Safety, Pharmacokinetics and Efficacy of Dupilumab in Patients ≥6 Months to <6 Years With Moderate-to-Severe Atopic Dermatitis (Liberty AD PRESCHOOL)

Study Overview
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Brief Summary
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This study is a 2-part (parts A and B) phase 2/3 study to evaluate the safety, pharmacokinetics (PK) and efficacy of dupilumab in participants 6 months to less than 6 years of age with moderate-to-severe atopic dermatitis (AD).

Detailed Description
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Part A (open-label, single-ascending-dose, sequential cohort phase 2 study): Primary objective is to characterize the safety and PK of dupilumab administered as a single dose in pediatric participants, 6 months to less than 6 years of age, with severe AD. Secondary objective is to evaluate the efficacy and immunogenicity of a single dose of dupilumab in participants 6 months to less than 6 years of age with severe AD. Part B (randomized, double-blind, parallel-group, placebo-controlled phase 3 study): Primary objective is to demonstrate the efficacy of multiple doses of dupilumab over 16 weeks of treatment when administered concomitantly with topical corticosteroids (TCS) in pediatric participants, 6 months to less than 6 years of age, with moderate-to-severe AD. Secondary objective is to assess the safety and immunogenicity of multiple doses of dupilumab over 16 weeks of treatment when administered concomitantly with TCS in participants 6 months to less than 6 years of age with moderate-to-severe AD.

Official Title
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A Phase 2/3 Study Investigating the Pharmacokinetics, Safety, and Efficacy of Dupilumab in Patients Aged ≥6 Months to <6 Years With Moderate-to-Severe Atopic Dermatitis

Conditions
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Dermatitis, Atopic

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Diagnosis of atopic dermatitis (AD) according to the American Academy of Dermatology consensus criteria at the screening visit Participants with documented recent history (within 6 months before the screening visit) of inadequate response to topical AD medication(s) IGA score at screening and baseline visits part A: IGA = 4 part B: IGA ≥3 EASI score at screening and baseline visits part A: EASI ≥21 part B: EASI ≥16 Body Surface Area (BSA) involvement at screening and baseline visits part A: ≥15% part B: ≥10% At least 11 (of a total of 14*) applications of a topical emollient (moisturizer) during the 7 consecutive days immediately before the baseline visit (not including the day of randomization) (for part B of the study only) Baseline worst scratch/itch score weekly average score for maximum scratch/itch intensity ≥4 (for part B of the study only) At least 11 (of a total of 14) daily applications of low potency TCS during the 2-week TCS standardization period (beginning on day -14) leading up to the baseline visit (for part B of the study only). Key Exclusion Criteria Prior treatment with dupilumab History of important side effects of low potency topical corticosteroids (only applicable for part B of the study) Having used immunosuppressive/immunomodulating drugs within 4 weeks before the baseline visit Treatment with a live (attenuated) vaccine within 4 weeks before the baseline visit 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 at any time before the baseline visit Diagnosed active endoparasitic infections or at high risk of these infections Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect the patient's participation in the study Body weight <5 kg or ≥30 kg at baseline (only applicable part B of the study) Note: Other protocol defined Inclusion/ Exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 5 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: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Part A: Single-ascending-dose cohorts staggered by age; Part B: Parallel Group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A (Open label Dupilumab): Age cohorts 1 & 2<br>Age cohort 1: ≥2 years old to <6 years old Age cohort 2: ≥6 months to <2 years old | Drug: Dupilumab<br>* Solution for injection, subcutaneous (SC)<br>* Other names: SAR231893;|
| Experimental: Part B (Double-blind): Dupilumab dose 1<br>The results of part A will be used to guide the selection of dose levels and dosing frequency for part B. | Drug: Dupilumab<br>* Solution for injection, subcutaneous (SC)<br>* Other names: SAR231893;|
| Experimental: Part B (Double-blind): Dupilumab dose 2<br>The results of part A will be used to guide the selection of dose levels and dosing frequency for part B. | Drug: Dupilumab<br>* Solution for injection, subcutaneous (SC)<br>* Other names: SAR231893;|
