Study of Dupilumab and Immune Responses in Adults With Atopic Dermatitis (AD)

• Sponsor: Regeneron Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02210780
• Collaborator: Sanofi (Industry)
• Enrollment: 194
• Locations: 42
• Arms: 2
• Actual Duration (Months): 13.3
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This was a 32-week, randomized, double-blind, placebo-controlled, parallel-group study assessing immunization responses to vaccination in adults with moderate to severe atopic dermatitis who are treated with subcutaneous dupilumab.

Condition or Disease	Intervention/Treatment	Phase
Atopic Dermatitis	Drug: Dupilumab; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 194 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Study Investigating Vaccine Responses in Adults With Moderate to Severe Atopic Dermatitis Treated With Dupilumab
• Actual Study Start Date: Aug 5, 2014
• Actual Primary Completion Date: Sep 15, 2015
• Actual Study Completion Date: Sep 15, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo qw Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Drug: Placebo; An inactive substance containing no medicine administered via subcutaneous injection.
Experimental: Dupilumab 300 mg qw Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.	Drug: Dupilumab; Administered via subcutaneous injection.; Other Names: REGN668 SAR231893 Dupixent

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a Positive Response (≥4-Fold Increase) to Tetanus Toxoid (the Adacel [Tdap] Vaccine) at Week 16 [Week 16]

   A positive response was defined as a ≥ 4-fold increase from pre-vaccination at baseline in anti-tetanus immunoglobulin G (IgG) titer for participants with a pre-vaccination tetanus antibody titers ≥ 0.1 IU/ml or a titer of ≥ 0.2 IU/ml for participants with pre-vaccination titers of <0.1 IU/ml. There was no planned statistical hypothesis testing regarding the difference in immune response between the 2 treatment groups for this study, therefore no formal statistical hypothesis between groups was performed.

Secondary Outcome Measures

1. Percentage of Participants With a Positive Response (≥2-Fold Increase) to Tetanus Toxoid (the Adacel [Tdap] Vaccine) at Week 16 [Week 16]

   Participants with positive response defined as a ≥2-fold increase from pre-vaccination baseline in anti-tetanus IgG titer for participants with pre-vaccination tetanus antibody titers ≥0.1 IU/ml or a titer of ≥0.2 IU/ml for participants with pre-vaccination titers of <0.1 IU/ml.

2. Percentage of Participants With a Positive Response (SBA Antibody Titer of ≥8 for Serogroup C) to Menomune Vaccine at Week 16 [Week 16]

   A positive response to the Menomune vaccine was a serum bactericidal antibody (SBA) titer of ≥8 for serogroup C.

3. Percentage of Participants Achieving an Investigator's Global Assessment (IGA) Score of "0" or "1" at Week 16 [Week 16]

   IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear). Values after first rescue treatment were set to missing and participants with missing IGA scores at Week 16 were counted as non-responders.

4. Percentage of Participants Achieving an Eczema Area and Severity Index-50 (EASI-50) (≥50% Improvement From Baseline) at Week 16 [Week 16]

   The EASI score was used to measure the severity and extent of atopic dermatitis (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 reflecting the worse severity of AD. EASI-50 responders were the participants who achieved ≥50% overall improvement in EASI score from baseline to Week 16. Values after first rescue treatment were set to missing and participants with missing EASI score at Week 16 were counted as non-responders.

5. Percentage of Participants Achieving an Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 16 [Week 16]

   The EASI score was used to measure the severity and extent of atopic dermatitis (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 reflecting the worse severity of AD. EASI-75 responders were the participants who achieved ≥75% overall improvement in EASI score from baseline to Week 16. Values after first rescue treatment use were set to missing and participants with missing EASI score at Week 16 were considered as non-responders.

6. Change From Baseline in Peak Weekly Averaged Pruritis Numerical Rating Scale (NRS) Scores at Week 16 [Baseline to Week 16]

   Pruritus NRS was an assessment tool that was used to report the intensity of participant's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Participants were asked the following question: how would a participant rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Weekly average obtained in the 7-day period prior to the baseline visit. Values after first rescue medication use were set to missing and missing values were imputed by Last observation carried forward (LOCF).

7. Change From Baseline in Body Surface Area (BSA) Affected by AD at Week 16 [Baseline to Week 16]

   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. Values after first rescue medication use were set to missing and missing values were imputed by LOCF.

