Study to Assess the Efficacy and Long-term Safety of Dupilumab (REGN668/SAR231893) in Adult Participants With Moderate-to-Severe Atopic Dermatitis

Study Overview
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Brief Summary
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The primary objective of the study was to demonstrate the efficacy of Dupilumab administered concomitantly with topical corticosteroid (TCS) through Week 16 in adult participants with moderate-to-severe atopic dermatitis (AD) compared to placebo administered concomitantly with TCS.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study to Demonstrate the Efficacy and Long-Term Safety of Dupilumab in Adult Patients With Moderate-to-Severe Atopic Dermatitis

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo (for Dupilumab)
* Other: Topical Corticosteroid (TCS)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Chronic AD that had been present for at least 3 years before the screening visit; Documented recent history (within 6 months before the screening visit) of inadequate response to a sufficient course of out-patient treatment with topical AD medication(s). Key Exclusion Criteria: Participation in a prior Dupilumab clinical trial; Important side effects of topical medication (e.g. intolerance to treatment, hypersensitivity reactions, significant skin atrophy, systemic effects), as assessed by the investigator or treating physician; Having used any of the following treatments within 4 weeks before the baseline visit, or any condition that, in the opinion of the investigator, was likely to require such treatment(s) during the first 2 weeks of study treatment: Immunosuppressive/immunomodulating drugs (e.g, systemic steroids, cyclosporine, mycophenolate-mofetil, Janus kinase inhibitors, interferon-gamma [IFN-γ], azathioprine, methotrexate, etc.); Phototherapy for AD; Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit; History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening; Positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody at the screening visit; Active or acute infection requiring systemic treatment within 2 weeks before baseline visit; Known or suspected history of immunosuppression; Pregnant or breastfeeding women, or planning to become pregnant or breastfeed during the participant's participation in this study. Note: The eligibility criteria 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo qw<br>Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection weekly (qw) from Week 1 to Week 51. | Drug: Placebo (for Dupilumab)<br>* Subcutaneous injection in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs<br>Other: Topical Corticosteroid (TCS)<br>* All participants were required to treatment with a (TCS) using a standardized regimen. It was recommended that participants use triamcinolone acetonide 0.1% cream or fluocinolone acetonide 0.025% ointment for medium potency, and hydrocortisone 1% cream for low potency.<br>|
| Experimental: Dupilumab 300 mg q2w<br>Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab every 2 weeks (q2w) from Week 1 to Week 51. During weeks in which Dupilumab was not administered, participants received placebo. | Drug: Dupilumab<br>* Subcutaneous injection in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs<br>* Other names: Dupixent;Drug: Placebo (for Dupilumab)<br>* Subcutaneous injection in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs<br>Other: Topical Corticosteroid (TCS)<br>* All participants were required to treatment with a (TCS) using a standardized regimen. It was recommended that participants use triamcinolone acetonide 0.1% cream or fluocinolone acetonide 0.025% ointment for medium potency, and hydrocortisone 1% cream for low potency.<br>|
| Experimental: Dupilumab 300 mg qw<br>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 of Dupilumab qw from Week 1 to Week 51. | Drug: Dupilumab<br>* Subcutaneous injection in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs<br>* Other names: Dupixent;Other: Topical Corticosteroid (TCS)<br>* All participants were required to treatment with a (TCS) using a standardized regimen. It was recommended that participants use triamcinolone acetonide 0.1% cream or fluocinolone acetonide 0.025% ointment for medium potency, and hydrocortisone 1% cream for low potency.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Investigator's Global Assessment (IGA) Score of 0 or 1 and Reduction From Baseline of ≥2 Points at Week 16 | IGA is 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 is an IGA score of 0 (clear) or 1 (almost clear). Participants with IGA score 0 or 1 and a reduction from baseline of ≥2 points at Week 16 were reported. | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at 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. | Baseline to Week 16 | 
| Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From 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]). Participants achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. | Baseline to Week 16 | 
| Percentage of Participants With Improvement (Reduction ≥3 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From 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]). Participants achieving a reduction of ≥3 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. | Baseline to Week 16 | 
| Percentage of Participants With Investigator's Global Assessment (IGA) Score of 0 or 1 and Reduction From Baseline of ≥2 Points at Week 52 | IGA is 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 is an IGA score of 0 (clear) or 1 (almost clear). Participants with IGA score of 0 or 1 and a reduction from baseline of ≥2 points at Week 52 were reported. | Baseline to Week 52 | 
| Percentage of Participants With Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 52 | 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. EASI-75 responders were the participants who achieved ≥75% overall improvement in EASI score from baseline to Week 52. | Baseline to Week 52 | 
| Percent Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score 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]). | Baseline to Week 16 | 
| Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 52 | 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]). Participants achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 52 were reported. | Baseline to Week 52 | 
| Percentage of Participants With Improvement (Reduction ≥3 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 52 | 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]). Participants achieving a reduction of ≥3 points from baseline in weekly average of peak daily pruritus NRS score at Week 52 were reported. | Baseline to Week 52 | 
| Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 24 | 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]). Participants achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 24 were reported. | Baseline to Week 24 | 
| Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 4 | 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]). Participants achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 4 were reported. | Baseline to Week 4 | 
| Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 2 | 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]). Participants achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 2 were reported. | Baseline to Week 2 | 
| Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score 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]). | Baseline to Week 16 | 
| Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score 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. | Baseline to Week 16 | 
| Change From Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis 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. | Baseline to Week 16 | 
| Percent Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Score to Week 16 | SCORAD was a clinical tool for assessing the severity of AD 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). | Baseline to Week 16 | 
| Change From Baseline in Dermatology Life Quality Index (DLQI) to Week 16 | The DLQI was a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL). The 10 questions assessed QOL over the past week, with an overall scoring of 0 (absent disease) to 30 (severe disease); a high score was indicative of a poor QOL. | Baseline to Week 16 | 
| Change From Baseline in Patient Oriented Eczema Measure (POEM) to Week 16 | The 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]). | Baseline to Week 16 | 
| Change From Baseline in Hospital Anxiety Depression Scale (HADS) to Week 16 | HADS is a fourteen item scale. Seven of the items relate to anxiety and seven items relate to depression. Each item on the questionnaire scored from 0 (minimum score) - 3 (maximum score) and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. Cut-offs for identifying psychiatric distress has been reported as 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression. | Baseline to Week 16 | 
| Percent Change From Baseline in Total Global Individual Signs Score (GISS) 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). | Baseline to Week 16 | 
| Proportion of Topical Atopic Dermatitis Medication-Free Days Through Week 52 | Proportion of topical AD medication-free days through Week 52 was calculated as the number of days that a participant used neither topical corticosteroid (TCS)/ topical calcineurin inhibitors (TCI) nor system rescue therapy divided by the study days of each period. | Baseline to Week 52 | 
| Percent Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 2 | 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]). | Baseline to Week 2 | 
| Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score to Week 52 | 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. | Baseline to Week 52 | 
| Change From Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis to Week 52 | 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. | Baseline to Week 52 | 
| Percent Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Score to Week 52 | SCORAD was a clinical tool for assessing the severity of AD 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). | Baseline to Week 52 | 
| Percent Change From Baseline in Global Individual Signs Score (GISS) to Week 52 | 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). | Baseline to Week 52 | 
| Change From Baseline in Dermatology Life Quality Index (DLQI) to Week 52 | The DLQI was a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL). The 10 questions assessed QOL over the past week, with an overall scoring of 0 (absent disease) to 30 (severe disease); a high score was indicative of a poor QOL. | Baseline to Week 52 | 
| Change From Baseline in Patient Oriented Eczema Measure (POEM) to Week 52 | 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]). | Baseline to Week 52 | 
| Change From Baseline in Hospital Anxiety Depression Scale (HADS) to Week 52 | HADS is a fourteen item scale. Seven of the items relate to anxiety and seven items relate to depression. Each item on the questionnaire is scored from 0 (minimum score) - 3 (maximum score) and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. Cut-offs for identifying psychiatric distress has been reported as 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression. | Baseline to Week 52 | 
| Number of Flares Through Week 52 | Atopic dermatitis (AD) flares were defined as worsening of the disease that required escalation/intensification of AD treatment. Number of flares occurred in the participants starting from first dose through Week 52 were reported. | Baseline up to Week 52 | 
| Number of Serious Treatment Emergent Adverse Events (TEAEs) Leading to Study Drug Discontinuation Through Week 52 | Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. A Serious adverse event (SAE) 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. Any TEAE included participants with both serious and non-serious AEs. | Baseline up to Week 52 | 
| Percentage of Participants With Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) From Baseline Through Week 52 | Any untoward medical occurrence in a participants who received IMP was considered an AE without regard to possibility of causal relationship with this treatment. TEAEs were defined as AEs that developed or worsened or became serious during on-treatment period (time from the first dose of study drug up to end of treatment at Week 52). Any TEAE included participants with both serious and non-serious AEs. 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. Blinded adjudication was performed and finalized by the study medical monitor before database lock. | Baseline up to Week 52 | 
| Number of Skin Infection TEAEs (Excluding Herpetic Infections) From Baseline Through Week 52 | Any untoward medical occurrence in a participant who received IMP was considered an AE without regard to possibility of causal relationship with this treatment. TEAEs were defined as AEs that developed or worsened or became serious during on-treatment period (time from the first dose of study drug up to end of treatment at Week 52). Any TEAE included participants with both serious and non-serious AEs. 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. Blinded adjudication was performed and finalized by the study medical monitor before database lock. | Baseline up to Week 52 | 
| Percentage of Participants With Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) Requiring Systemic Treatment From Baseline Through Week 52 | Any untoward medical occurrence in a participant who received IMP was considered an AE without regard to possibility of causal relationship with this treatment. TEAEs were defined as AEs that developed or worsened or became serious during on-treatment period (time from the first dose of study drug up to end of treatment at Week 52). Any TEAE included participants with both serious and non-serious AEs. 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. Blinded adjudication was performed and finalized by the study medical monitor before database lock. | Baseline up to Week 52 | 
| Number of Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) Requiring Systemic Treatment From Baseline Through Week 52 | Any untoward medical occurrence in a participant who received IMP was considered an AE without regard to possibility of causal relationship with this treatment. TEAEs were defined as AEs that developed or worsened or became serious during on-treatment period (time from the first dose of study drug up to end of treatment at Week 52). Any TEAE included participants with both serious and non-serious AEs. 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. Blinded adjudication was performed and finalized by the study medical monitor before database lock. | Baseline up to Week 52 |