| Experimental: Part B (Double-Blind): Placebo<br> | Drug: Matching placebo<br>* Solution for injection, subcutaneous (SC)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Maximum Observed Serum Concentration (Cmax) of Functional Dupilumab | Serum concentration of functional dupilumab was reported. | Post-dose on Days 1, 3, 8, 18, and 29 | 
| Part A: Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Dupilumab | Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in Milligrams per Liter/Milligrams per Kilogram ([mg/L]/[mg/kg]). | Post-dose on Days 1, 3, 8, 18, and 29 | 
| Part A: Time to Reach the Maximum Serum Concentration (Tmax) of Dupilumab | Tmax was obtained directly from the concentration versus time curve. | Post-dose on Days 1, 3, 8, 18, and 29 | 
| Part A: Last Quantifiable Serum Concentration (Clast) of Dupilumab | Clast is the last measurable serum concentration of dupilumab. | Post-dose on Days 1, 3, 8, 18, and 29 | 
| Part A: Time of the Last Quantifiable Serum Concentration (Tlast) of Dupilumab | Tlast was defined as the last time point with a measurable serum concentration of dupilumab. | Post-dose on Days 1, 3, 8, 18, and 29 | 
| Part A: Area Under the Serum Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) of Dupilumab | AUClast was defined as area under the serum concentration time-curve from zero to the last measured concentration. | Post-dose on Days 1, 3, 8, 18, and 29 | 
| Part A: Dose Normalized Area Under the Serum Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast/Dose) of Dupilumab | Dose normalized AUClast was calculated by AUClast/dose. | Post-dose on Days 1, 3, 8, 18, and 29 | 
| Part A: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) | Adverse Event (AE) was defined as any untoward medical occurrence in a participant administered a study drug which may/may not have a causal relationship with study drug. Serious AE (SAE) was defined as any untoward medical occurrence that resulted in any of following outcomes: death, life-threatening, required initial/prolonged in-participant hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect/considered as medically important event. TEAE was defined as AE starting/worsening after first intake of study drug. TEAEs included participants with both SAEs and non-SAEs. Number of participants with TEAEs is reported. | Baseline up to Week 4 | 
| Part A: Number of Participants With TEAEs by Severity According to Qualitative Toxicity Scale | Severity of TEAEs were graded using Qualitative Toxicity Scale, as follows: Mild: Participant is aware of the event or symptom, but the event or symptom is easily tolerated; Moderate: Participant experiences sufficient discomfort to interfere with or reduce his or her usual level of activity; Severe: Significant impairment of functioning: the participant is unable to carry out his or her usual activities. Number of participants with TEAEs by severity were reported. | Baseline up to Week 4 | 
| Part B: Percentage of Participants With Investigator's Global Assessment (IGA) Score 0 or 1 at Week 16 | The IGA is an assessment scale used in clinical studies to rate the severity of AD globally, based on a 5-point scale ranging from 0 to 4 where 0 = clear; 1=almost clear; 2=mild; 3=moderate; 4=severe. A negative change from baseline indicated improvement. Percentage of participants with IGA score of '0' or '1' is reported. | Week 16 | 
| Part B: Percentage of Participants With Eczema Area and Severity Index (EASI) -75 (EASI-75) (≥75% Improvement From Baseline) at Week 16 | The EASI score is used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper, and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores indicating the worse severity of AD. EASI-75 responders were the participants who achieved ≥75% overall improvement in EASI score from baseline at Week 16. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Serious TEAEs and Severe TEAEs | Adverse Event (AE) was defined as any untoward medical occurrence in a participant administered a study drug which may/may not have a causal relationship with study drug. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Severe TEAE: significant impairment of functioning the participant is unable to carry out his or her usual activities. | Baseline up to Week 4 | 
| Part A: Percent Change From Baseline in EASI Score at Week 4 | The EASI score is used to measure the severity and extent of AD and measured erythema, infiltration, excoriation, and lichenification on 4 anatomic regions of the body: head, trunk, upper, and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores indicated the worse severity of AD. A negative change from baseline indicated improvement. | Week 4 | 
