growth charts from CDC for ages 0 to 20 years [for ages 2 to <12 years] and World Health Organization (WHO) growth charts for ages 0 to <2 years [for ages 1 to <2 years]). An increase in the mean change in weight for age z-score (increase in the SD from the reference growth chart) indicates an increase in weight for age relative to the reference.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	16	29	35
Units: z-score
arithmetic mean (standard deviation)	0.0640 ( 0.46264 )	0.2016 ( 0.39446 )	0.1445 ( 0.40310 )	0.2049 ( 0.40305 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Body Weight From Height Z-score at Week 52

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End point title

Part B: Change From Baseline in Body Weight From Height Z-score at Week 52

End point description

Weight for height z-score indicates how much higher or lower a participant’s weight for height is relative to a reference growth chart (based on the growth charts from CDC for ages 0 to 20 years [for ages 2 to <12 years] and WHO growth charts for ages 0 to <2 years [for ages 1 to <2 years]). An increase in the mean change in weight for height z-score (increase in the SD from the reference growth chart) indicates an increase in weight for height relative to the reference.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	2	3	9	12
Units: z-score
arithmetic mean (standard deviation)	0.0962 ( 0.48902 )	-0.0100 ( 0.51706 )	-0.2700 ( 1.04895 )	-0.0151 ( 0.67968 )

No statistical analyses for this end point

Secondary: Part B: Concentration of Functional Dupilumab in Serum at Week 32 and 52

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End point title

Part B: Concentration of Functional Dupilumab in Serum at Week 32 and 52

End point description

Concentration of functional dupilumab in serum at Week 32 and 52 was reported in this outcome measure.

End point type

Secondary

End point timeframe

Week 32 and 52

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	18	29	37
Units: mg/L
arithmetic mean (standard deviation)
Week 32	105 ( 49.8 )	142 ( 48.5 )	99.0 ( 42.8 )	186 ( 59.5 )
Week 52	101 ( 44.3 )	149 ( 59.1 )	83.0 ( 33.2 )	179 ( 75.3 )

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. A serious AE was any untoward medical occurrence that at any dose resulted in death, life-threatening, initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or a medically important event. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. An AESI was defined as one of scientific and medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor was appropriate.

End point type

Secondary

End point timeframe

From Baseline up to Week 16 in Part A

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	34	30	37
Units: Participants
Participants with any TEAE	31	26	27
Participants with any Serious TEAE	0	1	2
Participants with any AESI	1	1	2
Any TEAE leading to discontinuation of study drug	2	0	0

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

An AE was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. A serious AE was any untoward medical occurrence that at any dose resulted in death, life-threatening, initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or a medically important event. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. An AESI was defined as one of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor was appropriate.

End point type

Secondary

End point timeframe

From Week 16 up to Week 52 in Part B

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	18	29	37
Units: Participants
Participants with any TEAE	14	15	28	34
Participants with any Serious TEAE	1	0	3	2
Participants with any AESI	0	1	3	4
Any TEAE leading to discontinuation of study drug	0	0	0	1

No statistical analyses for this end point

Secondary: Part A: Number of Participants With Positive Treatment-emergent Antidrug Antibodies (ADA) Response

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End point title

Part A: Number of Participants With Positive Treatment-emergent Antidrug Antibodies (ADA) Response

End point description

Treatment-emergent ADA was defined as a negative result or missing result at baseline with at least one positive post baseline result in the ADA assay. Samples positive in the dupilumab ADA assay were characterized for ADA titers (low, moderate and high). The low treatment-emergent ADA titer as defined as titer level <1000, moderate as 1000 to 10000 and high as >10000.

End point type

Secondary

End point timeframe

From Baseline up to Week 16 in Part A

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	25	26	31
Units: Participants	1	0	1

No statistical analyses for this end point

Secondary: Part A: Number of Participants With Positive Treatment-emergent Antidrug Antibodies (ADA) by Maximum Titer Category

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End point title

Part A: Number of Participants With Positive Treatment-emergent Antidrug Antibodies (ADA) by Maximum Titer Category

End point description

End point type

Secondary

End point timeframe

From Baseline up to Week 16 in Part A

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	1	0 ^[20]	1
Units: Participants
Treatment-emergent ADA Titer: Low	1		1
Treatment-emergent ADA Titer: Moderate	0		0
Treatment-emergent ADA Titer: High	0		0

Notes
[20] - Number of participants analyzed of 0 = none had positive TE ADA response to measure titer level.

No statistical analyses for this end point

Secondary: Part B: Number of Participants With Positive Treatment-emergent Antidrug Antibodies (ADA) Response and Titer

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End point title

Part B: Number of Participants With Positive Treatment-emergent Antidrug Antibodies (ADA) Response and Titer

End point description

End point type

Secondary

End point timeframe

From Week 16 up to Week 52 in Part B

End point values	Part B: Placebo to Dupilumab Low Dose	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose
Number of subjects analysed	14	18	29	37
Units: Participants	0	0	0	0

No statistical analyses for this end point

Secondary: Part C: Percentage of participants achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf At Week 160

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End point title

Part C: Percentage of participants achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf At Week 160

End point description

End point type

Secondary

End point timeframe

At Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[21]
Units: Percentage
number (not applicable)

Notes
[21] - No data was collected for this endpoint.

