Study to Investigate the Efficacy and Safety of Dupilumab Administered With Topical Corticosteroids (TCS) in Participants ≥6 to <12 Years With Severe Atopic Dermatitis (AD)

Dermatitis, Atopic Clinical Trial

Official title:

A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Dupilumab Administered Concomitantly With Topical Corticosteroids in Patients, ≥6 Years to <12 Years of Age, With Severe Atopic Dermatitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03345914
• Other study ID #: R668-AD-1652
• Secondary ID: 2016-004997-16
• Status: Completed
• Phase: Phase 3
• Start date: November 17, 2017
• Est. completion date: September 10, 2019

Study information

• Verified date: July 2020
• Source: Regeneron Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main objective of the trial is to demonstrate the efficacy of dupilumab administered concomitantly with topical corticosteroids (TCS) in participants ≥6 years to <12 years of age with severe atopic dermatitis (AD).

The secondary objective is to assess the safety of dupilumab administered concomitantly with TCS in patients ≥6 years to <12 years of age with severe AD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 367
• Est. completion date: September 10, 2019
• Est. primary completion date: June 20, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 11 Years

Eligibility

Key Inclusion Criteria:

1. Diagnosis of AD according to the American Academy of Dermatology consensus criteria (Eichenfield 2003) at screening visit

2. Chronic AD diagnosed at least 1 year prior to the screening visit

3. IGA = 4 at screening and baseline visits

4. EASI =21 at the screening and baseline visits

5. BSA =15% at screening and baseline visits

6. Documented recent history (within 6 months before the baseline visit) of inadequate response to topical AD medication(s)

7. At least 11 (of a total of 14) applications of a stable dose of topical emollient (moisturizer) twice daily during the 7 consecutive days immediately before the baseline visit

Key Exclusion Criteria:

1. Participation in a prior dupilumab clinical study

2. Treatment with a systemic investigational drug before the baseline visit

3. Treatment with a topical investigational drug within 2 weeks prior to the baseline visit

4. Treatment with crisabarole within 2 weeks prior to the baseline visit

5. History of important side effects of medium potency topical corticosteroids (e.g, intolerance to treatment, hypersensitivity reactions, significant skin atrophy, systemic effects), as assessed by the investigator or patient's treating physician

6. Treatment with a topical calcineurin inhibitor (TCI) within 2 weeks prior to the baseline visit

7. Having used any of the following treatments within 4 weeks before the baseline visit, or any condition that, in the opinion of the investigator, is likely to require such treatment(s) during the first 4 weeks of study treatment:

1. Immunosuppressive/immunomodulating drugs (e.g, systemic corticosteroids, cyclosporine, mycophenolate-mofetil, interferon gamma, Janus kinase inhibitors, azathioprine, methotrexate, etc.)

2. Phototherapy for AD

8. Treatment with biologics, as follows:

1. Any cell-depleting agents including but not limited to rituximab:

within 6 months before the baseline visit, or until lymphocyte and CD 19+ lymphocyte count returns to normal, whichever is longer

2. Other biologics: within 5 half-lives (if known) or 16 weeks before the baseline visit, whichever is longer

9. Treatment with a live (attenuated) vaccine within 4 weeks before the baseline visit

10. Body weight <15 kg at baseline

Note: Other Inclusion/ Exclusion criteria apply

Related Conditions & MeSH terms

• Dermatitis
• Dermatitis, Atopic

Intervention

Drug:
• Dupilumab
Pharmaceutical form: Solution for injection in pre-filled syringe; Route of administration: Subcutaneous (SC)
• Matching Placebo
Pharmaceutical form: Solution for injection; Route of administration: Subcutaneous (SC)

Other:
• Background Treatment: Topical Corticosteroids
All participants are required to initiate treatment with a medium potency TCS using a standardized regimen. It is recommended that participants use triamcinolone acetonide 0.1% cream, fluocinolone acetonide 0.025% cream, or clobetasone butyrate 0.05%.
• Background Treatment: Moisturizers
All participants should apply moisturizers throughout the study. All types of moisturizers are permitted, but participants may not initiate treatment with prescription moisturizers. Participants may continue using stable doses of such moisturizers if initiated before the screening visit.