8. Change From Baseline in Global Individual Signs Score (GISS) Components (Erythema, Infiltration/Papulation, Excoriations and Lichenification) at Week 16 [Baseline to Week 16]

   Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0 = none, 1 = mild, 2 = moderate and 3 = severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease). Values after first rescue treatment were set to missing. Analysis was completed using MMRM model which includes treatment, randomization strata, visit, baseline value, treatment-by-visit interaction, and baseline-by-visit interaction as covariates. These results are observed results without imputation.

9. Changes From Baseline in GISS Cumulative Score to Week 16 [Baseline to Week 16]

   Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0 = none, 1 = mild, 2 = moderate and 3 = severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease). Values after first rescue medication use were set to missing and missing values were imputed by LOCF.

10. Change in Patient Oriented Eczema Measure (POEM) Score From Baseline to Week 16 [Baseline to Week 16]

    The POEM was 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]). Values after first rescue medication use were set to missing and missing values were imputed by LOCF.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Male or female adults ages 18 to 64 years with Chronic AD (according to the American Academy of Dermatology Consensus Criteria, [Eichenfeld 2004])that has been present for at least 3 years before the screening visit

2. Participants with documented recent history (within 6 months before the screening visit) of inadequate response to a sufficient course of outpatient treatment with topical AD medication(s), or for whom topical AD therapies are otherwise inadvisable (e.g., because of side effects or safety risks).

3. Eczema Area and Severity Index (EASI) score ≥16 at the screening visit and the baseline visit

4. Investigator's Global Assessment (IGA) score ≥3 (on the 0-4 IGA scale) at the screening and baseline visits

5. ≥10% body surface area (BSA) of AD involvement at the screening and baseline visits

Key Exclusion Criteria:

1. Prior treatment with dupilumab (REGN668/ SAR231893)

2. Patients needing >10 mg of daily prednisone (including equivalent doses of other steroids) or high dose systemic corticosteroids (≥2 mg/kg) for 14 days or longer during the 16 week treatment period of the study

3. History of Guillain-Barre syndrome

4. History of severe allergic reaction to either vaccine or to vaccine components including alum, thimerosal, phenol

5. Patients with a severe reaction to natural rubber latex products (some packaging components of the vaccines contain rubber latex and may cause a reaction in susceptible individuals)

6. Treatment with biologics within 4 months of baseline visit

7. Chronic or acute infection requiring treatment with antibiotics, antivirals, antiparasitics, antifungals within 4 weeks before screening visit or superficial skin infections within 1 week of screening visit

The information listed above is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial and not all inclusion/ exclusion criteria are listed.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Fort Smith	Arkansas	United States
3		Long Beach	California	United States
4		Los Angeles	California	United States
5		Mission Viejo	California	United States
6		Rolling Hills Estates	California	United States
7		San Diego	California	United States
8		Santa Monica	California	United States
9		Denver	Colorado	United States
10		Jacksonville	Florida	United States
11		Miami	Florida	United States
12		Tampa	Florida	United States
13		Macon	Georgia	United States
14		Chicago	Illinois	United States
15		Maywood	Illinois	United States
16		West Dundee	Illinois	United States
17		Indianapolis	Indiana	United States
18		Plainfield	Indiana	United States
19		Overland Park	Kansas	United States
20		Boston	Massachusetts	United States
21		Ann Arbor	Michigan	United States
22		Troy	Michigan	United States
23		Saint Louis	Missouri	United States
24		Hackensack	New Jersey	United States
25		Albuquerque	New Mexico	United States
26		Buffalo	New York	United States
27		Forest Hills	New York	United States
28		New York	New York	United States
29		Cleveland	Ohio	United States
30		Norman	Oklahoma	United States
31		Tulsa	Oklahoma	United States
32		Medford	Oregon	United States
33		Portland	Oregon	United States
34		Pittsburgh	Pennsylvania	United States
35		Charleston	South Carolina	United States
36		Greer	South Carolina	United States
37		Arlington	Texas	United States
38		Austin	Texas	United States
39		Houston	Texas	United States
40		Webster	Texas	United States
41		Richmond	Virginia	United States
42		Seattle	Washington	United States

Sponsors and Collaborators

• Regeneron Pharmaceuticals
• Sanofi

Investigators

• Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Regeneron Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02210780
• Other Study ID Numbers: R668-AD-1314
• First Posted: Aug 7, 2014
• Last Update Posted: May 7, 2020
• Last Verified: Apr 1, 2020