No statistical analyses for this end point

Secondary: Part C: Percentage of participants achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf At Week 100

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End point title

Part C: Percentage of participants achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf At Week 100

End point description

End point type

Secondary

End point timeframe

At Week 100

End point values	Part C: Dupilumab
Number of subjects analysed	41
Units: Percentage of participants
number (not applicable)	92.7

No statistical analyses for this end point

Secondary: Part C: Percentage of participants achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (400×) at Week 160

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End point title

Part C: Percentage of participants achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (400×) at Week 160

End point description

End point type

Secondary

End point timeframe

At Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[22]
Units: Percentage of participants
number (not applicable)

Notes
[22] - No data was collected for this endpoint

No statistical analyses for this end point

Secondary: Part C: Percentage of participants achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (400×) At Week 100

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End point title

Part C: Percentage of participants achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (400×) At Week 100

End point description

End point type

Secondary

End point timeframe

At Week 100

End point values	Part C: Dupilumab
Number of subjects analysed	41
Units: Percentage of participants
number (not applicable)	70.7

No statistical analyses for this end point

Secondary: Part C: Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from Baseline to Week 100

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End point title

Part C: Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from Baseline to Week 100

End point description

End point type

Secondary

End point timeframe

Baseline to Week 100

End point values	Part C: Dupilumab
Number of subjects analysed	41
Units: Percentage of change
arithmetic mean (standard deviation)	-91.50 ( 13.348 )

No statistical analyses for this end point

Secondary: Part C: Absolute change in mean EoE-HSS from Baseline to Week 100

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End point title

Part C: Absolute change in mean EoE-HSS from Baseline to Week 100

End point description

End point type

Secondary

End point timeframe

Baseline to Week 100

End point values	Part C: Dupilumab
Number of subjects analysed	61
Units: Score on a scale
arithmetic mean (standard deviation)
EoE-HSS Grade Score	1.213 ( 0.3720 )
EoE-HSS Stage Score	1.232 ( 0.3526 )

No statistical analyses for this end point

Secondary: Part C: Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from Baseline to Week 160

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End point title

Part C: Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from Baseline to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[23]
Units: Percentage of change
number (not applicable)

Notes
[23] - No data was collected for this endpoint.

No statistical analyses for this end point

Secondary: Part C: Absolute change in EoE-EREFS from Baseline to Week 100

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End point title

Part C: Absolute change in EoE-EREFS from Baseline to Week 100

End point description

End point type

Secondary

End point timeframe

Baseline to Week 100

End point values	Part C: Dupilumab
Number of subjects analysed	32
Units: Score on a scale
arithmetic mean (standard deviation)	-5.34 ( 2.535 )

No statistical analyses for this end point

Secondary: Part C: Absolute change in mean EoE-HSS from Baseline to Week 160

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End point title

Part C: Absolute change in mean EoE-HSS from Baseline to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[24]
Units: Score on a scale
arithmetic mean (standard deviation)	( )

Notes
[24] - No data was collected for this endpoint.

No statistical analyses for this end point

Secondary: Part C: Absolute change in EoE-EREFS from Baseline to Week 160

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End point title

Part C: Absolute change in EoE-EREFS from Baseline to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[25]
Units: Score on a scale
arithmetic mean (standard deviation)	( )

Notes
[25] - No data was collected for this endpoint.

No statistical analyses for this end point

Secondary: Part C: Change in total score as measured by the PEESSv2.0- caregiver version questionnaire from Baseline to Week 160

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End point title

Part C: Change in total score as measured by the PEESSv2.0- caregiver version questionnaire from Baseline to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[26]
Units: Score on a scale
number (not applicable)

Notes
[26] - No data was collected for this endpoint.

No statistical analyses for this end point

Secondary: Part C: NES for the relative change in the EDP transcriptome signature from Baseline to Week 100

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End point title

Part C: NES for the relative change in the EDP transcriptome signature from Baseline to Week 100

End point description

A Normalized Enrichment Score (NES) is a way to generate a single numerical value to represent a complex gene expression signature. Changes in NES score represented the overall changes in the expression of that molecular phenotype. The NESs calculated for the EDP reflect the expression at Week 16 relative to Baseline of a gene set that is differentially expressed between esophageal biopsies from EoE participants compared to healthy controls as a way to evaluate normalization of the molecular pathology. For each subject, an NES of 0 indicates no change from baseline, a negative score shows a reduction in disease score (more like normal) and positive score shows worsening (more active disease). NES does not have minimum/maximum score.