Locations

Country	Name	City	State
Canada	Regeneron Research Site	Calgary	Alberta
Canada	Regeneron Research Site	Markham	Ontario
Canada	Regeneron Research Site	Montréal	Quebec
Canada	Regeneron Research Site	Peterborough	Ontario
Czechia	Regeneron Research Site	Kutná Hora
Czechia	Regeneron Research Site	Ústí Nad Labem
Germany	Regeneron Research Site	Bad Bentheim
Germany	Regeneron Research Site	Dresden	Sachsen
Germany	Regeneron Research Site	Gera	Thuringen
Germany	Regeneron Research Site	Hamburg
Germany	Regeneron Research Site	Muenchen	Bavaria
Germany	Regeneron Research Site	Munster	Nordrhein-Westfalen
Germany	Regeneron Research Site	Osnabruck	Lower Saxony
Poland	Regeneron Research Site	Bialystok
Poland	Regeneron Research Site	Bydgoszcz
Poland	Regeneron Research Site	Gdansk
Poland	Regeneron Research Site	Katowice
Poland	Regeneron Research Site	Katowice
Poland	Regeneron Research Site	Katowice
Poland	Regeneron Research Site	Krakow	Malopolska
Poland	Regeneron Research Site	Lódz
Poland	Regeneron Research Site	Swietokrzyskie
Poland	Regeneron Research Site	Warszawa
Poland	Regeneron Research Site	Warszawa
Poland	Regeneron Research Site	Warszawa
Poland	Regeneron Research Site	Wroclaw	Dolnoslaskie
United Kingdom	Regeneron Research Site	London
United Kingdom	Regeneron Research Site	Manchester
United Kingdom	Regeneron Research Site	Newcastle Upon Tyne
United Kingdom	Regeneron Research Site	Sheffield
United States	Regeneron Research Site	Bakersfield	California
United States	Regeneron Research Site	Bellaire	Texas
United States	Regeneron Research Site	Birmingham	Alabama
United States	Regeneron Research Site	Charleston	South Carolina
United States	Regeneron Research Site	Chicago	Illinois
United States	Regeneron Research Site	Coral Gables	Florida
United States	Regeneron Research Site	Denver	Colorado
United States	Regeneron Research Site	Forest Hills	New York
United States	Regeneron Research Site	Gahanna	Ohio
United States	Regeneron Research Site	Gilbert	Arizona
United States	Regeneron Research Site	Long Beach	California
United States	Regeneron Research Site	Macon	Georgia
United States	Regeneron Research Site	Minneapolis	Minnesota
United States	Regeneron Research Site	Mission Viejo	California
United States	Regeneron Research Site	New York	New York
United States	Regeneron Research Site	Norfolk	Virginia
United States	Regeneron Research Site	Normal	Illinois
United States	Regeneron Research Site	North Charleston	South Carolina
United States	Regeneron Research Site	Philadelphia	Pennsylvania
United States	Regeneron Research Site	Portland	Oregon
United States	Regeneron Research Site	Rochester	New York
United States	Regeneron Research Site	Rockville	Maryland
United States	Regeneron Research Site	Rolling Hills Estates	California
United States	Regeneron Research Site	Saint Louis	Missouri
United States	Regeneron Research Site	San Antonio	Texas
United States	Regeneron Research Site	San Diego	California
United States	Regeneron Research Site	Sandy Springs	Georgia
United States	Regeneron Research Site	Seattle	Washington
United States	Regeneron Research Site	Tampa	Florida
United States	Regeneron Research Site	Tampa	Florida
United States	Regeneron Research Site	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Regeneron Pharmaceuticals	Sanofi

