Efficacy and Safety of Dupilumab in Participants ≥12 to <18 Years of Age, 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 as a monotherapy in participants ≥12 years to <18 years of age with moderate-to-severe atopic dermatitis (AD). The secondary objective of the study was to assess the safety of dupilumab as a monotherapy in participants ≥12 years to <18 years of age with moderate-to-severe AD.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Dupilumab Monotherapy in Patients ≥12 to <18 Years of Age, With Moderate-to-severe Atopic Dermatitis

Conditions
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Moderate-to-Severe Atopic Dermatitis, Dermatitis, Dermatitis Atopic, Eczema, Skin Diseases, Skin, Diseases Genetic, Genetic, Diseases Inborn, Skin, Disease, Eczematous Skin, Hypersensitivity, Immediate, Hypersensitivity, Immune System Diseases, Dermatitis, Atopic

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥12 to <18 years of age at time of screening visit Diagnosis of AD according to the American Academy of Dermatology consensus criteria at screening visit IGA ≥3 at screening and baseline visit EASI ≥16 at the screening and baseline visit Baseline Pruritus NRS average score for maximum itch intensity ≥4 ≥10% BSA of AD involvement at the screening and baseline visits With documented recent history (within 6 months before the screening visit) of inadequate response to topical AD medication(s) or for whom topical treatments is medically inadvisable Exclusion Criteria: Participation in a prior dupilumab clinical study Treatment with topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI) within 2 weeks before the baseline visit Having used immunosuppressive/immunomodulating drugs within 4 weeks before the baseline visit Body weight <30 kg at baseline Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before the baseline visit Known or suspected immunodeficiency, known history of human immunodeficiency virus (HIV) infection or HIV seropositivity at the screening visit, established diagnosis of HBV infection or HBV seropositivity at screening, established diagnosis of HCV infection or HCV seropositivity at screening History of malignancy before the baseline visit Diagnosed active endoparasitic infections or at high risk of these infections Patient is female who is pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study Patient is female of childbearing potential and sexually active, who is unwilling to use adequate methods of contraception throughout the duration of the study and for 120 days after the last dose of study drug Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br>Participants received placebo matching dupilumab once every 2 weeks (Q2W) (including doubling the amount of placebo on day 1 to match the loading dose). In order to maintain blinding for the study, participants in the <60 kilogram (kg) weight stratum received, in a 1:1 ratio, either placebo matching 200 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose) or placebo matching 300 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose). In the ≥60 kg weight stratum, the participants randomized to the placebo group received placebo matching 300 mg dupilumab (including doubling the amount of placebo on day 1 to match the loading dose). | Drug: Placebo<br>* Subcutaneous injection among the different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.<br>|
| Experimental: Dupilumab 300 mg Q4W<br>Participants received once every 4 weeks (Q4W) subcutaneous (SC) injections of 300 milligrams (mg) dupilumab following a loading dose of 600 mg on day 1. In order to maintain blinding, all participants received an injection once every 2 weeks (Q2W) from day 1 to week 14. Participants received placebo 2 milliliter (mL) injection at the weeks dupilumab was not given. | Drug: Dupilumab<br>* Subcutaneous injection among the different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.<br>* Other names: REGN668;|
| Experimental: Dupilumab 200 mg or 300 mg Q2W<br>Participants with baseline weight <60 kg received once every 2 weeks (Q2W) subcutaneous (SC) injections of 200 milligrams (mg) dupilumab following a loading dose of 400 mg on day 1. Participants with baseline weight ≥60 kg received Q2W SC injections of 300 mg dupilumab following a loading dose of 600 mg on day 1. | Drug: Dupilumab<br>* Subcutaneous injection among the different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.<br>* Other names: REGN668;|

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) 0 or 1 (and Reduction From Baseline of ≥2 Points) at Week 16 | IGA is an assessment scale used to determine severity of atopic dermatitis (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). Participants with IGA 0 or 1 and a reduction from baseline of ≥2 points at Week 16 were reported. [Values after first rescue treatment used were set to missing. Participants with missing score at week 16 were considered as a non-responder. Participant considered non-responder after rescue treatment use. Efficacy analyses were based on the treatment allocated at randomization (as randomized).] | Baseline and Week 16 | 