End point type

Secondary

End point timeframe

Baseline to Week 100

End point values	Part C: Dupilumab
Number of subjects analysed	39
Units: Score on a scale
median (inter-quartile range (Q1-Q3))	-2.720 (-2.800 to -2.510)

No statistical analyses for this end point

Secondary: Part C: NES for the relative change in the EDP transcriptome signature from Baseline to Week 160

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End point title

Part C: NES for the relative change in the EDP transcriptome signature from Baseline to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[27]
Units: Score on a scale
number (not applicable)

Notes
[27] - No data collected for this endpoint

No statistical analyses for this end point

Secondary: Part C: NES for the relative change in the type 2 inflammation transcriptome signature Baseline to Week 100

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End point title

Part C: NES for the relative change in the type 2 inflammation transcriptome signature Baseline to Week 100

End point description

End point type

Secondary

End point timeframe

Baseline to Week 100

End point values	Part C: Dupilumab
Number of subjects analysed	39
Units: Score on a scale
number (not applicable)	-1.970

No statistical analyses for this end point

Secondary: Part C: Change in body weight for age percentile from Baseline up to Week 160

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End point title

Part C: Change in body weight for age percentile from Baseline up to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[28]
Units: kilograms (kg)
number (not applicable)

Notes
[28] - No data was collected for this endpoint

No statistical analyses for this end point

Secondary: Part C: NES for the relative change in the type 2 inflammation transcriptome signature from Baseline to Week 160

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End point title

Part C: NES for the relative change in the type 2 inflammation transcriptome signature from Baseline to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[29]
Units: Score on a scale
number (not applicable)

Notes
[29] - No data was collected for this endpoint

No statistical analyses for this end point

Secondary: Part C: Change in body mass index for age z-score from Baseline to up to Week 160

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End point title

Part C: Change in body mass index for age z-score from Baseline to up to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline to up to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[30]
Units: z-score
arithmetic mean (standard deviation)	( )

Notes
[30] - No data was collected for this endpoint

No statistical analyses for this end point

Secondary: Part C: Incidence of TEAEs Up to Week 160

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End point title

Part C: Incidence of TEAEs Up to Week 160

End point description

End point type

Secondary

End point timeframe

Up to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	61
Units: Events
number (not applicable)	86.9

No statistical analyses for this end point

Secondary: Part C: Percentage of participants (with food elimination diet regimens at baseline) that have a re-introduction of a previously eliminated food group from Baseline by Week 160

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End point title

Part C: Percentage of participants (with food elimination diet regimens at baseline) that have a re-introduction of a previously eliminated food group from Baseline by Week 160

End point description

End point type

Secondary

End point timeframe

Baseline by Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[31]
Units: Percentage of participants
number (not applicable)

Notes
[31] - No data was collected for this endpoint

No statistical analyses for this end point

Secondary: Part C: Percentage of participants (with food elimination diet regimens at baseline) that have a re-introduction of a previously eliminated food group from Baseline by Week 100

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End point title

Part C: Percentage of participants (with food elimination diet regimens at baseline) that have a re-introduction of a previously eliminated food group from Baseline by Week 100

End point description

End point type

Secondary

End point timeframe

Baseline by Week 100

End point values	Part C: Dupilumab
Number of subjects analysed	61
Units: Percentage of participants
number (not applicable)	14.8

No statistical analyses for this end point

Secondary: Part C: Change in weight for height z-score from Baseline up to Week 160

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End point title

Part C: Change in weight for height z-score from Baseline up to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[32]
Units: z-score
arithmetic mean (standard deviation)	( )

Notes
[32] - No data was collected for this endpoint

No statistical analyses for this end point

Secondary: Part C: Change in weight for age z-score from Baseline up to Week 160

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End point title

Part C: Change in weight for age z-score from Baseline up to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	0 ^[33]
Units: z-score
arithmetic mean (standard deviation)	( )

Notes
[33] - No data was collected for this endpoint

No statistical analyses for this end point

Secondary: Part C: Number of Participants with treatment-emergent ADA responses and titer Up to Week 160

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End point title

Part C: Number of Participants with treatment-emergent ADA responses and titer Up to Week 160

End point description

Anti-Drug Antibody Analysis Set (AAS): The Part C AAS included all participants who received any amount of study drug in Part C and had at least 1 non-missing ADA result following the first dose of study drug. Analysis was based on treatment received.

End point type

Secondary

End point timeframe

Up to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	39
Units: Participants
number (not applicable)	0

No statistical analyses for this end point

Secondary: Part C: Incidence of treatment-emergent AESIs Up to Week 160

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End point title

Part C: Incidence of treatment-emergent AESIs Up to Week 160

End point description

End point type

Secondary

End point timeframe

Up to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	61
Units: Events
number (not applicable)	9.8

No statistical analyses for this end point

Secondary: Part C: Incidence of treatment-emergent SAEs Up to Week 160

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End point title

Part C: Incidence of treatment-emergent SAEs Up to Week 160

End point description

End point type

Secondary

End point timeframe

Up to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	61
Units: Events
number (not applicable)	4.9

No statistical analyses for this end point

Secondary: Part C: Incidence of TEAEs leading to permanent discontinuation of study treatment Up to Week 160

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End point title

Part C: Incidence of TEAEs leading to permanent discontinuation of study treatment Up to Week 160

End point description

End point type

Secondary

End point timeframe

Up to Week 160

End point values	Part C: Dupilumab
Number of subjects analysed	61
Units: Events
number (not applicable)	0

