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Clinical Trial Results:
A Phase 2/3 Study Investigating the Pharmacokinetics, Safety, and Efficacy of Dupilumab in Patients Aged ≥ 6 Months to < 6 Years with Moderate-to-Severe Atopic Dermatitis

Summary
EudraCT number	2016-000955-28
Trial protocol	DE GB PL
Global end of trial date	08 Jul 2021

Results information
Results version number	v1(current)
This version publication date	22 Jan 2022
First version publication date	22 Jan 2022
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-AD-1539

ISRCTN number

US NCT number

NCT03346434

WHO universal trial number (UTN)

Sponsor organisation name

Regeneron Pharmaceuticals, Inc.

Sponsor organisation address

777 Old Saw Mill River Rd., Tarrytown, NY, United States, 10591

Public contact

Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com

Scientific contact

Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001501-PIP01-13

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

08 Jul 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

The main objective of Part A of this study was to characterize the safety and pharmacokinetics (PK) of dupilumab administered as a single dose in pediatric subjects, greater than or equal to (≥) 6 months to less than (<) 6 years of age with severe atopic dermatitis (AD). The main objective of Part B of this study was to demonstrate the efficacy of multiple doses of dupilumab over 16 weeks of treatment when administered concomitantly with topical corticosteroids (TCS) in pediatric subjects, greater than or equal to (≥) 6 months to less than (<) 6 years of age, with moderate-to-severe AD.

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Nov 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 41

Country: Number of subjects enrolled

United Kingdom: 15

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

United States: 138

Worldwide total number of subjects

202

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)

171

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

This study was conducted in 2 parts: Part A and Part B. Part A enrolled subjects in the United States, Germany, and the United Kingdom. Part B enrolled subjects in the United States, Germany, Poland, and the United Kingdom. Subjects who enrolled in Part A of study were not eligible to participate in Part B.

Screening details

Subjects in Part A enrolled in 2 sequential age cohorts: Cohort 1 (≥2 to <6 yrs) and Cohort 2 (≥6 months to <2 yrs). Each age cohort received dupilumab in 1 of 2 doses: 3 milligrams per kilogram (mg/kg) or 6 mg/kg. Subjects in Part B were randomized to 1 of 2 treatment groups: placebo + TCS or dupilumab 200/300 mg every four weeks (Q4W) + TCS.

Period 1 title

Part A and Part B (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

Part A was an open-label, single ascending dose, sequential cohort study and Part B was a randomized, double-blind, placebo-controlled study.

Are arms mutually exclusive

Yes

Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg

Arm description

Subjects received a single subcutaneous (SC) injection of dupilumab at a dose of 3 mg/kg at Day 1. At week 4, subjects could roll over into an open-label extension (OLE) study (R668-AD-1434), if considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 4 weeks for safety.

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

DUPIXENT®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received SC injection of dupilumab on different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.

Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg

Arm description

Subjects received a single SC injection of dupilumab at a dose of 6 mg/kg at Day 1. At week 4, subjects could roll over into an OLE study (R668-AD-1434), if considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 4 weeks for safety.

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

DUPIXENT®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received SC injection of dupilumab on different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.

Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg

Arm description

Subjects received a single SC injection of dupilumab at a dose of 3 mg/kg at Day 1. At week 4, subjects could roll over into an OLE study (R668-AD-1434), if considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 4 weeks for safety.

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

DUPIXENT®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received SC injection of dupilumab on different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.

Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg

Arm description

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

DUPIXENT®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received SC injection of dupilumab on different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.

Part B: Placebo + TCS

Arm description

Subjects received SC injection of placebo matched to dupilumab Q4W along with low potency TCS on areas of thin skin (face, neck, intertriginous, and genital areas, areas of skin atrophy) for 16 weeks. At week 16, subjects could roll over into an OLE study (R668-AD-1434), if considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

Arm type

Experimental

Investigational medicinal product name

TCS

Investigational medicinal product code

Other name

Pharmaceutical forms

Cream

Routes of administration

Topical use

Dosage and administration details

Subjects applied low potency TCS once daily to areas with active lesions.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received SC injection placebo matched to dupilumab on different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.

Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Arm description

Subjects with baseline weight of ≥ 5 to < 15 kilogram (kg) received SC injections of 200 mg or subjects with baseline weight ≥ 15 to < 30 kg received SC injections of 300 mg of dupilumab at Day 1 and Q4W from Week 4 to Week 12. Subjects applied daily low potency TCS on areas of thin skin (face, neck, intertriginous, and genital areas, areas of skin atrophy) for 16 weeks. At week 16, subjects could roll over into an OLE study (R668-AD-1434), if considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, EOS period].

Arm type

Experimental

Investigational medicinal product name

TCS

Investigational medicinal product code

Other name

Pharmaceutical forms

Cream

Routes of administration

Topical use

Dosage and administration details

Subjects applied low potency TCS once daily to areas with active lesions.

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

REGN668

Other name

DUPIXENT®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received SC injection of dupilumab on different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms

Number of subjects in period 1	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Started	10	10	10	10	79	83
Completed Part A	10	10	9	10	0 ^[1]	0 ^[2]
Completed Part B	0 ^[3]	0 ^[4]	0 ^[5]	0 ^[6]	1	1
Completed	10	10	9	10	1	1
Not completed	0	0	1	0	78	82
Consent withdrawn by subject	-	-	1	-	1	-
Subject randomised in error	-	-	-	-	1	-
Subjects transitioned to OLE study	-	-	-	-	75	81
Lost to follow-up	-	-	-	-	1	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects who completed Part B, thus not entering OLE period were reported in this milestone for more clarity of study design.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects who completed Part B, thus not entering OLE period were reported in this milestone for more clarity of study design.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: 10 subjects completed Part A of the study and all subjects transitioned to OLE study at Week 4.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: 10 subjects completed Part A of the study and all subjects transitioned to OLE study at Week 4.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: 10 subjects completed Part A of the study, out of which 9 subjects transitioned to OLE study at Week 4.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: 10 subjects completed Part A of the study and all subjects transitioned to OLE study at Week 4.