| Percentage of Participants With Eczema Area and Severity Index (EASI)-75 (≥75% Improvement From Baseline) at Week 16 | The EASI score was 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 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 used were set to missing. Participants with missing score at week 16 were considered as a non-responder. Participant considered nonresponder after rescue treatment use. Efficacy analyses were based on the treatment allocated at randomization (as randomized).] | Baseline and Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in EASI Score at Week 16 | The Eczema Area and Severity Index (EASI) score was 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 reflecting the worse severity of AD. [Values after first rescue treatment use were set to missing and participants with missing EASI score at Week 16 were considered as non-responders.] | Baseline and Week 16 | 
| Percent Change From Baseline in Weekly Average of Daily Peak Pruritus Numerical Rating Scale (NRS) Score at Week 16 | Peak Pruritus NRS is an assessment tool used by subjects to report intensity of pruritus (itch) during a 24-hour recall period. Participants were asked the following question: For maximum itch intensity: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable,' how would you rate your itch at the worst moment during the previous 24 hours? For post-baseline NRS, the mean weekly NRS was calculated as the prorated average of the reported daily NRS within the week. For example, if there were 3 scores in a week, the prorated average = (score1 + score2 + score3) /3. [Values after first rescue treatment were set to missing and participants with missing peak NRS at Week 16 were counted as non-responders.] | Baseline and Week 16 | 
| Percentage of Participants With Improvement (Reduction ≥3 Points) of Weekly Average of Daily Peak Pruritus NRS From Baseline to Week 16 | Peak Pruritus NRS is an assessment tool used by participants to report intensity of pruritus (itch) during a 24-hour recall period. Participants were asked the following question: For maximum itch intensity: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable,' how would you rate your itch at the worst moment during the previous 24 hours? [For this endpoint, participants achieving a reduction of ≥3 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. Values after first rescue treatment were set to missing and participants with missing peak NRS at Week 16 were counted as non-responders.] | Baseline to Week 16 | 
| Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Daily Peak Pruritus NRS From Baseline to Week 16 | Peak Pruritus NRS is an assessment tool used by participants to report intensity of pruritus (itch) during a 24-hour recall period. Participants were asked the following question: For maximum itch intensity: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable,' how would you rate your itch at the worst moment during the previous 24 hours? [For this endpoint, participants achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. Values after first rescue treatment were set to missing and participants with missing peak NRS at Week 16 were counted as non-responders.] | Baseline to Week 16 | 
| Percentage of Participants With EASI-50 (≥50% Improvement From Baseline) at 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. EASI-50 responders were the participants who achieved ≥50% overall improvement in EASI score at Week 16. [Values after first rescue treatment used were set to missing. Participants with missing value at Week 16 were considered as a non-responder]. | Baseline and Week 16 | 
| Percentage of Participants With EASI-90 (≥90% Improvement From Baseline) at 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. EASI-90 responders were the participants who achieved ≥90% overall improvement in EASI score at Week 16. [Values after first rescue treatment used were set to missing. Participants with missing value at week 16 were considered as a non-responder.] | Baeline and Week 16 | 
| Time to Onset of Effect on Pruritus as Measured by Percentage of Participants With Improvement (Reduction ≥3 Points) of Weekly Average of Daily Peak Pruritus NRS From Baseline | Peak Pruritus NRS is an assessment tool used by participants to report intensity of pruritus (itch) during a 24-hour recall period. Participants were asked the following question: For maximum itch intensity: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable,' how would you rate your itch at the worst moment during the previous 24 hours? [For this endpoint, participants achieving a reduction of ≥3 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. Values after first rescue treatment were set to missing and participants with missing peak NRS at Week 16 were counted as non-responders.] | Baseline up to week 16 | 
| Time to Onset of Effect on Pruritus as Measured by Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Daily Peak Pruritus NRS From Baseline | Peak Pruritus NRS is an assessment tool used by participants to report intensity of pruritus (itch) during a 24-hour recall period. Participants were asked the following question: For maximum itch intensity: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable,' how would you rate your itch at the worst moment during the previous 24 hours? [For this endpoint, subjects achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. Values after first rescue treatment were set to missing and participants with missing peak NRS at Week 16 were counted as non-responders.] | Baseline up to Week 16 | 