No statistical analyses for this end point

Secondary: Part C: Concentration of functional dupilumab in serum up to Week 160

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End point title

Part C: Concentration of functional dupilumab in serum up to Week 160

End point description

End point type

Secondary

End point timeframe

Baseline to end of study, Up to Week 160

End point values	Part A: Pooled Placebo	Part A: Dupilumab Low Dose	Part A: Dupilumab High Dose
Number of subjects analysed	0 ^[34]	0 ^[35]	0 ^[36]
Units: mg/L
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[34] - No data was collected for this endpoint
[35] - No data was collected for this endpoint
[36] - No data was collected for this endpoint

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From signing of the informed consent through week 160 + 12 week follow-up

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Part A: Pooled Placebo

Reporting group description

Reporting group title

Part A: Dupilumab High Dose

Reporting group description

Reporting group title

Part C: Dupilumab

Reporting group description

Participants who completed Part A or B were eligible to enroll in Part C and receive Dupilumab extended active treatment

Reporting group title

Part B: Placebo to Dupilumab High Dose

Reporting group description

Reporting group title

Part B: Dupilumab Low Dose to Dupilumab Low Dose

Reporting group description

Reporting group title

Part B: Dupilumab High Dose to Dupilumab High Dose

Reporting group description

Reporting group title

Part A: Dupilumab Low Dose

Reporting group description

Reporting group title

Part B: Placebo to Dupilumab Low Dose

Reporting group description

Serious adverse events	Part A: Pooled Placebo	Part A: Dupilumab High Dose	Part C: Dupilumab	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose	Part A: Dupilumab Low Dose	Part B: Placebo to Dupilumab Low Dose
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 34 (0.00%)	2 / 37 (5.41%)	3 / 61 (4.92%)	0 / 18 (0.00%)	2 / 29 (6.90%)	2 / 37 (5.41%)	0 / 30 (0.00%)	1 / 14 (7.14%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Investigations
Endoscopy gastrointestinal
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Oesophageal food impaction
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Sleep apnoea syndrome
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Throat tightness
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive sleep apnoea syndrome
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
HCoV-OC43 infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part A: Pooled Placebo	Part A: Dupilumab High Dose	Part C: Dupilumab	Part B: Placebo to Dupilumab High Dose	Part B: Dupilumab Low Dose to Dupilumab Low Dose	Part B: Dupilumab High Dose to Dupilumab High Dose	Part A: Dupilumab Low Dose	Part B: Placebo to Dupilumab Low Dose
Total subjects affected by non serious adverse events
subjects affected / exposed	28 / 34 (82.35%)	26 / 37 (70.27%)	52 / 61 (85.25%)	16 / 18 (88.89%)	27 / 29 (93.10%)	31 / 37 (83.78%)	24 / 30 (80.00%)	14 / 14 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	2	0	1	0	0
Vascular disorders
Flushing
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
General disorders and administration site conditions
Injection site reaction
subjects affected / exposed	7 / 34 (20.59%)	4 / 37 (10.81%)	5 / 61 (8.20%)	5 / 18 (27.78%)	4 / 29 (13.79%)	5 / 37 (13.51%)	4 / 30 (13.33%)	4 / 14 (28.57%)
occurrences all number	8	11	32	21	17	18	11	34
Injection site erythema
subjects affected / exposed	1 / 34 (2.94%)	4 / 37 (10.81%)	2 / 61 (3.28%)	2 / 18 (11.11%)	0 / 29 (0.00%)	0 / 37 (0.00%)	1 / 30 (3.33%)	1 / 14 (7.14%)
occurrences all number	1	8	2	2	0	0	2	1
Pyrexia
subjects affected / exposed	1 / 34 (2.94%)	2 / 37 (5.41%)	11 / 61 (18.03%)	2 / 18 (11.11%)	3 / 29 (10.34%)	6 / 37 (16.22%)	0 / 30 (0.00%)	3 / 14 (21.43%)
occurrences all number	1	2	18	4	3	7	0	3
Fatigue
subjects affected / exposed	0 / 34 (0.00%)	2 / 37 (5.41%)	0 / 61 (0.00%)	3 / 18 (16.67%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	0	3	1	0	0	0
Injection site pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	3 / 61 (4.92%)	1 / 18 (5.56%)	1 / 29 (3.45%)	1 / 37 (2.70%)	3 / 30 (10.00%)	3 / 14 (21.43%)
occurrences all number	0	0	5	1	3	1	3	6
Injection site haemorrhage
subjects affected / exposed	1 / 34 (2.94%)	1 / 37 (2.70%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	2 / 37 (5.41%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	2	0	0	2	0	1
Injection site swelling
subjects affected / exposed	1 / 34 (2.94%)	1 / 37 (2.70%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	2 / 37 (5.41%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	0	2	0	1
Chest pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	3 / 37 (8.11%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	3	0	0
Malaise
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0
Injection site induration
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Injection site inflammation
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	0 / 61 (0.00%)	0 / 18 (0.00%)	2 / 29 (6.90%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	4	1	0	0
Injection site oedema
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	1 / 61 (1.64%)	1 / 18 (5.56%)	1 / 29 (3.45%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	4	1	1	1	1	0	0
Influenza like illness
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	1 / 30 (3.33%)	1 / 14 (7.14%)
occurrences all number	0	0	1	0	0	0	1	1
Vessel puncture site pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Injection site mass