Baseline characteristics

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Reporting group title

Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg

Reporting group description

Reporting group title

Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg

Reporting group description

Reporting group title

Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg

Reporting group description

Reporting group title

Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg

Reporting group description

Reporting group title

Part B: Placebo + TCS

Reporting group description

Reporting group title

Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Reporting group description

Reporting group values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS	Total
Number of subjects	10	10	10	10	79	83	202
Age categorical
Units: Subjects
6 months - <2 years	0	0	10	10	5	6	31
≥2 years and <6 years	10	10	0	0	74	77	171
Gender categorical
Units: Subjects
Female	4	3	1	2	24	39	73
Male	6	7	9	8	55	44	129
Eczema Area and Severity Index (EASI)
EASI score is used to measure severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of body: head, trunk, upper and lower extremities. Total EASI score ranges from 0 (minimum) to 72 (maximum) points, with higher scores indicating worse severity of AD. Part A: Safety analysis set (SAF) included all subjects who received any study drug and were analysed based on actual treatment received. Part B: Full analysis set (FAS) included all randomised subjects and analyses were based on treatment allocated at randomisation (as randomised).
Units: Score on a Scale
arithmetic mean (standard deviation)	35.2 ± 9.21	40.2 ± 11.81	34.4 ± 14.25	36.1 ± 12.94	33.1 ± 12.18	35.1 ± 13.88	-

End points

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Reporting group title

Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg

Reporting group description

Reporting group title

Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg

Reporting group description

Reporting group title

Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg

Reporting group description

Reporting group title

Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg

Reporting group description

Reporting group title

Part B: Placebo + TCS

Reporting group description

Reporting group title

Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Reporting group description

Primary: Part A: Maximum Observed Serum Concentration (Cmax) of Functional Dupilumab

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End point title

Part A: Maximum Observed Serum Concentration (Cmax) of Functional Dupilumab ^[1] ^[2]

End point description

Serum concentration of functional dupilumab was reported. The Pharmacokinetic Analysis Set (PKAS) included all treated subjects who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

End point type

Primary

End point timeframe

Post-dose on Days 1, 3, 8, 18, and 29

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Data for this endpoint was planned to be reported for Part A arms only.
[2] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	9	10	10	10
Units: Milligrams per Liter (mg/L)
arithmetic mean (standard deviation)	25.2 ± 7.44	49.8 ± 11.3	20.1 ± 6.81	46.1 ± 11.1

No statistical analyses for this end point

Primary: Part A: Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Dupilumab

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End point title

Part A: Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Dupilumab ^[3] ^[4]

End point description

Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. PKAS included all treated subjects who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug. Cmax/dose was measured in Milligrams per Liter/Milligrams per Kilogram ([mg/L]/[mg/kg]).

End point type

Primary

End point timeframe

Post-dose on Days 1, 3, 8, 18, and 29

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Data for this endpoint was planned to be reported for Part A arms only.
[4] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	9	10	10	10
Units: [mg/L]/[mg/kg]
arithmetic mean (standard deviation)	8.39 ± 2.48	8.30 ± 1.89	6.70 ± 2.27	7.68 ± 1.86

No statistical analyses for this end point

Primary: Part A: Time to Reach the Maximum Serum Concentration (tmax) of Dupilumab

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End point title

Part A: Time to Reach the Maximum Serum Concentration (tmax) of Dupilumab ^[5] ^[6]

End point description

Tmax was obtained directly from the concentration versus time curve. PKAS included all treated subjects who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

End point type

Primary

End point timeframe

Post-dose on Days 1, 3, 8, 18, and 29

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Data for this endpoint was planned to be reported for Part A arms only.
[6] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	9	10	10	10
Units: Days
median (full range (min-max))	1.92 (1.72 to 3.02)	1.97 (1.87 to 7.82)	1.95 (1.75 to 3.08)	2.10 (1.80 to 7.99)

No statistical analyses for this end point

Primary: Part A: Last Quantifiable Serum Concentration (Clast) of Dupilumab

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End point title

Part A: Last Quantifiable Serum Concentration (Clast) of Dupilumab ^[7] ^[8]

End point description

Clast is the last measurable serum concentration of dupilumab. PKAS included all treated subjects who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

End point type

Primary

End point timeframe

Post-dose on Days 1, 3, 8, 18, and 29

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Data for this endpoint was planned to be reported for Part A arms only.
[8] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	9	10	10	10
Units: mg/L
arithmetic mean (standard deviation)	6.64 ± 6.16	6.14 ± 4.69	5.64 ± 4.52	15.1 ± 9.48

No statistical analyses for this end point

Primary: Part A: Time of the Last Quantifiable Serum Concentration (tlast) of Dupilumab

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End point title

Part A: Time of the Last Quantifiable Serum Concentration (tlast) of Dupilumab ^[9] ^[10]

End point description

Tlast was defined as the last time point with a measurable serum concentration of dupilumab. PKAS included all treated subjects who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

End point type

Primary

End point timeframe

Post-dose on Days 1, 3, 8, 18, and 29

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Data for this endpoint was planned to be reported for Part A arms only.
[10] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	9	10	10	10
Units: Days
median (full range (min-max))	14.8 (6.79 to 28.0)	26.5 (15.0 to 32.0)	8.56 (6.88 to 16.9)	16.0 (6.95 to 28.0)

No statistical analyses for this end point

Primary: Part A: Area Under the Serum Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast) of Dupilumab

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End point title

Part A: Area Under the Serum Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast) of Dupilumab ^[11] ^[12]

End point description

AUClast was defined as area under the serum concentration time-curve from zero to the last measured concentration. PKAS included all treated subjects who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

End point type

Primary

End point timeframe

Post-dose on Days 1, 3, 8, 18, and 29

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Data for this endpoint was planned to be reported for Part A arms only.
[12] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	9	10	10	10
Units: DaysMilligrams per Liter (daymg/L)
arithmetic mean (standard deviation)	198 ± 125	622 ± 184	123 ± 86.0	493 ± 294

No statistical analyses for this end point

Primary: Part A: Dose Normalized Area Under the Serum Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast/Dose) of Dupilumab

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End point title

Part A: Dose Normalized Area Under the Serum Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast/Dose) of Dupilumab ^[13] ^[14]

End point description

Dose normalized AUClast was calculated by AUClast/dose. PKAS included all treated subjects who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

End point type

Primary

End point timeframe

Post-dose on Days 1, 3, 8, 18, and 29

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was reported for this endpoint
[14] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	9	10	10	10
Units: [day*mg/L]/[mg/kg]
arithmetic mean (standard deviation)	66.0 ± 41.6	104 ± 30.6	41.0 ± 28.7	82.1 ± 48.9

No statistical analyses for this end point

Primary: Part A: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs)

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End point title

Part A: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) ^[15] ^[16]

End point description

Adverse Event (AE) was defined as any untoward medical occurrence in a subject administered a study drug which may/may not have a causal relationship with study drug. Serious AE (SAE) was defined as any untoward medical occurrence that resulted in any of following outcomes: death, life-threatening, required initial/prolonged in-participant hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect/considered as medically important event. TEAE was defined as AE starting/worsening after first intake of study drug. TEAEs included subjects with both SAEs and non-SAEs. Number of subjects with TEAEs were reported. The safety analysis set (SAF) included all subjects who received any study drug and were analysed based on the actual treatment received.