• Additional relevant MeSH terms: Dermatitis, Atopic; Dermatitis; Eczema

Study Results

Participant Flow

Recruitment Details	The study was conducted at approximately 50 study sites in United States (US) between 05 August 2014 and 15 September 2015. A total of 243 participants were screened in the study.
Pre-assignment Detail	Out of 243 participants, 194 were randomized and treated in the study. Participants were randomized in 1:1 ratio to receive 600 mg subcutaneous (SC) dupilumab loading dose on day 1 and then dupilumab 300 mg once weekly (qw) or placebo qw.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Period Title: Overall Study
STARTED	97	97
COMPLETED	92	89
NOT COMPLETED	5	8

Baseline Characteristics

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw	Total
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.	Total of all reporting groups
Overall Participants	97	97	194
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.9 (14.04)	39.2 (13.55)	39.6 (13.77)
Sex: Female, Male (Count of Participants)
Female	51 52.6%	48 49.5%	99 51%
Male	46 47.4%	49 50.5%	95 49%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	13 13.4%	15 15.5%	28 14.4%
Not Hispanic or Latino	84 86.6%	81 83.5%	165 85.1%
Unknown or Not Reported	0 0%	1 1%	1 0.5%
Race/Ethnicity, Customized (Count of Participants)
White	67 69.1%	60 61.9%	127 65.5%
Black or African American	17 17.5%	23 23.7%	40 20.6%
Asian	11 11.3%	12 12.4%	23 11.9%
American Indian or Alaska Native	0 0%	1 1%	1 0.5%
Other	2 2.1%	1 1%	3 1.5%
Anti-tetanus Immunoglobulin G (IgG) Titer (IU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [IU/mL]	1.74 (1.908)	1.51 (1.328)	1.62 (1.644)
Eczema Area and Severity Index (EASI) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	31.23 (13.771)	29.04 (13.085)	30.14 (13.442)
Investigator Global Assessment (IGA) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.4 (0.49)	3.4 (0.49)	3.4 (0.49)
Weekly Peak Pruritus Numeric Rating Scale (NRS) (Units on a Scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a Scale]	7.3 (2.19)	7.4 (2.20)	7.3 (2.19)
Global Individual Signs Score (GISS) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	8.8 (1.80)	8.8 (1.76)	8.8 (1.78)
Patient Oriented Eczema Measure (POEM) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	20.6 (5.59)	21.5 (6.04)	21.1 (5.82)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Positive Response (≥4-Fold Increase) to Tetanus Toxoid (the Adacel [Tdap] Vaccine) at Week 16
Description	A positive response was defined as a ≥ 4-fold increase from pre-vaccination at baseline in anti-tetanus immunoglobulin G (IgG) titer for participants with a pre-vaccination tetanus antibody titers ≥ 0.1 IU/ml or a titer of ≥ 0.2 IU/ml for participants with pre-vaccination titers of <0.1 IU/ml. There was no planned statistical hypothesis testing regarding the difference in immune response between the 2 treatment groups for this study, therefore no formal statistical hypothesis between groups was performed.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

The immune response analysis set (IRS) included all randomized participants who received any study drug, vaccine injection at Week 12, and had 1 measurement for responses to tetanus toxoid vaccine at Week 16.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	92	90
Number [Percentage of participants]	83.7 86.3%	83.3 85.9%

2. Secondary Outcome

Title	Percentage of Participants With a Positive Response (≥2-Fold Increase) to Tetanus Toxoid (the Adacel [Tdap] Vaccine) at Week 16
Description	Participants with positive response defined as a ≥2-fold increase from pre-vaccination baseline in anti-tetanus IgG titer for participants with pre-vaccination tetanus antibody titers ≥0.1 IU/ml or a titer of ≥0.2 IU/ml for participants with pre-vaccination titers of <0.1 IU/ml.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

The immune response analysis set (IRS) included all randomized participants who received any study drug, vaccine injection at Week 12, and had 1 measurement for responses to tetanus toxoid vaccine at Week 16.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	92	90
Number [Percentage of participants]	94.6 97.5%	95.6 98.6%

3. Secondary Outcome

Title	Percentage of Participants With a Positive Response (SBA Antibody Titer of ≥8 for Serogroup C) to Menomune Vaccine at Week 16
Description	A positive response to the Menomune vaccine was a serum bactericidal antibody (SBA) titer of ≥8 for serogroup C.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

