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

AUClast was defined as area under the serum concentration time-curve from zero to the last measured concentration.

Time frame: Post-dose on Days 1, 3, 8, 18, and 29

Population: The PKAS included all treated participants who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

Dose normalized AUClast was calculated by AUClast/dose.

Time frame: Post-dose on Days 1, 3, 8, 18, and 29

Population: The PKAS included all treated participants who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

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 (\[mg/L\]/\[mg/kg\]).

Time frame: Post-dose on Days 1, 3, 8, 18, and 29

Population: The PKAS included all treated participants who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

Clast is the last measurable serum concentration of dupilumab.

Time frame: Post-dose on Days 1, 3, 8, 18, and 29

Population: The PKAS included all treated participants who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

Serum concentration of functional dupilumab was reported.

Time frame: Post-dose on Days 1, 3, 8, 18, and 29

Population: The Pharmacokinetic Analysis Set (PKAS) included all treated participants who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

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.

Time frame: Baseline up to Week 4

Population: The safety analysis set (SAF) included all participants who received any study drug and were analyzed based on the actual treatment received.

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.

Time frame: Baseline up to Week 4

Population: The SAF included all participants who received any study drug and were analyzed based on the actual treatment received.

Tlast was defined as the last time point with a measurable serum concentration of dupilumab.

Time frame: Post-dose on Days 1, 3, 8, 18, and 29

Population: The PKAS included all treated participants who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

Tmax was obtained directly from the concentration versus time curve.

Time frame: Post-dose on Days 1, 3, 8, 18, and 29

Population: The PKAS included all treated participants who received any study drug (safety analysis set) and who had at least 1 non-missing functional dupilumab measurement following the administration of the first dose of study drug.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Participants were considered as non-responders after initiation of rescue treatment.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, adverse event (AE), lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using multiple imputation (MI). Participants were considered as non-responders after initiation of rescue treatment.

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.

Time frame: Baseline up to Day 57

Population: The ADA Analysis Set (AAS) included all treated participants who received any study drug and who had at least 1 non-missing ADA result following the first dose of study drug.

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.

Time frame: Baseline up to Week 4

Population: The SAF included all participants who received any study drug and was analyzed based on the actual treatment received.

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.

Time frame: Week 4

Population: SAF included all participants who received any study drug and was analyzed based on the actual treatment received.

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.

Time frame: Week 4

Population: The SAF included all participants who received any study drug and was analyzed based on the actual treatment received.

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.

Time frame: Week 4

Population: SAF included all participants who received any study drug and was analyzed based on the actual treatment received.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

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.

Time frame: Week 16

Population: The FAS included all randomized participant. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

Mean of number of caregiver missed work days through Week 16 is reported.

Time frame: Baseline through Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).

Mean weekly dose of TCS in grams/week for low potency TCS from baseline to Week 16 is reported.

Time frame: Baseline up to Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).

Mean weekly dose of TCS in grams/week for medium or high potency TCS from baseline to Week 16 is reported.

Time frame: Baseline up to Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).

Treatment emergent (TE): Post-dose positive result when baseline results were negative.

Time frame: Baseline up to Day 197

Population: AAS included all participants who received any study drug and who had at least one non-missing ADA result after the first dose of the study drug.

Time frame: Baseline through Week 16

Population: SAF included all randomized participants who received at least one dose of study drug and was analysed as treated.

Time frame: Baseline through Week 16

Population: SAF included all randomized participants who received at least one dose of study drug and was analysed as treated.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Participants were considered as non-responders after initiation of rescue treatment.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Participants were considered as non-responders after initiation of rescue treatment.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Participants were considered as non-responders after initiation of rescue treatment.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, lack of efficacy were imputed as non responder. Missing data due to any other reason including COVID-19 were imputed using MI. Participants were considered as non-responders after initiation of rescue treatment.

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.

Time frame: Baseline up to Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).

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.

Time frame: Week 16

Population: FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomisation (as randomised). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline worst observation carried forward (WOCF). If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

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.

Time frame: Week 16

Population: The FAS included all randomized participant. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.

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.

Time frame: Week 16

Population: The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Missing data due to withdrawn consent, AE, or lack of efficacy and data after rescue were imputed by post baseline WOCF. If there was no post baseline assessment, the baseline value was used. Missing values due to other reasons including COVID-19 were imputed by MI approach.