End point type

Primary

End point timeframe

Baseline up to Week 4

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was reported for this endpoint
[16] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	10	10	10	10
Units: Subjects	3	2	7	7

No statistical analyses for this end point

Primary: Part A: Number of Subjects with TEAEs by Severity According to Qualitative Toxicity Scale

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End point title

Part A: Number of Subjects with TEAEs by Severity According to Qualitative Toxicity Scale ^[17] ^[18]

End point description

Severity of TEAEs were graded using Qualitative Toxicity Scale, as follows: Mild: Subject is aware of the event or symptom, but the event or symptom is easily tolerated; Moderate: Subject experiences sufficient discomfort to interfere with or reduce his or her usual level of activity; Severe: Significant impairment of functioning: the Subject is unable to carry out his or her usual activities. Number of subjects with TEAEs by severity were reported. The SAF included all subjects who received any study drug and were analysed based on the actual treatment received.

End point type

Primary

End point timeframe

Baseline up to Week 4

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was reported for this endpoint
[18] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	10	10	10	10
Units: Subjects
Mild	1	2	4	5
Moderate	2	0	2	2
Severe	0	0	1	0

No statistical analyses for this end point

Primary: Part B: Percentage of Subjects With Investigator's Global Assessment (IGA) Score 0 or 1 at Week 16

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End point title

Part B: Percentage of Subjects With Investigator's Global Assessment (IGA) Score 0 or 1 at Week 16 ^[19]

End point description

The IGA is an assessment scale used in clinical studies to rate the severity of AD globally, based on a 5-point scale ranging from 0 to 4 where 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe. A negative change from baseline indicated improvement. Percentage of subjects with IGA score of '0' or '1' is reported. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, adverse event (AE), lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using multiple imputation (MI). Subjects were considered as non-responders after initiation of rescue treatment.

End point type

Primary

End point timeframe

Week 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Percentage of Subjects
number (confidence interval 95%)	3.9 (-0.42 to 8.21)	27.7 (18.45 to 38.62)

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Dupilumab 200 mg or 300 mg Q4W + TCS v Part B: Placebo + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[20]

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage difference

Point estimate

23.8

Confidence interval

level

95%

sides

2-sided

lower limit

13.27

upper limit

34.37

Notes
[20] - Threshold for significance at 0.05 level.

Primary: Part B: Percentage of Subjects with Eczema Area and Severity Index (EASI) -75 (EASI-75) (≥75% Improvement from Baseline) at Week 16

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End point title

Part B: Percentage of Subjects with Eczema Area and Severity Index (EASI) -75 (EASI-75) (≥75% Improvement from Baseline) at Week 16 ^[21]

End point description

The EASI score is used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper, and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores indicating the worse severity of AD. EASI-75 responders were the subjects who achieved ≥75% overall improvement in EASI score from baseline at Week 16. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Subjects were considered as non-responders after initiation of rescue treatment.

End point type

Primary

End point timeframe

Week 16

Notes
[21] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Percentage of Subjects
number (confidence interval 95%)	10.7 (3.65 to 17.74)	53.0 (41.74 to 64.07)

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[22]

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage difference

Point estimate

42.3

Confidence interval

level

95%

sides

2-sided

lower limit

29.47

upper limit

55.16

Notes
[22] - Threshold for significance at 0.05 level.

Secondary: Part A: Number of Subjects with Serious TEAEs and Severe TEAEs

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End point title

Part A: Number of Subjects with Serious TEAEs and Severe TEAEs ^[23]

End point description

Adverse Event (AE) was defined as any untoward medical occurrence in a subject administered a study drug which may/may not have a causal relationship with study drug. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Severe TEAE: significant impairment of functioning the subject is unable to carry out his or her usual activities. The SAF included all subjects who received any study drug and were analysed based on the actual treatment received.

End point type

Secondary

End point timeframe

Baseline up to Week 4

Notes
[23] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	10	10	10	10
Units: Subjects
Subjects with serious TEAEs	1	0	1	0
Subjects with severe TEAEs	0	0	1	0

No statistical analyses for this end point

Secondary: Part A: Percent Change From Baseline in EASI Score at Week 4

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End point title

Part A: Percent Change From Baseline in EASI Score at Week 4 ^[24]

End point description

End point type

Secondary

End point timeframe

Week 4

Notes
[24] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	10	10	10	10
Units: Percent Change
arithmetic mean (standard deviation)	-26.6 ± 47.37	-48.7 ± 28.89	-22.4 ± 42.52	-43.2 ± 35.55

No statistical analyses for this end point

Secondary: Part A: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 4

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End point title

Part A: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 4 ^[25]

End point description

SCORAD was used to assess the extent and severity of AD. Extent and severity of eczema as well as subjective symptoms (insomnia, etc) were assessed and scored. SCORAD total score ranges from 0 (absent disease) to 103 (severe disease). A negative change from baseline indicated improvement. SAF included all subjects who received any study drug and was analysed based on the actual treatment received.