subjects affected / exposed	1 / 34 (2.94%)	1 / 37 (2.70%)	2 / 61 (3.28%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	1	11	0	0	2	0	0
Injection site bruising
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	2 / 34 (5.88%)	0 / 37 (0.00%)	4 / 61 (6.56%)	1 / 18 (5.56%)	4 / 29 (13.79%)	2 / 37 (5.41%)	1 / 30 (3.33%)	1 / 14 (7.14%)
occurrences all number	2	0	5	1	4	2	1	1
Food allergy
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	2 / 18 (11.11%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	2	0	1	0	0
Immunisation reaction
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0
Anaphylactic reaction
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	1 / 61 (1.64%)	0 / 18 (0.00%)	2 / 29 (6.90%)	0 / 37 (0.00%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	0	1	1	0	2	0	1	0
Reproductive system and breast disorders
Genital rash
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	0	1
Genital pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 34 (5.88%)	1 / 37 (2.70%)	8 / 61 (13.11%)	5 / 18 (27.78%)	4 / 29 (13.79%)	5 / 37 (13.51%)	2 / 30 (6.67%)	1 / 14 (7.14%)
occurrences all number	2	2	11	7	4	6	2	1
Rhinitis allergic
subjects affected / exposed	3 / 34 (8.82%)	1 / 37 (2.70%)	0 / 61 (0.00%)	0 / 18 (0.00%)	3 / 29 (10.34%)	2 / 37 (5.41%)	2 / 30 (6.67%)	0 / 14 (0.00%)
occurrences all number	3	1	0	0	4	2	2	0
Asthma
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	2 / 61 (3.28%)	0 / 18 (0.00%)	5 / 29 (17.24%)	3 / 37 (8.11%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	2	0	6	3	0	1
Oropharyngeal pain
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	6 / 61 (9.84%)	2 / 18 (11.11%)	1 / 29 (3.45%)	2 / 37 (5.41%)	1 / 30 (3.33%)	2 / 14 (14.29%)
occurrences all number	1	0	6	2	1	3	1	2
Epistaxis
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	3 / 61 (4.92%)	1 / 18 (5.56%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	1	4	2	0	2	0	1
Wheezing
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0
Bronchial hyperreactivity
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Upper-airway cough syndrome
subjects affected / exposed	1 / 34 (2.94%)	1 / 37 (2.70%)	2 / 61 (3.28%)	1 / 18 (5.56%)	0 / 29 (0.00%)	2 / 37 (5.41%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	1	2	1	0	2	0	0
Laryngospasm
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	0	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	1 / 18 (5.56%)	1 / 29 (3.45%)	4 / 37 (10.81%)	1 / 30 (3.33%)	1 / 14 (7.14%)
occurrences all number	0	0	1	1	1	4	1	1
Oropharyngeal cobble stone mucosa
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	1	0	0	0	0	1
Rhinorrhoea
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	3 / 61 (4.92%)	2 / 18 (11.11%)	0 / 29 (0.00%)	1 / 37 (2.70%)	1 / 30 (3.33%)	2 / 14 (14.29%)
occurrences all number	0	0	4	2	0	2	1	3
Productive cough
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0
Throat irritation
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Throat tightness
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Psychiatric disorders
Fear of injection
subjects affected / exposed	2 / 34 (5.88%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	9	0	0	0	0	0	1	0
Insomnia
subjects affected / exposed	2 / 34 (5.88%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	2 / 29 (6.90%)	0 / 37 (0.00%)	1 / 30 (3.33%)	1 / 14 (7.14%)
occurrences all number	2	0	0	0	2	0	1	1
Enuresis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Encopresis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Attention deficit hyperactivity disorder
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	3 / 61 (4.92%)	0 / 18 (0.00%)	1 / 29 (3.45%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	3	0	1	1	0	0
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Blood potassium increased
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	0	1
Alanine aminotransferase increased
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	0	1
Neutrophil count decreased
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Blood parathyroid hormone increased
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Serum ferritin decreased
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	2 / 37 (5.41%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	0	1	0	2	0	0
Ligament sprain
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	2	0	1	0	0	1
Arthropod sting
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	2 / 61 (3.28%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	1	2	0	0	1	0	1
Face injury
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	0 / 18 (0.00%)	2 / 29 (6.90%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	2	0	0	0
Wrist fracture
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	0 / 61 (0.00%)	1 / 18 (5.56%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	1	1	0	0	0
Sunburn
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Gas poisoning
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Nasal injury
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Foot fracture
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0
Animal bite
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0
Hand fracture
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Joint injury
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	0 / 18 (0.00%)	1 / 29 (3.45%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	1	1	0	0
Limb injury
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	2 / 37 (5.41%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	2	0	0
Ligament rupture
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 34 (5.88%)	1 / 37 (2.70%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	2	1	1	0	0	0	2	0