The immune response analysis set (IRS) included all randomized participants who received any study drug, vaccine injection at Week 12, and had 1 measurement for responses to tetanus toxoid vaccine at Week 16.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	92	90
Number [Percentage of participants]	87.0 89.7%	86.7 89.4%

4. Secondary Outcome

Title	Percentage of Participants Achieving an Investigator's Global Assessment (IGA) Score of "0" or "1" at Week 16
Description	IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear). Values after first rescue treatment were set to missing and participants with missing IGA scores at Week 16 were counted as non-responders.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) that included all randomized participants.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	97	97
Number [Percentage of participants]	10.3 10.6%	44.3 45.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo qw, Dupilumab 300 mg qw
	Comments	Analysis was performed using Cochran-Mantel-Haenszel test stratified by randomization strata (moderate [IGA=3] vs. severe [IGA=4] AD).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	34.0
	Confidence Interval	(2-Sided) 90%; 24.29 to 43.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Dupilumab 300 mg qw vs. Placebo qw

5. Secondary Outcome

Title	Percentage of Participants Achieving an Eczema Area and Severity Index-50 (EASI-50) (≥50% Improvement From Baseline) at Week 16
Description	The EASI score was used to measure the severity and extent of atopic dermatitis (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 reflecting the worse severity of AD. EASI-50 responders were the participants who achieved ≥50% overall improvement in EASI score from baseline to Week 16. Values after first rescue treatment were set to missing and participants with missing EASI score at Week 16 were counted as non-responders.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) that included all randomized participants.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	97	97
Number [Percentage of participants]	32.0 33%	72.2 74.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo qw, Dupilumab 300 mg qw
	Comments	Analysis was performed using Cochran-Mantel-Haenszel test stratified by randomization strata (moderate [IGA=3] vs. severe [IGA=4] AD).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	40.2
	Confidence Interval	(2-Sided) 90%; 29.40 to 51.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Dupilumab 300 mg qw vs. Placebo qw

6. Secondary Outcome

Title	Percentage of Participants Achieving an Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 16
Description	The EASI score was used to measure the severity and extent of atopic dermatitis (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 reflecting the worse severity of AD. EASI-75 responders were the participants who achieved ≥75% overall improvement in EASI score from baseline to Week 16. Values after first rescue treatment use were set to missing and participants with missing EASI score at Week 16 were considered as non-responders.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) that included all randomized participants.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	97	97
Number [Percentage of participants]	19.6 20.2%	53.6 55.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo qw, Dupilumab 300 mg qw
	Comments	Analysis was performed using Cochran-Mantel-Haenszel test stratified by randomization strata (moderate [IGA=3] vs. severe [IGA=4] AD).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	34.0
	Confidence Interval	(2-Sided) 90%; 23.38 to 44.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Dupilumab 300 mg qw vs. Placebo qw

7. Secondary Outcome

Title	Change From Baseline in Peak Weekly Averaged Pruritis Numerical Rating Scale (NRS) Scores at Week 16
Description	Pruritus NRS was an assessment tool that was used to report the intensity of participant's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Participants were asked the following question: how would a participant rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Weekly average obtained in the 7-day period prior to the baseline visit. Values after first rescue medication use were set to missing and missing values were imputed by Last observation carried forward (LOCF).
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) that included all randomized participants. Here, number of participants analyzed=participants with available data for this endpoint.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	90	94
Least Squares Mean (Standard Error) [Units on a scale]	-2.11 (0.259)	-4.24 (0.250)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo qw, Dupilumab 300 mg qw
	Comments	Analysis was performed using ANCOVA model which includes treatment, randomization strata, and baseline value as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.13
	Confidence Interval	(2-Sided) 90%; -2.72 to -1.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.354
	Estimation Comments	Dupilumab 300 mg qw vs. Placebo qw

8. Secondary Outcome

Title	Change From Baseline in Body Surface Area (BSA) Affected by AD at Week 16
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. Values after first rescue medication use were set to missing and missing values were imputed by LOCF.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) that included all randomized participants. Here, number of participants analyzed=participants with available data for this endpoint.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	97	97
Least Squares Mean (Standard Error) [Percentage of BSA]	-11.0 (2.11)	-28.7 (2.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo qw, Dupilumab 300 mg qw
	Comments	Analysis was performed using ANCOVA model that includes treatment, randomization strata and baseline value as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-17.8
	Confidence Interval	(2-Sided) 90%; -22.5 to -13.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.84
	Estimation Comments	Dupilumab 300 mg qw vs. Placebo qw