End point type

Secondary

End point timeframe

Week 4

Notes
[25] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	10	10	10	10
Units: Percent Change
arithmetic mean (standard deviation)	-18.6 ± 26.18	-31.9 ± 17.45	-22.4 ± 26.44	-28.1 ± 27.84

No statistical analyses for this end point

Secondary: Part A: Percentage of Subjects with IGA Score 0 or 1 at Week 4

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End point title

Part A: Percentage of Subjects with IGA Score 0 or 1 at Week 4 ^[26]

End point description

The IGA is an assessment scale used in clinical studies to rate the severity of AD globally, based on a 5-point scale ranging from 0 to 4 where 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe. Percentage of subjects with IGA score of '0' or '1' were reported. SAF included all subjects who received any study drug and was analysed based on the actual treatment received.

End point type

Secondary

End point timeframe

Week 4

Notes
[26] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	10	10	10	10
Units: Percentage of Subjects
number (confidence interval 95%)	10.0 (0.25 to 44.50)	0.0 (0.00 to 30.85)	10.0 (0.25 to 44.50)	10.0 (0.25 to 44.50)

No statistical analyses for this end point

Secondary: Part A: Number of Subjects with At least One Positive Treatment-Emergent Anti-Drug Antibodies (ADA)

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End point title

Part A: Number of Subjects with At least One Positive Treatment-Emergent Anti-Drug Antibodies (ADA) ^[27]

End point description

Treatment boosted (TB) Response: Any post-dose positive result at least 9-fold over the baseline level when baseline is positive; Treatment emergent (TE) Response: Post-dose positive result when baseline results were negative. The ADA Analysis Set (AAS) included all treated subjects who received any study drug and who had at least 1 non-missing ADA result following the first dose of study drug.

End point type

Secondary

End point timeframe

Baseline up to Day 57

Notes
[27] - 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: Data for this endpoint was planned to be reported for Part A arms only.

End point values	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg
Number of subjects analysed	10	10	10	10
Units: Subjects
TB Response	0	0	1	0
TE Response	5	4	5	5

No statistical analyses for this end point

Secondary: Part B: Number of Subjects with Serious TEAEs and Skin Infection TEAEs (Excluding Herpetic Infections) Through Week 16

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End point title

Part B: Number of Subjects with Serious TEAEs and Skin Infection TEAEs (Excluding Herpetic Infections) Through Week 16 ^[28]

End point description

Adverse Event (AE) was defined as any untoward medical occurrence in a subject administered a study drug which may/may not have a causal relationship with study drug. A serious TEAE was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Skin infection TEAEs were identified based on blinded adjudication of all reported TEAEs under the 2 primary System Organ Classes (SOC): SOC = 'Infection and Infestations' or SOC = 'Skin and Subcutaneous Tissue Disorders.' SAF included all randomized subjects who received at least one dose of study drug and was analysed as treated.

End point type

Secondary

End point timeframe

Baseline through Week 16

Notes
[28] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	78	83
Units: Subjects
Subjects with serious TEAEs	4	0
Subjects with skin infection TEAEs	19	10

No statistical analyses for this end point

Secondary: Part B: Number of Subjects with At least One Positive Treatment-Emergent ADA

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End point title

Part B: Number of Subjects with At least One Positive Treatment-Emergent ADA ^[29]

End point description

Treatment emergent (TE): Post-dose positive result when baseline results were negative. AAS included all subjects who received any study drug and who had at least one non-missing ADA result after the first dose of the study drug.

End point type

Secondary

End point timeframe

Baseline up to Day 197

Notes
[29] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	69	74
Units: Subjects	0	1

No statistical analyses for this end point

Secondary: Part B: Percent Change From Baseline in EASI Score at Week 16

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End point title

Part B: Percent Change From Baseline in EASI Score at Week 16 ^[30]

End point description

The EASI score is used to measure the severity and extent of AD and measures erythema, infiltration, excoriation, and lichenification on 4 anatomic regions of the body: head, trunk, upper, and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores indicating the worse severity of AD. A negative change from baseline indicated improvement. FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline worst observation carried forward (WOCF). If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[30] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Percent Change
least squares mean (standard error)	-19.6 ± 5.13	-70.0 ± 4.85

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[31]

Method

ANCOVA

Parameter type

Least Square (LS) Mean Difference

Point estimate

-50.4

Confidence interval

level

95%

sides

2-sided

lower limit

-62.38

upper limit

-38.4

Notes
[31] - Threshold for significance at 0.05 level.

Secondary: Part B: Percent Change From Baseline in Weekly Average of Daily Worst Scratch/Itch/Numerical Rating Scale (NRS) at Week 16

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End point title

Part B: Percent Change From Baseline in Weekly Average of Daily Worst Scratch/Itch/Numerical Rating Scale (NRS) at Week 16 ^[32]

End point description

Pruritus NRS is an assessment tool used to report intensity of subject’s pruritus (itch), both average & maximum intensity, during 24-hr recall period. Subjects were asked two questions: 1) For average itch intensity: how would you rate your itch overall (on average) during the previous 24 hrs; 2) For maximum itch intensity: How would you rate your itch at the worst moment during the previous 24 hrs? Both questions were rated on a scale: 0-10 with 0=no itch & 10=worst itch imaginable. A negative change from baseline indicated improvement. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[32] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Percent Change
least squares mean (standard error)	-2.2 ± 5.22	-49.4 ± 5.03

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[33]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-47.1

Confidence interval

level

95%

sides

2-sided

lower limit

-59.47

upper limit

-34.79

Notes
[33] - Threshold for significance at 0.05 level.

Secondary: Part B: Percentage of Subjects with Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥4 Points at Week 16

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End point title

Part B: Percentage of Subjects with Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥4 Points at Week 16 ^[34]

End point description

Pruritus NRS is an assessment tool used to report intensity of subject’s pruritus (itch), both average & maximum intensity, during 24-hr recall period. Subjects were asked two questions: 1) For average itch intensity: how would you rate your itch overall (on average) during the previous 24 hrs; & 2) For maximum itch intensity: How would you rate your itch at the worst moment during the previous 24 hrs? Both questions were rated on a scale: 0-10 with 0=no itch & 10=worst itch imaginable. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Subjects were considered as non-responders after initiation of rescue treatment.

End point type

Secondary

End point timeframe

Week 16

Notes
[34] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	78	83
Units: Percentage of Subjects
number (confidence interval 95%)	8.9 (2.25 to 15.51)	48.1 (37.05 to 59.15)

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[35]

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage difference

Point estimate

39.2

Confidence interval

level

95%

sides

2-sided

lower limit

26.18

upper limit

52.27

Notes
[35] - Threshold for significance at 0.05 level.