Headache
subjects affected / exposed	1 / 34 (2.94%)	2 / 37 (5.41%)	6 / 61 (9.84%)	4 / 18 (22.22%)	3 / 29 (10.34%)	4 / 37 (10.81%)	4 / 30 (13.33%)	0 / 14 (0.00%)
occurrences all number	1	2	9	4	5	4	5	0
Lethargy
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Ear and labyrinth disorders
Otorrhoea
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0
Ear pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	1 / 18 (5.56%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	1	0	1	0	0
Motion sickness
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	3 / 61 (4.92%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	5	0	3	0	0	0	0	0
Eye disorders
Eye swelling
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	3 / 29 (10.34%)	0 / 37 (0.00%)	2 / 30 (6.67%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	3	0	2	0
Ocular hyperaemia
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	4 / 29 (13.79%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	7	0	0	0
Eye pruritus
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	2	0	1	0	0	1
Dry eye
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0
Conjunctivitis allergic
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	0	1	0	0	0	1
Astigmatism
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	6 / 34 (17.65%)	3 / 37 (8.11%)	11 / 61 (18.03%)	2 / 18 (11.11%)	3 / 29 (10.34%)	5 / 37 (13.51%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	15	7	24	2	6	7	1	0
Abdominal pain
subjects affected / exposed	3 / 34 (8.82%)	1 / 37 (2.70%)	3 / 61 (4.92%)	2 / 18 (11.11%)	3 / 29 (10.34%)	4 / 37 (10.81%)	1 / 30 (3.33%)	1 / 14 (7.14%)
occurrences all number	3	1	3	3	3	4	1	1
Constipation
subjects affected / exposed	2 / 34 (5.88%)	2 / 37 (5.41%)	3 / 61 (4.92%)	0 / 18 (0.00%)	2 / 29 (6.90%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	2	3	0	2	1	0	0
Abdominal pain upper
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	2 / 61 (3.28%)	0 / 18 (0.00%)	3 / 29 (10.34%)	2 / 37 (5.41%)	2 / 30 (6.67%)	1 / 14 (7.14%)
occurrences all number	0	2	2	0	3	2	2	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	5 / 61 (8.20%)	1 / 18 (5.56%)	1 / 29 (3.45%)	1 / 37 (2.70%)	2 / 30 (6.67%)	0 / 14 (0.00%)
occurrences all number	0	0	5	1	2	1	2	0
Nausea
subjects affected / exposed	0 / 34 (0.00%)	2 / 37 (5.41%)	2 / 61 (3.28%)	2 / 18 (11.11%)	2 / 29 (6.90%)	1 / 37 (2.70%)	3 / 30 (10.00%)	1 / 14 (7.14%)
occurrences all number	0	3	3	2	2	1	3	1
Diarrhoea
subjects affected / exposed	1 / 34 (2.94%)	2 / 37 (5.41%)	1 / 61 (1.64%)	3 / 18 (16.67%)	3 / 29 (10.34%)	3 / 37 (8.11%)	2 / 30 (6.67%)	1 / 14 (7.14%)
occurrences all number	1	2	1	9	3	3	3	2
Eosinophilic oesophagitis
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	1 / 29 (3.45%)	1 / 37 (2.70%)	0 / 30 (0.00%)	2 / 14 (14.29%)
occurrences all number	1	0	0	0	1	1	0	2
Oral pain
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	0	0	0	0	0	1
Oral discomfort
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Dysphagia
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	2 / 29 (6.90%)	1 / 37 (2.70%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	1	0	3	1	0	1
Lip blister
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Dyspepsia
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	2 / 18 (11.11%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	2	1	0	0	0
Abdominal discomfort
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Faeces hard
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Flatulence
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 34 (5.88%)	3 / 37 (8.11%)	5 / 61 (8.20%)	2 / 18 (11.11%)	1 / 29 (3.45%)	4 / 37 (10.81%)	3 / 30 (10.00%)	2 / 14 (14.29%)
occurrences all number	2	4	5	4	2	7	3	4
Eczema
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	3 / 61 (4.92%)	2 / 18 (11.11%)	2 / 29 (6.90%)	0 / 37 (0.00%)	2 / 30 (6.67%)	0 / 14 (0.00%)
occurrences all number	2	0	3	2	2	0	2	0
Urticaria
subjects affected / exposed	2 / 34 (5.88%)	1 / 37 (2.70%)	2 / 61 (3.28%)	0 / 18 (0.00%)	2 / 29 (6.90%)	1 / 37 (2.70%)	2 / 30 (6.67%)	3 / 14 (21.43%)
occurrences all number	2	3	2	0	2	2	2	3
Dry skin
subjects affected / exposed	2 / 34 (5.88%)	1 / 37 (2.70%)	3 / 61 (4.92%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	2	1	3	0	0	1	1	0
Rash papular
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	2 / 37 (5.41%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	3	0	0
Dermatitis
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	3 / 61 (4.92%)	0 / 18 (0.00%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	1	3	0	1	0	0	1
Hand dermatitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Keratosis pilaris
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0
Perioral dermatitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	1 / 30 (3.33%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	1	1
Petechiae
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	0	1
Pruritus
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	1	0	0	0	0
Skin lesion
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0
Rash erythematous
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0
Erythema
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	0 / 18 (0.00%)	1 / 29 (3.45%)	1 / 37 (2.70%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	1	1	1	0
Macule
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Rash macular
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Acne
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Dermatitis contact
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Tendon pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	0	1
Musculoskeletal discomfort
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Pain in extremity
