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

Dermatitis, Atopic Clinical Trial

— Liberty AD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03346434
• Other study ID #: R668-AD-1539
• Secondary ID: 2016-000955-28
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: November 30, 2017
• Est. completion date: July 8, 2021

Study information

• Verified date: July 2022
• Source: Regeneron Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

1. 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.

2. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 202
• Est. completion date: July 8, 2021
• Est. primary completion date: July 8, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 5 Years

Eligibility

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

Related Conditions & MeSH terms

• Dermatitis
• Dermatitis, Atopic

Intervention

Drug:
• Dupilumab
Solution for injection, subcutaneous (SC)
• Matching placebo
Solution for injection, subcutaneous (SC)

Locations

Country	Name	City	State
Germany	Regeneron Investigational Site	Dresden	Sachsen
Germany	Regeneron Investigational site	Frankfurt/ Main
Germany	Regeneron Investigational Site	Kiel
Germany	Regeneron Investigational Site	Muenchen
Germany	Regeneron Investigational site	Muenchen
Germany	Regeneron Investigational site	Muenster	North Rhine-Westphal
Germany	Regeneron Investigational Site	Osnabrück	Lower Saxony
Poland	Regeneron Investigational Site	Bialystok
Poland	Regeneron Investigational Site	Katowice
Poland	Regeneron Investigational Site	Krakow
Poland	Regeneron Investigational Site	Ostrowiec Swietokrzyski
Poland	Regeneron Investigational Site	Warszawa
Poland	Regeneron Investigational Site	Warszawa
United Kingdom	Regeneron Investigational Site	Manchester	Lancashire
United Kingdom	Regeneron Investigational Site	Sheffield	South Yorkshire
United States	Regeneron Investigational Site	Ann Arbor	Michigan
United States	Regeneron Investigational Site	Austin	Texas
United States	Regeneron Investigational Site	Birmingham	Alabama
United States	Regeneron Investigational Site	Boston	Massachusetts
United States	Regeneron Investigational Site	Charleston	South Carolina
United States	Regeneron Investigational Site	Chicago	Illinois
United States	Regeneron Investigational Site	Columbus	Georgia
United States	Regeneron Investigational Site	Coral Gables	Florida
United States	Regeneron Investigational Site	Forest Hills	New York
United States	Regeneron Investigational Site	Gilbert	Arizona
United States	Regeneron Investigational Site	Hackensack	New Jersey
United States	Regeneron Investigational Site	Lincoln	Nebraska
United States	Regeneron Investigational Site	Long Beach	California
United States	Regeneron Investigational site	Los Angeles	California
United States	Regeneron Investigational Site	Macon	Georgia
United States	Regeneron Investigational Site	Milwaukee	Wisconsin
United States	Regeneron Investigational Site	New York	New York
United States	Regeneron Investigational Site	Norfolk	Virginia
United States	Regeneron Investigational Site	North Charleston	South Carolina
United States	Regeneron Investigational Site	Palo Alto	California
United States	Regeneron Investigational Site	Philadelphia	Pennsylvania
United States	Regeneron Investigational Site	Portland	Oregon
United States	Regeneron Investigational Site	Rochester	New York
United States	Regeneron Investigational Site	Rockville	Maryland
United States	Regeneron Investigational Site	Rolling Hills Estates	California
United States	Regeneron Investigational Site	Saint Louis	Missouri
United States	Regeneron Investigational Site	San Antonio	Texas
United States	Regeneron Investigational Site	San Diego	California
United States	Regeneron Investigational Site	Sandy Springs	Georgia
United States	Regeneron Investigational Site	Seattle	Washington
United States	Regeneron Investigational Site	Tampa	Florida
United States	Regeneron Investigational Site	Washington	District of Columbia
United States	Regeneron Investigational Site	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Regeneron Pharmaceuticals	Sanofi

Countries where clinical trial is conducted

United States,  Germany,  Poland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part B: Number of Participants With at Least One Serious Adverse Event (SAE) Through Week 16		Baseline through Week 16
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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