Secondary: Part B: Percentage of Subjects with Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥3 Points at Week 16

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End point title

Part B: Percentage of Subjects with Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥3 Points at Week 16 ^[36]

End point description

Pruritus NRS is an assessment tool used to report intensity of subject’s pruritus (itch), both average & maximum intensity, during 24-hr recall period. Subjects were asked two questions: 1) For average itch intensity: how would you rate your itch overall (on average) during the previous 24 hrs; & 2) For maximum itch intensity: How would you rate your itch at the worst moment during the previous 24 hrs? Both questions were rated on a scale: 0-10 with 0=no itch & 10=worst itch imaginable. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Subjects were considered as non-responders after initiation of rescue treatment.

End point type

Secondary

End point timeframe

Week 16

Notes
[36] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	78	83
Units: Percentage of Subjects
number (confidence interval 95%)	9.9 (2.59 to 17.22)	53.3 (42.29 to 64.22)

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[37]

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage difference

Point estimate

43.3

Confidence interval

level

95%

sides

2-sided

lower limit

30.03

upper limit

56.67

Notes
[37] - Threshold for significance at 0.05 level.

Secondary: Part B: Percentage of Subjects Who Achieved EASI-50 (≥50% Improvement From Baseline) at Week 16

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End point title

Part B: Percentage of Subjects Who Achieved EASI-50 (≥50% Improvement From Baseline) at Week 16 ^[38]

End point description

The EASI score is used to measure the severity and extent of AD and measured erythema, infiltration, excoriation, and lichenification on 4 anatomic regions of the body: head, trunk, upper, and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores indicating the worse severity of AD. EASI-50 responders were the subjects who achieved ≥50% overall improvement in EASI score from baseline at Week 16. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Subjects were considered as non-responders after initiation of rescue treatment.

End point type

Secondary

End point timeframe

Week 16

Notes
[38] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Percentage of Subjects
number (confidence interval 95%)	20.2 (11.09 to 29.23)	68.7 (57.56 to 78.41)

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Dupilumab 200 mg or 300 mg Q4W + TCS v Part B: Placebo + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[39]

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage difference

Point estimate

48.5

Confidence interval

level

95%

sides

2-sided

lower limit

35.03

upper limit

Notes
[39] - Threshold for significance at 0.05 level.

Secondary: Part B: Percentage of Subjects Who Achieved EASI-90 (≥90% Improvement From Baseline) at Week 16

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End point title

Part B: Percentage of Subjects Who Achieved EASI-90 (≥90% Improvement From Baseline) at Week 16 ^[40]

End point description

The EASI score is used to measure the severity and extent of AD and measured erythema, infiltration, excoriation, and lichenification on 4 anatomic regions of the body: head, trunk, upper, and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores indicating the worse severity of AD. EASI-90 responders were the subjects who achieved ≥90% overall improvement in EASI score from baseline at Week 16. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Subjects were considered as non-responders after initiation of rescue treatment.

End point type

Secondary

End point timeframe

Week 16

Notes
[40] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Percentage of Subjects
number (confidence interval 95%)	2.8 (-1.02 to 6.66)	25.3 (16.39 to 36.04)

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[41]

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage difference

Point estimate

22.5

Confidence interval

level

95%

sides

2-sided

lower limit

12.37

upper limit

32.6

Notes
[41] - Threshold for significance at 0.05 level.

Secondary: Part B: Change From Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis (AD) at Week 16

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End point title

Part B: Change From Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis (AD) at Week 16 ^[42]

End point description

BSA affected by AD was assessed for each section of the body (the possible highest score for each region was: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]). It was reported as a percentage of all major body sections combined. A negative change from baseline indicated improvement. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[42] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Percent of BSA
least squares mean (standard error)	-10.74 ± 2.926	-35.00 ± 2.815

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Dupilumab 200 mg or 300 mg Q4W + TCS v Part B: Placebo + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[43]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-24.27

Confidence interval

level

95%

sides

2-sided

lower limit

-31.204

upper limit

-17.329

Notes
[43] - Threshold for significance at 0.05 level.

Secondary: Part B: Change From Baseline in Patient Oriented Eczema Measure (POEM) at Week 16

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End point title

Part B: Change From Baseline in Patient Oriented Eczema Measure (POEM) at Week 16 ^[44]

End point description

The POEM is a 7-item questionnaire that assesses disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding and weeping) with a scoring system of 0 (absent disease) to 28 (severe disease) (high score indicative of poor quality of life [QOL]). A negative change from baseline indicated improvement. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[44] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Score on a Scale
least squares mean (standard error)	-3.8 ± 0.92	-12.9 ± 0.89

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[45]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-9.1

Confidence interval

level

95%

sides

2-sided

lower limit

-11.26

upper limit

-6.89

Notes
[45] - Threshold for significance at 0.05 level.

Secondary: Part B: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) at Week 16

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End point title

Part B: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) at Week 16 ^[46]

End point description

The SCORAD index is a clinical tool for assessing the severity of atopic dermatitis (AD). Extent and intensity of eczema as well as subjective signs (insomnia, etc.) are assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). A negative change from baseline indicated improvement. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[46] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Percent Change
least squares mean (standard error)	-16.2 ± 3.54	-54.7 ± 3.39

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[47]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-38.4

Confidence interval

level

95%

sides

2-sided

lower limit

-46.65

upper limit

-30.21

Notes
[47] - Threshold for significance at 0.05 level.

Secondary: Part B: Change from Baseline in Subject’s Sleep Quality NRS at Week 16

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End point title

Part B: Change from Baseline in Subject’s Sleep Quality NRS at Week 16 ^[48]

End point description

A sleep diary was completed by the parent/caregiver, included 2 questions assessing the caregiver’s sleep, and 6 questions assessing the child’s sleep based on caregiver observation. Sleep diary items, either alone or in combination served as subjective measures of sleep quality, difficulty falling asleep, nighttime awakenings, and sleep duration. Sleep quality was measured using an 11-point NRS (0 to 10) in which 0 indicated worst possible sleep while 10 indicated best possible sleep. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[48] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Score on a Scale
least squares mean (standard error)	0.34 ± 0.256	2.04 ± 0.251

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[49]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

1.093

upper limit

2.317

Notes
[49] - Threshold significance was at 0.05 level.