Countries where clinical trial is conducted

United States,  Canada,  Czechia,  Germany,  Poland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Investigator's Global Assessment (IGA) 0 or 1 at Week 16	The IGA was an assessment instrument used in clinical studies to rate the severity of AD globally, based on a 5-point scale ranging from 0 (clear) to 4 (severe). The full analysis set (FAS) included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Participants with missing score at Week 16 were considered as a non-responder.	Week 16
Secondary	Percentage of Participants With Eczema Area and Severity Index -75 (EASI-75) (= 75 Percent (%) Improvement From Baseline) at Week 16	The EASI assesses severity and extent of atopic dermatitis (AD). Scores range from 0-72. Four AD disease characteristics (erythema, thickness, scratching, and lichenification) were assessed for severity on a scale of "0" (absent) through "3" (severe). Area of involvement assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Participants with missing score at week 16 were considered as a non-responder.	Week 16
Secondary	Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score at Week 16	The EASI assesses severity and extent of AD. Scores range from 0-72. Four AD disease characteristics (erythema, thickness, scratching, and lichenification) were assessed for severity on a scale of "0" (absent) through "3" (severe). Area of involvement assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).	Baseline (Day 1), Week 16
Secondary	Percent Change From Baseline in Weekly Average of Daily Worst Itch Score at Week 16	The worst itch scale was a simple assessment tool that participants used to report the intensity of their pruritus (itch). This was an 11-point scale (0 to 10) in which 0 indicated no itching while 10 indicated worst itching possible. Participants were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as the worse of the scores for the 2 questions. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).	Baseline (Day 1), Week 16
Secondary	Percentage of Participants With Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Itch Score =3 Points at Week 16	The worst itch scale was a simple assessment tool that participants used to report the intensity of their pruritus (itch). This was an 11-point scale (0 to 10) in which 0 indicated no itching while 10 indicated worst itching possible. Participants were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as the worse of the scores for the 2 questions. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Participants with missing score at week 16 were considered as a non-responder. Here "Number of participants analyzed" = number of participants who were evaluated for this specific endpoint.	Week 16
Secondary	Percentage of Participants With Improvement (Reduction From Baseline) of Weekly Average of Daily Worst Itch Score =4 Points at Week 16	The worst itch scale was a simple assessment tool that participants used to report the intensity of their pruritus (itch). This was an 11-point scale (0 to 10) in which 0 indicated no itching while 10 indicated worst itching possible. Participants were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as the worse of the scores for the 2 questions. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Participants with missing score at week 16 were considered as a non-responder. Here "Number of participants analyzed" = number of participants who were evaluated for this specific endpoint.	Week 16
Secondary	Percentage of Participants Achieving Eczema Area and Severity Index - 50 (EASI-50) (= 50% Improvement From Baseline) at Week 16	The EASI assessed severity and extent of AD. Scores range from 0-72. Four AD disease characteristics (erythema, thickness, scratching, and lichenification) were assessed for severity on a scale of "0" (absent) through "3" (severe). Area of involvement assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Participants with missing score at week 16 were considered as a non-responder.	Week 16
Secondary	Percentage of Participants Achieving Eczema Area and Severity Index - 90 (EASI - 90) (= 90% Improvement From Baseline) at Week 16	The EASI assessed the severity and extent of atopic dermatitis (AD). Scores range from 0-72. Four AD disease characteristics (erythema, thickness, scratching, and lichenification) were assessed for severity on a scale of "0" (absent) through "3" (severe). Area of involvement assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Participants with missing score at week 16 were considered as a non-responder.	Week 16
Secondary	Time to Achieve = 4 Point Reduction of Weekly Average of Daily Worst Itch Score From Baseline During the 16-week Treatment Period	The worst itch scale: simple assessment tool that participants used to report intensity of their pruritus (itch). This was an 11-point scale (0 to 10) where 0 (no itching) and 10 (worst itching) possible. Participants were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, & follow-up period). The daily worst itch score was calculated as worse of scores for 2 questions. FAS was used. Time to event is calculated in weeks as (date of first event - date of first dose)/7. The event of NRS reduction = 4 was based on observed data without setting data to be non-responder after rescue treatment use. Here "Number of participants analyzed" = number of participants who were evaluated for this specific endpoint & "NA" represents "Not computable" as only 12.3% of participants achieved NRS reduction during 16-week treatment period & hence median time to achieve = 4-point reduction of NRS for placebo +TCS treated participants could not be reported.	Baseline (Day 1) up to Week 16
Secondary	Time to Achieve = 3 Point Reduction of Weekly Average of Daily Worst Itch Score From Baseline During the 16-week Treatment Period	The worst itch scale: a simple assessment tool that participants used to report intensity of their pruritus (itch). This was an 11-point scale (0 to 10) where 0 (no itching) & 10 (worst itching) possible. Participants were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, & follow-up period). Daily worst itch score was calculated as worse of scores for 2 questions. FAS was used. Time to event is calculated in weeks as (date of first event - date of first dose)/7. The event of NRS reduction = 3 was based on observed data without setting data to be non-responder after rescue treatment use. Here "Number of participants analyzed" = number of participants who were evaluated for this specific endpoint & "NA" represents "Not computable" as only 21.1% of participants achieved NRS reduction during 16-week treatment period & hence median time to achieve = 3-point reduction of NRS for placebo +TCS treated participants could not be reported.	Baseline (Day 1) up to Week 16