| Part A: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 4 | The SCORAD is used to assess the extent and severity of AD. Extent and severity of eczema as well as subjective symptoms (insomnia, etc) were assessed and scored. SCORAD total score ranges from 0 (absent disease) to 103 (severe disease). A negative change from baseline indicated improvement. | Week 4 | 
| Part A: Percentage of Participants With IGA Score 0 or 1 at Week 4 | The IGA is an assessment scale used in clinical studies to rate the severity of AD globally, based on a 5-point scale ranging from 0 to 4 where 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe. Percentage of participants with IGA score of '0' or '1' were reported. | Week 4 | 
| Part A: Number of Participants With at Least One Positive Treatment-Emergent Anti-Drug Antibodies (ADA) | Treatment boosted (TB) Response: Any post-dose positive result at least 9-fold over the baseline level when baseline is positive; Treatment emergent (TE) Response: Post-dose positive result when baseline results were negative. | Baseline up to Day 57 | 
| Part B: Number of Participants With at Least One Serious Adverse Event (SAE) Through Week 16 |  | Baseline through Week 16 | 
| Part B: Number of Participants With at Least One Skin Infection Treatment Emergent Adverse Event (TEAE) (Excluding Herpetic Infection) Through Week 16 |  | Baseline through Week 16 | 
| Part B: Number of Participants With at Least One Positive Treatment-Emergent ADA | Treatment emergent (TE): Post-dose positive result when baseline results were negative. | Baseline up to Day 197 | 
| Part B: Percent Change From Baseline in EASI Score at Week 16 | The EASI score is used to measure the severity and extent of AD and measures erythema, infiltration, excoriation, and lichenification on 4 anatomic regions of the body: head, trunk, upper, and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores indicating the worse severity of AD. A negative change from baseline indicated improvement. | Week 16 | 
| Part B: Percent Change From Baseline in Weekly Average of Daily Worst Scratch/Itch/Numerical Rating Scale (NRS) at Week 16 | Pruritus NRS is an assessment tool used to report intensity of participant's pruritus (itch), both average & maximum intensity, during 24-hr recall period. Participants were asked two questions: 1) For average itch intensity: how would you rate your itch overall (on average) during the previous 24 hrs; 2) For maximum itch intensity: How would you rate your itch at the worst moment during the previous 24 hrs? Both questions were rated on a scale: 0-10 with 0=no itch & 10=worst itch imaginable. A negative change from baseline indicated improvement. | Week 16 | 
| Part B: Percentage of Participants With Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥4 Points at Week 16 | Pruritus NRS is an assessment tool used to report intensity of subject's pruritus (itch), both average & maximum intensity, during 24-hr recall period. Subjects were asked two questions: 1) For average itch intensity: how would you rate your itch overall (on average) during the previous 24 hrs; & 2) For maximum itch intensity: How would you rate your itch at the worst moment during the previous 24 hrs? Both questions were rated on a scale: 0-10 with 0=no itch & 10=worst itch imaginable. | Week 16 | 
| Part B: Percentage of Participants With Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Scratch/Itch/NRS ≥3 Points at Week 16 | Pruritus NRS is an assessment tool used to report intensity of participant's pruritus (itch), both average & maximum intensity, during 24-hr recall period. Participants were asked two questions: 1) For average itch intensity: how would you rate your itch overall (on average) during the previous 24 hrs; & 2) For maximum itch intensity: How would you rate your itch at the worst moment during the previous 24 hrs? Both questions were rated on a scale: 0-10 with 0=no itch & 10=worst itch imaginable. | Week 16 | 
| Part B: Percentage of Participants Who Achieved EASI-50 (≥50% Improvement From Baseline) at Week 16 | The EASI score is used to measure the severity and extent of AD and measured erythema, infiltration, excoriation, and lichenification on 4 anatomic regions of the body: head, trunk, upper, and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores indicating the worse severity of AD. EASI-50 responders were the participants who achieved ≥50% overall improvement in EASI score from baseline at Week 16. | Week 16 | 
| Part B: Percentage of Participants Who Achieved EASI-90 (≥90% Improvement From Baseline) at Week 16 | The EASI score is used to measure the severity and extent of AD and measured erythema, infiltration, excoriation, and lichenification on 4 anatomic regions of the body: head, trunk, upper, and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores indicating the worse severity of AD. EASI-90 responders were the participant who achieved ≥90% overall improvement in EASI score from baseline at Week 16. | Week 16 | 