9. Secondary Outcome

Title	Change From Baseline in Global Individual Signs Score (GISS) Components (Erythema, Infiltration/Papulation, Excoriations and Lichenification) at Week 16
Description	Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0 = none, 1 = mild, 2 = moderate and 3 = severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease). Values after first rescue treatment were set to missing. Analysis was completed using MMRM model which includes treatment, randomization strata, visit, baseline value, treatment-by-visit interaction, and baseline-by-visit interaction as covariates. These results are observed results without imputation.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) that included all randomized participants. Here, number of participants analyzed=participants with available data for this endpoint.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	97	97
Erythema	-0.4 (0.08)	-0.9 (0.08)
Infiltration/Papulation	-0.4 (0.08)	-1.1 (0.08)
Excoriations	-0.5 (0.09)	-1.2 (0.08)
Lichenification	-0.4 (0.09)	-1.0 (0.09)

10. Secondary Outcome

Title	Changes From Baseline in GISS Cumulative Score to Week 16
Description	Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0 = none, 1 = mild, 2 = moderate and 3 = severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease). Values after first rescue medication use were set to missing and missing values were imputed by LOCF.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) that included all randomized participants. Here, number of participants analyzed=participants with available data for this endpoint.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	97	97
Least Squares Mean (Standard Error) [Units on a scale]	-1.7 (0.28)	-4.1 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo qw, Dupilumab 300 mg qw
	Comments	Analysis was performed using the ANCOVA model which includes treatment, randomization strata, and baseline values as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 90%; -3.0 to -1.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.39
	Estimation Comments	Dupilumab 300 mg qw vs. Placebo qw

11. Secondary Outcome

Title	Change in Patient Oriented Eczema Measure (POEM) Score From Baseline to Week 16
Description	The POEM was 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]). Values after first rescue medication use were set to missing and missing values were imputed by LOCF.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) that included all randomized participants. Here, number of participants analyzed=participants with available data for this endpoint.

Arm/Group Title	Placebo qw	Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.	Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
Measure Participants	97	97
Least Squares Mean (Standard Error) [Units on a Scale]	-4.8 (0.72)	-13.1 (0.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo qw, Dupilumab 300 mg qw
	Comments	Analysis was performed using the ANCOVA model which included treatment, randomization strata, and baseline value as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-8.3
	Confidence Interval	(2-Sided) 90%; -9.9 to -6.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.99
	Estimation Comments	Dupilumab 300 mg qw vs. Placebo qw

Adverse Events

Time Frame	Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 32) regardless of seriousness or relationship to investigational product
Adverse Event Reporting Description	Reported AEs are treatment-emergent adverse events which are AEs that developed/worsened during the 'on treatment period' (from the administration of first dose of study drug up to the final visit [Week 32]).
Arm/Group Title	Placebo qw		Dupilumab 300 mg qw
Arm/Group Description	Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15.		Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15.
All Cause Mortality
	Placebo qw		Dupilumab 300 mg qw
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/97 (0%)		0/97 (0%)
Serious Adverse Events
	Placebo qw		Dupilumab 300 mg qw
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/97 (0%)		3/97 (3.1%)
Immune system disorders
Serum sickness-like reaction	0/97 (0%)		1/97 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Mycosis fungoides stage iv	0/97 (0%)		1/97 (1%)
Squamous cell carcinoma	0/97 (0%)		1/97 (1%)
Other (Not Including Serious) Adverse Events
	Placebo qw		Dupilumab 300 mg qw
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/97 (29.9%)		30/97 (30.9%)
General disorders
Injection site reaction	0/97 (0%)		5/97 (5.2%)
Infections and infestations
Conjunctivitis	0/97 (0%)		8/97 (8.2%)
Nasopharyngitis	5/97 (5.2%)		4/97 (4.1%)
Upper respiratory tract infection	14/97 (14.4%)		11/97 (11.3%)
Nervous system disorders
Headache	3/97 (3.1%)		5/97 (5.2%)
Skin and subcutaneous tissue disorders
Dermatitis atopic	11/97 (11.3%)		1/97 (1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The investigator has the right to independently publish study results from the investigator's site after a multi-center publication, or a defined period after the completion of the study by all sites. The investigator must provide the sponsor a copy of any such publication derived from the study for review and comment in advance of any submission, and delay publication, if requested, to allow the Sponsor to preserve its proprietary rights.