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	4 / 61 (6.56%)	3 / 18 (16.67%)	0 / 29 (0.00%)	2 / 37 (5.41%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	4	3	0	3	0	1
Arthralgia
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	2 / 61 (3.28%)	1 / 18 (5.56%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	3	2	0	1	0	0
Back pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	3 / 61 (4.92%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	2 / 29 (6.90%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	4	0	0	0
Infections and infestations
Sinusitis
subjects affected / exposed	3 / 34 (8.82%)	0 / 37 (0.00%)	1 / 61 (1.64%)	1 / 18 (5.56%)	1 / 29 (3.45%)	0 / 37 (0.00%)	1 / 30 (3.33%)	1 / 14 (7.14%)
occurrences all number	3	0	1	1	1	0	1	1
Upper respiratory tract infection
subjects affected / exposed	3 / 34 (8.82%)	0 / 37 (0.00%)	8 / 61 (13.11%)	1 / 18 (5.56%)	8 / 29 (27.59%)	2 / 37 (5.41%)	1 / 30 (3.33%)	2 / 14 (14.29%)
occurrences all number	3	0	8	1	9	2	1	2
Ear infection
subjects affected / exposed	2 / 34 (5.88%)	0 / 37 (0.00%)	5 / 61 (8.20%)	1 / 18 (5.56%)	1 / 29 (3.45%)	2 / 37 (5.41%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	3	0	5	1	1	2	0	1
Molluscum contagiosum
subjects affected / exposed	2 / 34 (5.88%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	1	0	0	0	0	0
COVID-19
subjects affected / exposed	0 / 34 (0.00%)	6 / 37 (16.22%)	5 / 61 (8.20%)	6 / 18 (33.33%)	7 / 29 (24.14%)	11 / 37 (29.73%)	9 / 30 (30.00%)	3 / 14 (21.43%)
occurrences all number	0	6	6	7	7	11	9	3
Viral upper respiratory tract infection
subjects affected / exposed	2 / 34 (5.88%)	0 / 37 (0.00%)	3 / 61 (4.92%)	1 / 18 (5.56%)	4 / 29 (13.79%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	4	1	4	1	0	0
Gastroenteritis viral
subjects affected / exposed	1 / 34 (2.94%)	4 / 37 (10.81%)	5 / 61 (8.20%)	1 / 18 (5.56%)	1 / 29 (3.45%)	2 / 37 (5.41%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	4	7	1	1	2	0	0
Nasopharyngitis
subjects affected / exposed	2 / 34 (5.88%)	2 / 37 (5.41%)	4 / 61 (6.56%)	1 / 18 (5.56%)	1 / 29 (3.45%)	3 / 37 (8.11%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	2	2	4	1	1	6	1	0
Respiratory tract infection viral
subjects affected / exposed	1 / 34 (2.94%)	1 / 37 (2.70%)	2 / 61 (3.28%)	1 / 18 (5.56%)	1 / 29 (3.45%)	1 / 37 (2.70%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	2	1	2	3	1	1	0	1
Hordeolum
subjects affected / exposed	1 / 34 (2.94%)	0 / 37 (0.00%)	2 / 61 (3.28%)	0 / 18 (0.00%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	4	0	3	0	1	0	0	3
Beta haemolytic streptococcal infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Conjunctivitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	4 / 61 (6.56%)	2 / 18 (11.11%)	4 / 29 (13.79%)	2 / 37 (5.41%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	0	0	5	2	4	2	1	0
Croup infectious
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	4 / 61 (6.56%)	1 / 18 (5.56%)	1 / 29 (3.45%)	2 / 37 (5.41%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	4	1	1	2	0	0
Ear infection viral
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Influenza
subjects affected / exposed	0 / 34 (0.00%)	1 / 37 (2.70%)	3 / 61 (4.92%)	1 / 18 (5.56%)	4 / 29 (13.79%)	4 / 37 (10.81%)	0 / 30 (0.00%)	4 / 14 (28.57%)
occurrences all number	0	1	3	1	4	4	0	4
Gastrointestinal viral infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	1 / 18 (5.56%)	2 / 29 (6.90%)	1 / 37 (2.70%)	1 / 30 (3.33%)	1 / 14 (7.14%)
occurrences all number	0	0	1	1	2	1	1	1
Groin infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Impetigo
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	0	1
Eye infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	2 / 29 (6.90%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0
Otitis media
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	1 / 18 (5.56%)	0 / 29 (0.00%)	3 / 37 (8.11%)	1 / 30 (3.33%)	0 / 14 (0.00%)
occurrences all number	0	0	2	1	0	3	1	0
Pharyngitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	1 / 18 (5.56%)	1 / 29 (3.45%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	4	1	1	0	0	0
Pharyngitis streptococcal
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	13 / 61 (21.31%)	1 / 18 (5.56%)	2 / 29 (6.90%)	0 / 37 (0.00%)	0 / 30 (0.00%)	2 / 14 (14.29%)
occurrences all number	0	0	15	2	2	0	0	2
Urinary tract infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	2 / 37 (5.41%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Stoma site infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Tonsillitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Rhinitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	2 / 18 (11.11%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	3	0	0	0	0
Viral infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	2 / 37 (5.41%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	2	0	0
Paronychia
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	1 / 61 (1.64%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	0 / 18 (0.00%)	1 / 29 (3.45%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	1	1	0	0
Cellulitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	2 / 61 (3.28%)	0 / 18 (0.00%)	0 / 29 (0.00%)	1 / 37 (2.70%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	1	0	0
Metabolism and nutrition disorders
Iron deficiency
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	0 / 18 (0.00%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	0	1
Decreased appetite
subjects affected / exposed	0 / 34 (0.00%)	0 / 37 (0.00%)	0 / 61 (0.00%)	1 / 18 (5.56%)	0 / 29 (0.00%)	0 / 37 (0.00%)	0 / 30 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