| Part B: Change From Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis (AD) 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. A negative change from baseline indicated improvement. | Week 16 | 
| Part B: Change From Baseline in Patient Oriented Eczema Measure (POEM) at Week 16 | The POEM is a 7-item questionnaire that assesses disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding and weeping) with a scoring system of 0 (absent disease) to 28 (severe disease) (high score indicative of poor quality of life [QOL]). A negative change from baseline indicated improvement. | Week 16 | 
| Part B: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) at Week 16 | The SCORAD index is a clinical tool for assessing the severity of atopic dermatitis (AD). Extent and intensity of eczema as well as subjective signs (insomnia, etc.) are assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). A negative change from baseline indicated improvement. | Week 16 | 
| Part B: Change From Baseline in Participant's Sleep Quality NRS at Week 16 | A sleep diary is completed by the parent/caregiver, included 2 questions assessing the caregiver's sleep, and 6 questions assessing the child's sleep based on caregiver observation. Sleep diary items, either alone or in combination serve as subjective measures of sleep quality, difficulty falling asleep, nighttime awakenings, and sleep duration. Sleep quality is measured using an 11-point NRS (0 to 10) in which 0 indicates worst possible sleep while 10 indicates best possible sleep. | Week 16 | 
| Part B: Change From Baseline in Participant's Skin Pain NRS at Week 16 | Skin pain was assessed by the parent/caregiver and measured using a 11-point scale (0 to 10) in which 0 indicated no pain while 10 indicated worst pain possible. A negative change from baseline indicated improvement. | Week 16 | 
| Part B: Change From Baseline in Dermatitis Family Index (DFI) at Week 16 | DFI is a 10-item questionnaire with items inquiring about housework, food preparation, sleep, family leisure activity, shopping, expenditure, tiredness, emotional distress, relationships, and impact of helping with treatment on the primary caregiver's life. DFI questions were scored on a four-point Likert scale ranging from 0 to 3, so that the total DFI score ranges from 0 to 30. Timeframe of reference was the past week. A higher DFI score indicated greater impairment in family Quality of life (QOL) as affected by atopic dermatitis. A negative change from baseline indicated improvement. | Week 16 | 
| Part B: Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) at Week 16 | CDLQI is a validated 10 question tool to measure impact of skin disease on QOL in children by assessing how much the skin problem has affected the subjects over past week. Nine questions were scored as follows: Very much = 3, Quite a lot = 2, Only a little = 1, Not at all or unanswered = 0. Question 7 has an added possible response, which was scored as 3. CDLQI equals the sum of the score of each question (max. = 30, min. = 0). Higher the score, the greater the impact on QOL. A negative change from baseline indicated improvement. | Week 16 | 
| Part B: Change From Baseline in Infants' Dermatology Quality of Life Index (IDQOL) at Week 16 | Infants' Dermatitis Quality of Life Index (IDQOL) is used to evaluate quality of life for subjects of age less than 4 years. IDQOL questionnaires were designed for infants (below the age of 4 years) with atopic dermatitis. The IDQOL was calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score in each questionnaire, the more quality of life is impaired. A negative change from baseline indicated improvement. | Week 16 | 
| Part B: Percentage of Topical Corticosteroid (TCS) Medication-free Days From Baseline to Week 16 | Percentage of TCS medication-free days was calculated as the number of days that a subject used neither TCS/TCI nor system rescue therapy divided by the study days. | Baseline up to Week 16 | 
| Part B: Mean Weekly Dose of Low Potency TCS in Grams From Baseline to Week 16 | Mean weekly dose of TCS in grams/week for low potency TCS from baseline to Week 16 is reported. | Baseline up to Week 16 | 
| Part B: Mean Weekly Dose of TCS in Grams for Medium or High Potency TCS From Baseline to Week 16 | Mean weekly dose of TCS in grams/week for medium or high potency TCS from baseline to Week 16 is reported. | Baseline up to Week 16 | 
| Part B: Mean Number of Caregiver Missed Work Days Through Week 16 | Mean of number of caregiver missed work days through Week 16 is reported. | Baseline through Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eczema