Secondary: Part B: Change from Baseline in Subject’s Skin Pain NRS at Week 16

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End point title

Part B: Change from Baseline in Subject’s Skin Pain NRS at Week 16 ^[50]

End point description

Skin pain was assessed by the parent/caregiver and measured using a 11-point scale (0 to 10) in which 0 indicated no pain while 10 indicated worst pain possible. A negative change from baseline indicated improvement. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[50] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Score on a Scale
least squares mean (standard error)	-0.62 ± 0.302	-3.93 ± 0.295

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[51]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-3.31

Confidence interval

level

95%

sides

2-sided

lower limit

-4.029

upper limit

-2.6

Notes
[51] - Threshold significance at 0.05 level.

Secondary: Part B: Change From Baseline in Dermatitis Family Index (DFI) at Week 16

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End point title

Part B: Change From Baseline in Dermatitis Family Index (DFI) at Week 16 ^[52]

End point description

DFI is a 10-item questionnaire with items inquiring about housework, food preparation, sleep, family leisure activity, shopping, expenditure, tiredness, emotional distress, relationships, and impact of helping with treatment on the primary caregiver's life. DFI questions were scored on a four-point Likert scale ranging from 0 to 3, so that the total DFI score ranges from 0 to 30. Timeframe of reference was the past week. A higher DFI score indicated greater impairment in family Quality of life (QOL) as affected by atopic dermatitis. A negative change from baseline indicated improvement. FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[52] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	79	83
Units: Score on a Scale
least squares mean (standard error)	-2.68 ± 0.839	-10.48 ± 0.806

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[53]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-7.8

Confidence interval

level

95%

sides

2-sided

lower limit

-9.789

upper limit

-5.814

Notes
[53] - Threshold significance at 0.05 level.

Secondary: Part B: Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) at Week 16

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End point title

Part B: Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) at Week 16 ^[54]

End point description

CDLQI is a validated 10 question tool to measure impact of skin disease on QOL in children by assessing how much the skin problem has affected the subjects over past week. Nine questions were scored as follows: Very much = 3, Quite a lot = 2, Only a little = 1, Not at all or unanswered = 0. Question 7 has an added possible response, which was scored as 3. CDLQI equals the sum of the score of each question (max. = 30, min. = 0). Higher the score, the greater the impact on QOL. A negative change from baseline indicated improvement. FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Subjects ≥4 years of age were evaluated for this endpoint. Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[54] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	38	47
Units: Score on a Scale
least squares mean (standard error)	-2.5 ± 1.66	-10.0 ± 1.56

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[55]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-7.5

Confidence interval

level

95%

sides

2-sided

lower limit

-10.29

upper limit

-4.75

Notes
[55] - Threshold significance at 0.05 level.

Secondary: Part B: Change from Baseline in Infants' Dermatology Quality of Life Index (IDQOL) at Week 16

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End point title

Part B: Change from Baseline in Infants' Dermatology Quality of Life Index (IDQOL) at Week 16 ^[56]

End point description

Infants' Dermatitis Quality of Life Index (IDQOL) were used to evaluate quality of life for subjects of age less than 4 years. IDQOL questionnaires were designed for infants (below the age of 4 years) with atopic dermatitis. The IDQOL was calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score in each questionnaire, the more quality of life is impaired. A negative change from baseline indicated improvement. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

End point type

Secondary

End point timeframe

Week 16

Notes
[56] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	41	36
Units: Score on a Scale
least squares mean (standard error)	-1.95 ± 1.078	-10.91 ± 1.159

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[57]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-8.96

Confidence interval

level

95%

sides

2-sided

lower limit

-11.711

upper limit

-6.202

Notes
[57] - Threshold significance at 0.05 level.

Secondary: Part B: Percentage of Topical Corticosteroid (TCS) Medication-free Days From Baseline to Week 16

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End point title

Part B: Percentage of Topical Corticosteroid (TCS) Medication-free Days From Baseline to Week 16 ^[58]

End point description

Percentage of TCS medication-free days was calculated as the number of days that a subject used neither TCS/TCI nor system rescue therapy divided by the study days. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised).

End point type

Secondary

End point timeframe

Baseline up to Week 16

Notes
[58] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	77	82
Units: Percentage of Days
median (full range (min-max))	0.04 (0.0 to 0.9)	0.21 (0.0 to 1.0)

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

159

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0015 ^[59]

Method

ANCOVA

Confidence interval

Notes
[59] - Threshold significance is at 0.05 level.

Secondary: Part B: Mean Weekly Dose of Low Potency TCS in Grams From Baseline to Week 16

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End point title

Part B: Mean Weekly Dose of Low Potency TCS in Grams From Baseline to Week 16 ^[60]

End point description

Mean weekly dose of TCS in grams/week for low potency TCS from baseline to Week 16 were reported. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised).

End point type

Secondary

End point timeframe

Baseline up to Week 16

Notes
[60] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	78	81
Units: Grams per Week
least squares mean (standard error)	13.4 ± 1.44	10.5 ± 1.39

Placebo + TCS vs Dupilumab 200/300 mg Q4W

Comparison groups

Part B: Placebo + TCS v Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Number of subjects included in analysis

159

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0997 ^[61]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-6.35

upper limit

0.56

Notes
[61] - Threshold significance at 0.05 level.

Secondary: Part B: Mean Weekly Dose of TCS in Grams for Medium or High Potency TCS From Baseline to Week 16

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End point title

Part B: Mean Weekly Dose of TCS in Grams for Medium or High Potency TCS From Baseline to Week 16 ^[62]

End point description

Mean weekly dose of TCS in grams/week for medium or high potency TCS from baseline to Week 16 were reported. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised).

End point type

Secondary

End point timeframe

Baseline up to Week 16

Notes
[62] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	43	24
Units: Grams per Week
least squares mean (standard error)	6.1 ± 1.70	3.0 ± 1.54

No statistical analyses for this end point

Secondary: Part B: Mean of Caregiver Missed Work Days Through Week 16

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End point title

Part B: Mean of Caregiver Missed Work Days Through Week 16 ^[63]

End point description

Mean of caregiver missed work days through Week 16 was reported. The FAS included all randomised subjects. Efficacy analyses were based on the treatment allocated at randomisation (as randomised).