07 Apr 2020

Added the PEESSv2.0- caregiver version questionnaire as a secondary endpoint; Changed the PESQ-Caregiver and PESQ-Patient questionnaires to secondary endpoints; Clarifications; Added endpoints; Updated inclusion criteria

18 Nov 2020

Added additional treatment arm to evaluate a lower exposure of dupilumab; clariifications and updated language.

13 Jun 2021

Included an exit interview; added symptom/sign-free days based on the PESQ-P or PESQ-C as a secondary endpoint

03 Aug 2022

Added long-term extension period; Clarifications and editorial corrections

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

14May2024 - All participants met criteria defined in the protocol as reasons for treatment completion prior to reaching week 160. The study was not ended prematurely due to safety reasons.

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 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

Primary: 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

Secondary: Part A: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 16

Secondary: Part A: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 16

Secondary: Part A: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 16

Secondary: Part A: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 16

Secondary: Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 16

Secondary: Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 16

Secondary: Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 16

Secondary: Part A: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 16

Secondary: Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 16

Secondary: Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 16

Secondary: Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Eosinophilic Esophagitis (EoE) Diagnostic Panel (EDP) at Week 16

Secondary: Part A: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Eosinophilic Esophagitis (EoE) Diagnostic Panel (EDP) at Week 16

Secondary: Part A: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 16

Secondary: Part A: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 16

Secondary: 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)

Secondary: 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)

Secondary: 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)

Secondary: 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)

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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)

Secondary: 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)

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: Part A: Concentration of Functional Dupilumab in Serum at Baseline, Week 4 and 16

Secondary: Part A: Concentration of Functional Dupilumab in Serum at Baseline, Week 4 and 16

Secondary: Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤6 Eosinophils/High Power Field at Week 52

Secondary: Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of ≤6 Eosinophils/High Power Field at Week 52

Secondary: Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 52

Secondary: Part B: Percentage of Participants Achieving Peak Esophageal Intraepithelial Eosinophil Count of <15 Eosinophils/High Power Field at Week 52

Secondary: Part B: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 52

Secondary: Part B: Percent Change From Baseline in Peak Esophageal Intraepithelial Eosinophil Count at Week 52

Secondary: Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 52

Secondary: Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Grade Score at Week 52

Secondary: Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 52

Secondary: Part B: Change From Baseline in Mean Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) Stage Score at Week 52

Secondary: Part B: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 52

Secondary: Part B: Absolute Change From Baseline in EoE Endoscopic Reference Total Score (EoE-EREFS) at Week 52

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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)

Secondary: 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)

Secondary: 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)

Secondary: 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)

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the EoE Diagnostic Panel (EDP) at Week 52

Secondary: Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the EoE Diagnostic Panel (EDP) at Week 52

Secondary: Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 52

Secondary: Part B: Normalized Enrichment Score (NES) for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 52

Secondary: Part B: Change From Baseline in Body Weight for Age Percentile at Week 52

Secondary: Part B: Change From Baseline in Body Weight for Age Percentile at Week 52

Secondary: Part B: Change from Baseline in Body Mass Index (BMI) for Age Z-score for Participants ≥2 Years of Age at Week 52

Secondary: Part B: Change from Baseline in Body Mass Index (BMI) for Age Z-score for Participants ≥2 Years of Age at Week 52

Secondary: Part B: Change From Baseline in Weight for Age Z-score at Week 52

Secondary: Part B: Change From Baseline in Weight for Age Z-score at Week 52

Secondary: Part B: Change From Baseline in Body Weight From Height Z-score at Week 52

Secondary: Part B: Change From Baseline in Body Weight From Height Z-score at Week 52

Secondary: Part B: Concentration of Functional Dupilumab in Serum at Week 32 and 52

Secondary: Part B: Concentration of Functional Dupilumab in Serum at Week 32 and 52

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