Study of Dupilumab and Immune Responses in Adults With Atopic Dermatitis (AD)

Study Overview
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Brief Summary
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This was a 32-week, randomized, double-blind, placebo-controlled, parallel-group study assessing immunization responses to vaccination in adults with moderate to severe atopic dermatitis who are treated with subcutaneous dupilumab.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Study Investigating Vaccine Responses in Adults With Moderate to Severe Atopic Dermatitis Treated With Dupilumab

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female adults ages 18 to 64 years with Chronic AD (according to the American Academy of Dermatology Consensus Criteria, [Eichenfeld 2004])that has been present for at least 3 years before the screening visit Participants with documented recent history (within 6 months before the screening visit) of inadequate response to a sufficient course of outpatient treatment with topical AD medication(s), or for whom topical AD therapies are otherwise inadvisable (e.g., because of side effects or safety risks). Eczema Area and Severity Index (EASI) score ≥16 at the screening visit and the baseline visit Investigator's Global Assessment (IGA) score ≥3 (on the 0-4 IGA scale) at the screening and baseline visits ≥10% body surface area (BSA) of AD involvement at the screening and baseline visits Key Exclusion Criteria: Prior treatment with dupilumab (REGN668/ SAR231893) Patients needing >10 mg of daily prednisone (including equivalent doses of other steroids) or high dose systemic corticosteroids (≥2 mg/kg) for 14 days or longer during the 16 week treatment period of the study History of Guillain-Barre syndrome History of severe allergic reaction to either vaccine or to vaccine components including alum, thimerosal, phenol Patients with a severe reaction to natural rubber latex products (some packaging components of the vaccines contain rubber latex and may cause a reaction in susceptible individuals) Treatment with biologics within 4 months of baseline visit Chronic or acute infection requiring treatment with antibiotics, antivirals, antiparasitics, antifungals within 4 weeks before screening visit or superficial skin infections within 1 week of screening visit The information listed above is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial and not all inclusion/ exclusion criteria are listed.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo qw<br>Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 15. | Drug: Placebo<br>* An inactive substance containing no medicine administered via subcutaneous injection.<br>|
| Experimental: Dupilumab 300 mg qw<br>Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection qw from Week 1 to Week 15. | Drug: Dupilumab<br>* Administered via subcutaneous injection.<br>* Other names: Dupixent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Positive Response (≥4-Fold Increase) to Tetanus Toxoid (the Adacel [Tdap] Vaccine) at Week 16 | A positive response was defined as a ≥ 4-fold increase from pre-vaccination at baseline in anti-tetanus immunoglobulin G (IgG) titer for participants with a pre-vaccination tetanus antibody titers ≥ 0.1 IU/ml or a titer of ≥ 0.2 IU/ml for participants with pre-vaccination titers of <0.1 IU/ml. There was no planned statistical hypothesis testing regarding the difference in immune response between the 2 treatment groups for this study, therefore no formal statistical hypothesis between groups was performed. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Positive Response (≥2-Fold Increase) to Tetanus Toxoid (the Adacel [Tdap] Vaccine) at Week 16 | Participants with positive response defined as a ≥2-fold increase from pre-vaccination baseline in anti-tetanus IgG titer for participants with pre-vaccination tetanus antibody titers ≥0.1 IU/ml or a titer of ≥0.2 IU/ml for participants with pre-vaccination titers of <0.1 IU/ml. | Week 16 | 
| Percentage of Participants With a Positive Response (SBA Antibody Titer of ≥8 for Serogroup C) to Menomune Vaccine at Week 16 | A positive response to the Menomune vaccine was a serum bactericidal antibody (SBA) titer of ≥8 for serogroup C. | Week 16 | 
| Percentage of Participants Achieving an Investigator's Global Assessment (IGA) Score of 0 or 1 at Week 16 | IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear). Values after first rescue treatment were set to missing and participants with missing IGA scores at Week 16 were counted as non-responders. | Week 16 | 
| Percentage of Participants Achieving an Eczema Area and Severity Index-50 (EASI-50) (≥50% Improvement From Baseline) at Week 16 | The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-50 responders were the participants who achieved ≥50% overall improvement in EASI score from baseline to Week 16. Values after first rescue treatment were set to missing and participants with missing EASI score at Week 16 were counted as non-responders. | Week 16 | 
| Percentage of Participants Achieving an Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 16 | The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-75 responders were the participants who achieved ≥75% overall improvement in EASI score from baseline to Week 16. Values after first rescue treatment use were set to missing and participants with missing EASI score at Week 16 were considered as non-responders. | Week 16 | 
| Change From Baseline in Peak Weekly Averaged Pruritis Numerical Rating Scale (NRS) Scores at Week 16 | Pruritus NRS was an assessment tool that was used to report the intensity of participant's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Participants were asked the following question: how would a participant rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Weekly average obtained in the 7-day period prior to the baseline visit. Values after first rescue medication use were set to missing and missing values were imputed by Last observation carried forward (LOCF). | Baseline to Week 16 | 
| Change From Baseline in Body Surface Area (BSA) Affected by 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. Values after first rescue medication use were set to missing and missing values were imputed by LOCF. | Baseline to Week 16 | 
| Change From Baseline in Global Individual Signs Score (GISS) Components (Erythema, Infiltration/Papulation, Excoriations and Lichenification) at Week 16 | Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0 = none, 1 = mild, 2 = moderate and 3 = severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease). Values after first rescue treatment were set to missing. Analysis was completed using MMRM model which includes treatment, randomization strata, visit, baseline value, treatment-by-visit interaction, and baseline-by-visit interaction as covariates. These results are observed results without imputation. | Baseline to Week 16 | 
| Changes From Baseline in GISS Cumulative Score to Week 16 | Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0 = none, 1 = mild, 2 = moderate and 3 = severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease). Values after first rescue medication use were set to missing and missing values were imputed by LOCF. | Baseline to Week 16 | 
| Change in Patient Oriented Eczema Measure (POEM) Score From Baseline to Week 16 | The POEM was 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]). Values after first rescue medication use were set to missing and missing values were imputed by LOCF. | Baseline to Week 16 |