Secondary	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 using the rule of nines (the possible highest score for each region is: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]) and were reported as a percentage of all major body sections combined. The proportion assigned to different body regions were different in younger children as compared to older children (head and neck area is assigned a higher proportion in younger children as compared to older children). The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).	Baseline (Day 1), Week 16
Secondary	Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) at Week 16	SCORAD was 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). The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).	Baseline (Day 1), Week 16
Secondary	Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) at Week 16	CDLQI was a validated 10 question tool to measure the impact of skin disease on the quality of life (QOL) in children by assessing how much the skin problem has affected the participant over the 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 (maximum = 30, minimum = 0). Higher the score, the greater the impact on QOL. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Data presented reflects the mean & standard deviation of the CDLQI total scores.	Baseline (Day 1), Week 16
Secondary	Change From Baseline in Patient Oriented Eczema Measure (POEM) at Week 16	POEM was a 7-item, validated questionnaire used to assess disease symptoms in children and adults. The format was a response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency of these disease symptoms 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 = all days) with a scoring system of 0 to 28; the total score reflected the disease-related morbidity. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). A high score is indicative of a poor quality of life.	Baseline (Day 1), Week 16
Secondary	Change From Baseline in Weekly Average of Daily Worst Itch Score at Week 16	The worst itch scale was a simple assessment tool that participants used to report the intensity of their pruritus (itch). This was an 11-point scale (0 to 10) in which 0 indicated no itching while 10 indicated worst itching possible. Participants were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as the worse of the scores for the 2 questions. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).	Baseline (Day 1), Week 16
Secondary	Change From Baseline in Dermatitis Family Index (DFI) at Week 16	DFI was a 10-item questionnaire with items inquiring about housework, food preparation, sleep, family leisure activity, shopping, expenditure, tiredness, emotional distress, relationships and the impact of helping with treatment on the primary caregiver's life. The 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. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).	Baseline (Day 1) , Week 16
Secondary	Change From Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pediatric Anxiety Short Form Scale Total Score at Week 16	PROMIS Anxiety instrument measures self-reported fear (fearfulness, panic), anxious misery (worry, dread), hyperarousal (tension, nervousness, restlessness), & somatic symptoms related to arousal (racing heart, dizziness). Each question has 5 response options ranging in value from 1-5 (1=Never, 2=Almost never, 3=Sometimes, 4=Often, 5=Almost Always). Total raw score calculated using sum of response values: for 8-item form, lowest possible is 8 & highest possible is 40; For 6-item form: lowest possible is 6; highest possible is 30. Higher score indicates greater severity of symptoms.	Baseline (Day 1), Week 16
Secondary	Change From Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pediatric Depressive Symptoms Short Form Scale Score at Week 16	PROMIS Depression instrument assesses self-reported negative mood (sadness/guilt), views of self (self-criticism/worthlessness) & social cognition (loneliness/interpersonal alienation), & decreased positive affect & engagement (loss of interest/meaning/purpose). Each question has 5 response options with values from 1-5 (1=Never, 2=Almost never, 3=Sometimes, 4=Often, 5=Almost Always). Total raw score is the sum of response values. For 8-item form, lowest possible is 8, highest is 40; for 6-item form, lowest possible is 6, highest is 30. Higher score indicates greater severity of symptoms.	Baseline (Day 1), Week 16
Secondary	Percentage of Participants Having at Least One Skin Infection Treatment Emergent Adverse Event (TEAE) (Excluding Herpetic Infections) Through Week 16	Treatment-emergent adverse events (TEAEs) were defined as adverse events (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. 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-subjects 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. Percentage of participants having at least one skin infection TEAE (Excluding Herpetic Infections) through Week 16 were reported. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).	Baseline through Week 16
Secondary	Percentage of Participants Having at Least One Serious Treatment Emergent Adverse Event (TEAE) Through Week 16	Treatment-emergent adverse events (TEAEs) were defined as adverse events (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. 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-participants 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. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized).	Baseline (Day 1) through Week 16
Secondary	Proportion of Topical Corticosteroid (TCS) Medication-free Days From Baseline to Week 16	Proportion of TCS medication-free days is calculated as the number of days that a participant used neither TCS/TCI nor system rescue therapy divided by the study days of each period. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Here "Number of participants analyzed" = number of participants who were evaluated for this specific endpoint.	Baseline (Day 1), Week 16
Secondary	Mean Weekly Dose of Topical Corticosteroid (TCS) in Grams for Low or Medium Potency TCS From Baseline to Week 16	Mean weekly dose of TCS in grams for low or medium potency TCS from baseline to Week 16 were reported. The FAS included all randomized participants. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Here "Number of participants analyzed" = number of participants who were evaluated for this specific endpoint.	Baseline (Day 1), Week 16