Study to Determine the Safety and Effectiveness of Dupilumab for Treatment of Atopic Dermatitis (AD)

• Dupilumab (Drug), also known as REGN668, SAR231893, Dupixent
• Placebo (Drug): Matching placebo
• Background treatment (Other), also known as Topical emollient: Participants were required to apply stable doses of a topical emollient (moisturizer) twice daily for at least 7 days before the baseline visit and at least 7 days after the baseline visit (day -7 to day 8).

Primary outcomes

• Percent Change From Baseline in the Eczema Area Severity Index Score (EASI) to Week 16 [Baseline to Week 16]: The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema (E), infiltration (I), excoriation (Ex) and lichenification (L) 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. Values after first rescue medication use were set to missing and missing values imputed by last observation carried forward (LOCF).

Secondary outcomes

• Percentage of Participants With 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 medication were set to missing and participants with missing IGA score at Week 16 were considered as non-responders.
• Percentage of Participants Who Achieved IGA Score Reduction From Baseline of ≥2 Points at Week 16 [Baseline to 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. Participants with reduction in IGA score from baseline of ≥2 points at Week 16 were reported. Values after first rescue medication were set to missing and participants with missing IGA score at Week 16 were treated as non-responders.
• Absolute Change From Baseline in Pruritus Numeric Rating Scale (NRS) at Week 16 [Baseline to Week 16]: Pruritus NRS was an assessment tool that was used to report the intensity of a 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 \[0 = no itch; 10 = worst itch imaginable\]). Values after first rescue treatment were set to missing and missing values were imputed by LOCF.
• Percent Change From Baseline in Pruritus Numeric Rating Scale (NRS) at Week 16 [Baseline to Week 16]: Pruritus NRS was an assessment tool that was used to report the intensity of a 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 \[0 = no itch; 10 = worst itch imaginable\]). Values after first rescue treatment were set to missing and missing values were imputed by LOCF.
• Absolute Change From Baseline in EASI Score to Week 16 [Baseline to Week 16]: The EASI score was 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 reflecting the worse severity of AD. Values after first rescue medication use were set to missing and missing values were imputed by LOCF.
• Absolute Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score to Week 16 [Baseline to Week 16]: SCORAD was a clinical tool for assessing the severity of atopic dermatitis developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23-31. 1993. Extent and intensity of eczema as well as subjective signs (insomnia, etc.) were assessed and scored. Total score ranged from 0 (absent disease) to 103 (severe disease). Values after first rescue medication use were set to missing and missing values were imputed by LOCF.
• Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score to Week 16 [Baseline to Week 16]: SCORAD is a clinical tool for assessing the severity of atopic dermatitis developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23-31. 1993. 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). Values after first rescue medication use were set to missing and missing values were imputed by LOCF.
• Percentage of Participants Who Achieved 50%, 75% and 90% Reduction From Baseline in EASI Score ( EASI-50, EASI-75, and EASI-90 Respectively) at Week 16 [Baseline to Week 16]: EASI score was 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 ranged from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-50, EASI-75 and EASI-90 responders were the participants who achieved ≥50%, ≥75% and ≥90% respectively, 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.
• Percentage of Participants Who Achieved 50%, 75% and 90% Reduction From Baseline in SCORAD Score (SCORAD-50, SCORAD-75 and SCORAD-90 Respectively) at Week 16 [Baseline to Week 16]: SCORAD was a clinical tool for assessing the severity of atopic dermatitis developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23-31. 1993. Extent and intensity of eczema as well as subjective signs (insomnia, etc.) were assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). SCORAD-50, SCORAD-75 and SCORAD-90 responders were the participants who achieved ≥50%, ≥75% and ≥90% respectively, overall improvement in SCORAD score from baseline to Week 16. Values after first rescue treatment were set to missing and participants with missing SCORAD score at Week 16 were counted as non-responders.
• Absolute Change From Baseline in Participant's Oriented Eczema Measure (POEM) Score to Week 16 [Baseline to Week 16]: POEM was a 7-item questionnaire that assessed 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.
• Percent Change From Baseline in Participant's Oriented Eczema Measure (POEM) Score to Week 16 [Baseline to Week 16]: 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.
• Change From Baseline in Global Individual Signs Score (GISS) Components (Erythema, Infiltration/Papulation, Excoriations, and Lichenification) 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.
• 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.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Male or female, 18 years or older;
2. Chronic AD that had been present for at least 3 years before the screening visit;
3. Patients with documented recent history (within 6 months before the screening visit) of inadequate response to out-patient treatment with topical medications, or for whom topical treatments were otherwise inadvisable;
4. Willing and able to comply with all clinic visits and study-related procedures.