| Change From Baseline in Percent Body Surface Area (BSA) at 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 and Week 16 | 
| Percent Change From Baseline in Scoring Atopic Dermatitis (SCORAD) Score at Week 16 | The SCORAD index is a clinical tool for assessing the severity of atopic dermatitis. 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). | Baseline and Week 16 | 
| Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) Total Score at Week 16 | The CDLQI is a 10-item questionnaire used to measure how much a participant's skin problem had affected the participant's quality of life (QOL) over a recall period of the past week. The questionnaire consists of 10 items. For each item the scale is rated as follows: 0 = Not at all = Not relevant; 1 = Only a little; 2 = Quite a lot; 3 = Very much = Yes = Prevents school. The CDLQI total score is the sum of the score of each question with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact is on the QOL. | Baseline and Week 16 | 
| Change From Baseline in Patient Oriented Eczema Measure (POEM) at Week 16 | The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess disease symptoms in children and adults with atopic eczema. The format is subject response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on symptom frequency during the past week (ie, 0 = 'no days', 1 = '1 to 2 days', 2 = '3 to 4 days', 3 = '5 to 6' days, and 4 = 'every day'). The total score is the sum of the 7 items which is ranged from 0 to 28; a high score is indicative of a poor quality of life (QOL). | Baseline and Week 16 | 
| Change From Baseline in Weekly Average of Daily Peak Pruritus NRS at Week 16 | Peak Pruritus NRS is an assessment tool used by participants to report intensity of pruritus (itch) during a 24-hour recall period. Particpants were asked the following question for maximum itch intensity: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable,' how would you rate your itch at the worst moment during the previous 24 hours? For post-baseline NRS, the mean weekly NRS was calculated as the prorated average of the reported daily NRS within the week. For example, if there were 3 scores in a week, the prorated average = (score1 + score2 + score3)/ 3. | Baseline and Week 16 | 
| Percent Change From Baseline in Weekly Average of Daily Peak Pruritus NRS at Week 4 | Peak Pruritus NRS is an assessment tool used by participants to report intensity of pruritus (itch) during a 24-hour recall period. Participants were asked the following question for maximum itch intensity: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable,' how would you rate your itch at the worst moment during the previous 24 hours? For post-baseline NRS, the mean weekly NRS was calculated as the prorated average of the reported daily NRS within the week. For example, if there were 3 scores in a week, the prorated average = (score1 + score2 + score3)/ 3. | Baseline and Week 4 | 
| Change From Baseline in Total Hospital Anxiety and Depression Scale (HADS) at Week 16 | The HADS is 14-item questionnaire with two subscales: anxiety & depression. Each item is rated on a 4-point scale (0-3). A person could score between 0 & 21 for each subscale (anxiety & depression). A high score is indicative of a poor state. Scores of 11 or more on either subscale are considered a 'definite case' of psychological morbidity, while scores of 8 to 10 represents 'probable case' & 0 to 7 'not a case'. The total score was the sum of the 2 sub-scores; therefore, the full range of possible values for the reported data is 0-42. | Baseline and Week 16 | 
| Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Daily Peak Pruritus NRS From Baseline at Week 4 | Peak Pruritus NRS is an assessment tool used by participants to report intensity of pruritus (itch) during a 24-hour recall period. Participants were asked the following question for maximum itch intensity: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable,' how would you rate your itch at the worst moment during the previous 24 hours? For post-baseline NRS, the mean weekly NRS was calculated as the prorated average of the reported daily NRS within the week. For example, if there were 3 scores in a week, the prorated average = (score1 + score2 + score3)/ 3. | Baseline and Week 4 | 
| Percentage of Participants With Skin-infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) Through Week 16 | Any untoward medical occurrence in a subject who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (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 the end of study (Week 16)). 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 through Week 16 | 
| Percentage of Participants With Serious TEAEs Through Week 16 | 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. Treatment-emergent adverse events (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 the end of study (Week 28)). 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 through Week 16 |