End point type

Secondary

End point timeframe

Baseline through Week 16

Notes
[63] - 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: Data for this endpoint was planned to be reported for Part B arms only.

End point values	Part B: Placebo + TCS	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS
Number of subjects analysed	57	57
Units: Days
arithmetic mean (standard deviation)	5.05 ± 8.975	2.49 ± 5.524

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From day of first treatment until the end of study

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1, 23.1

Reporting group title

Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg

Reporting group description

Reporting group title

Part B: Dupilumab 200 mg or 300 mg Q4W + TCS

Reporting group description

Reporting group title

Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg

Reporting group description

Reporting group title

Part B: Placebo + TCS

Reporting group description

Reporting group title

Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg

Reporting group description

Reporting group title

Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg

Reporting group description

Serious adverse events	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg	Part B: Placebo + TCS	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 10 (10.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	4 / 78 (5.13%)	0 / 10 (0.00%)	1 / 10 (10.00%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 10 (10.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	0 / 78 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 1	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
Hypersensitivity
subjects affected / exposed	0 / 10 (0.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	1 / 78 (1.28%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	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
Skin and subcutaneous tissue disorders
Dermatitis atopic
subjects affected / exposed	0 / 10 (0.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	1 / 78 (1.28%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Cellulitis staphylococcal
subjects affected / exposed	0 / 10 (0.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	1 / 78 (1.28%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	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
Dermatitis infected
subjects affected / exposed	0 / 10 (0.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	1 / 78 (1.28%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	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
Staphylococcal bacteraemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	1 / 78 (1.28%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 3 mg/kg	Part B: Dupilumab 200 mg or 300 mg Q4W + TCS	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 6 mg/kg	Part B: Placebo + TCS	Part A: Cohort 1 (≥2 to <6 years old): Dupilumab 6 mg/kg	Part A: Cohort 2 (≥6 months to <2 years): Dupilumab 3 mg/kg
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 10 (70.00%)	29 / 83 (34.94%)	2 / 10 (20.00%)	45 / 78 (57.69%)	7 / 10 (70.00%)	3 / 10 (30.00%)
Injury, poisoning and procedural complications
Skin abrasion
subjects affected / exposed	0 / 10 (0.00%)	0 / 83 (0.00%)	1 / 10 (10.00%)	0 / 78 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 10 (0.00%)	3 / 83 (3.61%)	0 / 10 (0.00%)	6 / 78 (7.69%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	3	0	9	0	0
Thrombocytosis
subjects affected / exposed	0 / 10 (0.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	0 / 78 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	0 / 10 (0.00%)	1 / 83 (1.20%)	0 / 10 (0.00%)	0 / 78 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	1	0
Pyrexia
subjects affected / exposed	2 / 10 (20.00%)	1 / 83 (1.20%)	0 / 10 (0.00%)	7 / 78 (8.97%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	2	1	0	9	0	1
Eye disorders
Lacrimation increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	0 / 78 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 10 (10.00%)	2 / 83 (2.41%)	0 / 10 (0.00%)	0 / 78 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	3	0	0	0	0
Diarrhoea
subjects affected / exposed	1 / 10 (10.00%)	1 / 83 (1.20%)	0 / 10 (0.00%)	2 / 78 (2.56%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	2	1	0
Teething
subjects affected / exposed	1 / 10 (10.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	0 / 78 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 10 (0.00%)	3 / 83 (3.61%)	0 / 10 (0.00%)	5 / 78 (6.41%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	3	0	8	0	0
Cough
subjects affected / exposed	1 / 10 (10.00%)	0 / 83 (0.00%)	1 / 10 (10.00%)	5 / 78 (6.41%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	0	1	6	1	0
Skin and subcutaneous tissue disorders
Dermatitis atopic
subjects affected / exposed	0 / 10 (0.00%)	12 / 83 (14.46%)	0 / 10 (0.00%)	24 / 78 (30.77%)	1 / 10 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	17	0	46	1	1
Urticaria
subjects affected / exposed	1 / 10 (10.00%)	1 / 83 (1.20%)	0 / 10 (0.00%)	4 / 78 (5.13%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	4	1	0
Musculoskeletal and connective tissue disorders
Joint swelling
subjects affected / exposed	1 / 10 (10.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	0 / 78 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	1 / 10 (10.00%)	7 / 83 (8.43%)	1 / 10 (10.00%)	7 / 78 (8.97%)	2 / 10 (20.00%)	1 / 10 (10.00%)
occurrences all number	1	8	1	8	2	1
Upper respiratory tract infection
subjects affected / exposed	1 / 10 (10.00%)	5 / 83 (6.02%)	0 / 10 (0.00%)	7 / 78 (8.97%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	5	0	9	1	0
Impetigo
subjects affected / exposed	1 / 10 (10.00%)	3 / 83 (3.61%)	0 / 10 (0.00%)	6 / 78 (7.69%)	1 / 10 (10.00%)	1 / 10 (10.00%)
occurrences all number	1	3	0	7	1	1
Folliculitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 83 (0.00%)	0 / 10 (0.00%)	0 / 78 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

05 Jul 2017

The purpose of amendment 2 was to harmonize the protocol across regions and to simplify regulatory submissions.

22 Nov 2019

The purpose of amendment 3 was to seek approval of the dose regimens for part B of the study.

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.