Exclusion Criteria:

1. Prior participation in a Dupilumab clinical trial;
2. Treatment with an investigational drug within 8 weeks or within 5 half-lives before the baseline visit;
3. The following treatments within 4 weeks before the baseline visit, or any condition that, in the opinion of the investigator, will likely require such treatment(s) during the first 4 weeks of study treatment:

   * Systemic corticosteroids;
   * Immunosuppressive/immunomodulating drugs;
   * Phototherapy for AD;
4. Treatment with topical corticosteroids, tacrolimus and/or pimecrolimus within 1 week before the baseline visit;
5. Treatment with certain biologics;
6. Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks before the baseline visit;
7. Planned major surgical procedure during the participant's participation in this study;
8. Participant was a member of the investigational team or his/her immediate family;
9. Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit
10. Pregnant or breast-feeding women or women planning to become pregnant or breastfeed during the study;

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

Participant flow

Outcome results

• Percent Change From Baseline in the Eczema Area Severity Index Score (EASI) to Week 16 (Primary), Least squares mean, percent change: Placebo qw -5.8 +/- 8.16; Dupilumab 200 mg qw -75.2 +/- 8.15 (p < 0.0001)
• Percentage of Participants With Investigator's Global Assessment (IGA) Score of "0" or "1" at Week 16 (Secondary), Number, percentage of participants: Placebo qw 0; Dupilumab 200 mg qw 37.0 (p = 0.0006)
• Percentage of Participants Who Achieved IGA Score Reduction From Baseline of ≥2 Points at Week 16 (Secondary), Number, percentage of participants: Placebo qw 3.7; Dupilumab 200 mg qw 51.9 (p < 0.0001)
• Absolute Change From Baseline in Pruritus Numeric Rating Scale (NRS) at Week 16 (Secondary), Least squares mean, units on a scale: Placebo qw -0.98 +/- 0.398; Dupilumab 200 mg qw -3.64 +/- 0.405 (p < 0.0001)
• Percent Change From Baseline in Pruritus Numeric Rating Scale (NRS) at Week 16 (Secondary), Least squares mean, percent change: Placebo qw -8.36 +/- 8.098; Dupilumab 200 mg qw -56.44 +/- 8.248 (p = 0.0001)
• Absolute Change From Baseline in EASI Score to Week 16 (Secondary), Least squares mean, units on a scale: Placebo qw -3.7 +/- 2.65; Dupilumab 200 mg qw -25.2 +/- 2.65 (p <0.0001)
• Absolute Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score to Week 16 (Secondary), Least squares mean, units on a scale: Placebo qw -5.1 +/- 3.60; Dupilumab 200 mg qw -36.4 +/- 3.60 (p < 0.0001)
• Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score to Week 16 (Secondary), Least squares mean, percent change: Placebo qw -8.2 +/- 5.41; Dupilumab 200 mg qw -54.8 +/- 5.40 (p < 0.0001)
• Percentage of Participants Who Achieved 50%, 75% and 90% Reduction From Baseline in EASI Score ( EASI-50, EASI-75, and EASI-90 Respectively) at Week 16 (Secondary), Number, percentage of participants: Placebo qw 22.2; Dupilumab 200 mg qw 77.8 (p < 0.0001)
• Percentage of Participants Who Achieved 50%, 75% and 90% Reduction From Baseline in SCORAD Score (SCORAD-50, SCORAD-75 and SCORAD-90 Respectively) at Week 16 (Secondary), Number, percentage of participants: Placebo qw 7.4; Dupilumab 200 mg qw 55.6 (p = 0.0002)
• Absolute Change From Baseline in Participant's Oriented Eczema Measure (POEM) Score to Week 16 (Secondary), Least squares mean, units on a scale: Placebo qw -2.6 +/- 1.34; Dupilumab 200 mg qw -13.1 +/- 1.37 (p < 0.0001)
• Percent Change From Baseline in Participant's Oriented Eczema Measure (POEM) Score to Week 16 (Secondary), Least squares mean, percent change: Placebo qw -12.1 +/- 6.18; Dupilumab 200 mg qw -58.3 +/- 6.31 (p < 0.0001)
• Change From Baseline in Global Individual Signs Score (GISS) Components (Erythema, Infiltration/Papulation, Excoriations, and Lichenification) to Week 16 (Secondary), Least squares mean, units on a scale: Placebo qw 0.0 +/- 0.14; Dupilumab 200 mg qw -0.7 +/- 0.14
• Changes From Baseline in GISS Cumulative Score to Week 16 (Secondary), Least squares mean, units on a scale: Placebo qw -0.5 +/- 0.46; Dupilumab 200 mg qw -4.2 +/- 0.46 (p < 0.0001)

Adverse events

Time frame: All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Week 32) regardless of seriousness or relationship to investigational product.

Serious adverse events by term

Other adverse events by term

• Results publication: Callewaert C, Nakatsuji T, Knight R, Kosciolek T, Vrbanac A, Kotol P, Ardeleanu M, Hultsch T, Guttman-Yassky E, Bissonnette R, Silverberg JI, Krueger J, Menter A, Graham NMH, Pirozzi G, Hamilton JD, Gallo RL. IL-4Ralpha Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis. J Invest Dermatol. 2020 Jan;140(1):191-202.e7. doi: 10.1016/j.jid.2019.05.024. Epub 2019 Jun 25. PMID 31252032
• Results publication: Guttman-Yassky E, Bissonnette R, Ungar B, Suarez-Farinas M, Ardeleanu M, Esaki H, Suprun M, Estrada Y, Xu H, Peng X, Silverberg JI, Menter A, Krueger JG, Zhang R, Chaudhry U, Swanson B, Graham NMH, Pirozzi G, Yancopoulos GD, D Hamilton JD. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2019 Jan;143(1):155-172. doi: 10.1016/j.jaci.2018.08.022. Epub 2018 Sep 5. PMID 30194992

• Clinical Trial Management, Study director, Regeneron Pharmaceuticals