None reported

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Clinical trials

Clinical Trial Results: A Phase 2/3 Study Investigating the Pharmacokinetics, Safety, and Efficacy of Dupilumab in Patients Aged ≥ 6 Months to < 6 Years with Moderate-to-Severe Atopic Dermatitis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A: Maximum Observed Serum Concentration (Cmax) of Functional Dupilumab

Primary: Part A: Maximum Observed Serum Concentration (Cmax) of Functional Dupilumab

Primary: Part A: Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Dupilumab

Primary: Part A: Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Dupilumab

Primary: Part A: Time to Reach the Maximum Serum Concentration (tmax) of Dupilumab

Primary: Part A: Time to Reach the Maximum Serum Concentration (tmax) of Dupilumab

Primary: Part A: Last Quantifiable Serum Concentration (Clast) of Dupilumab

Primary: Part A: Last Quantifiable Serum Concentration (Clast) of Dupilumab

Primary: Part A: Time of the Last Quantifiable Serum Concentration (tlast) of Dupilumab

Primary: Part A: Time of the Last Quantifiable Serum Concentration (tlast) of Dupilumab

Primary: Part A: Area Under the Serum Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast) of Dupilumab

Primary: Part A: Area Under the Serum Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast) of Dupilumab

Primary: Part A: Dose Normalized Area Under the Serum Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast/Dose) of Dupilumab

Primary: Part A: Dose Normalized Area Under the Serum Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast/Dose) of Dupilumab

Primary: Part A: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs)

Primary: Part A: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs)

Primary: Part A: Number of Subjects with TEAEs by Severity According to Qualitative Toxicity Scale

Primary: Part A: Number of Subjects with TEAEs by Severity According to Qualitative Toxicity Scale

Primary: Part B: Percentage of Subjects With Investigator's Global Assessment (IGA) Score 0 or 1 at Week 16

Primary: Part B: Percentage of Subjects With Investigator's Global Assessment (IGA) Score 0 or 1 at Week 16

Primary: Part B: Percentage of Subjects with Eczema Area and Severity Index (EASI) -75 (EASI-75) (≥75% Improvement from Baseline) at Week 16

Primary: Part B: Percentage of Subjects with Eczema Area and Severity Index (EASI) -75 (EASI-75) (≥75% Improvement from Baseline) at Week 16

Secondary: Part A: Number of Subjects with Serious TEAEs and Severe TEAEs

Secondary: Part A: Number of Subjects with Serious TEAEs and Severe TEAEs

Secondary: Part A: Percent Change From Baseline in EASI Score at Week 4

Secondary: Part A: Percent Change From Baseline in EASI Score at Week 4

Secondary: Part A: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 4

Secondary: Part A: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 4

Secondary: Part A: Percentage of Subjects with IGA Score 0 or 1 at Week 4

Secondary: Part A: Percentage of Subjects with IGA Score 0 or 1 at Week 4

Secondary: Part A: Number of Subjects with At least One Positive Treatment-Emergent Anti-Drug Antibodies (ADA)

Secondary: Part A: Number of Subjects with At least One Positive Treatment-Emergent Anti-Drug Antibodies (ADA)

Secondary: Part B: Number of Subjects with Serious TEAEs and Skin Infection TEAEs (Excluding Herpetic Infections) Through Week 16

Secondary: Part B: Number of Subjects with Serious TEAEs and Skin Infection TEAEs (Excluding Herpetic Infections) Through Week 16

Secondary: Part B: Number of Subjects with At least One Positive Treatment-Emergent ADA

Secondary: Part B: Number of Subjects with At least One Positive Treatment-Emergent ADA

Secondary: Part B: Percent Change From Baseline in EASI Score at Week 16

Secondary: Part B: Percent Change From Baseline in EASI Score at Week 16

Secondary: Part B: Percent Change From Baseline in Weekly Average of Daily Worst Scratch/Itch/Numerical Rating Scale (NRS) at Week 16

Secondary: Part B: Percent Change From Baseline in Weekly Average of Daily Worst Scratch/Itch/Numerical Rating Scale (NRS) at Week 16

Secondary: Part B: Percentage of Subjects with Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥4 Points at Week 16

Secondary: Part B: Percentage of Subjects with Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥4 Points at Week 16

Secondary: Part B: Percentage of Subjects with Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥3 Points at Week 16

Secondary: Part B: Percentage of Subjects with Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥3 Points at Week 16

Secondary: Part B: Percentage of Subjects Who Achieved EASI-50 (≥50% Improvement From Baseline) at Week 16

Secondary: Part B: Percentage of Subjects Who Achieved EASI-50 (≥50% Improvement From Baseline) at Week 16

Secondary: Part B: Percentage of Subjects Who Achieved EASI-90 (≥90% Improvement From Baseline) at Week 16

Secondary: Part B: Percentage of Subjects Who Achieved EASI-90 (≥90% Improvement From Baseline) at Week 16

Secondary: Part B: Change From Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis (AD) at Week 16

Secondary: Part B: Change From Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis (AD) at Week 16

Secondary: Part B: Change From Baseline in Patient Oriented Eczema Measure (POEM) at Week 16

Secondary: Part B: Change From Baseline in Patient Oriented Eczema Measure (POEM) at Week 16

Secondary: Part B: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) at Week 16

Secondary: Part B: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) at Week 16

Secondary: Part B: Change from Baseline in Subject’s Sleep Quality NRS at Week 16

Secondary: Part B: Change from Baseline in Subject’s Sleep Quality NRS at Week 16

Secondary: Part B: Change from Baseline in Subject’s Skin Pain NRS at Week 16

Secondary: Part B: Change from Baseline in Subject’s Skin Pain NRS at Week 16

Secondary: Part B: Change From Baseline in Dermatitis Family Index (DFI) at Week 16

Secondary: Part B: Change From Baseline in Dermatitis Family Index (DFI) at Week 16

Secondary: Part B: Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) at Week 16

Secondary: Part B: Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) at Week 16

Secondary: Part B: Change from Baseline in Infants' Dermatology Quality of Life Index (IDQOL) at Week 16

Secondary: Part B: Change from Baseline in Infants' Dermatology Quality of Life Index (IDQOL) at Week 16

Secondary: Part B: Percentage of Topical Corticosteroid (TCS) Medication-free Days From Baseline to Week 16

Secondary: Part B: Percentage of Topical Corticosteroid (TCS) Medication-free Days From Baseline to Week 16

Secondary: Part B: Mean Weekly Dose of Low Potency TCS in Grams From Baseline to Week 16

Secondary: Part B: Mean Weekly Dose of Low Potency TCS in Grams From Baseline to Week 16

Secondary: Part B: Mean Weekly Dose of TCS in Grams for Medium or High Potency TCS From Baseline to Week 16

Secondary: Part B: Mean Weekly Dose of TCS in Grams for Medium or High Potency TCS From Baseline to Week 16

Clinical Trial Results:
A Phase 2/3 Study Investigating the Pharmacokinetics, Safety, and Efficacy of Dupilumab in Patients Aged ≥ 6 Months to < 6 Years with Moderate-to-Severe Atopic Dermatitis