Effect of Dupilumab (Anti-IL4Rα) on the Host-Microbe Interface in Atopic Dermatitis

Study Overview
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Brief Summary
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The purpose of this study is to understand the effect that T helper 2 (Th2) blockade has on well-described pathophysiological features of Atopic Dermatitis (AD), for example: barrier, epidermal activation, dysbiosis and epidermal lipids.

Detailed Description
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This is a multi-center, randomized, double-masked, placebo-controlled trial investigating the effect of 6 weeks of dupilumab treatment on quantitative and qualitative measures of cutaneous microbial community structure, skin barrier biology, and circulating T cell profiles, in adults with chronic moderate-to-severe atopic dermatitis (AD). After obtaining informed consent, eligible participants will return to clinic for their Treatment Initiation Visit (Day 0) and will be randomized 2:1 active to placebo. Participants will receive three doses of dupilumab or placebo based on their randomization assignment. The first dose (600 mg loading dose of dupilumab or placebo) will be administered on Day 0 and the second and third doses (300 mg dupilumab or placebo) on Day 14 and Day 28, respectively. Participants will return to clinic on Days 3, 7, and 21 during the double-masked portion of the study. Participants will begin the open-label extension (OLE) at Day 42 and will receive dupilumab (600 mg loading dose [two 300 mg injections] for those initially randomized to the placebo group and a 300 mg dose plus placebo injection for those initially randomized to the dupilumab group). Participants will return to clinic on Days 77 and 112 during the OLE portion of the study. During all visits (Day 0-Day 112), Adverse Events (AEs), concomitant medications, and medical history will be assessed and physical exams including assessment of AD severity will be performed. Blood, urine, skin swabs, skin tape strips, and skin biopsies, as applicable, will be collected, and barrier assessments will be performed per the Schedule of Events, per protocol. Samples will be collected prior to dupilumab or placebo administration on Days 0, 14, 28, and 42. After Day 112, a follow-up call (Day 182) will be made to assess for pregnancy, current medications, and adverse events (AEs). If concerns arise between regularly scheduled visits, participants will be instructed to contact study personnel and may be asked to return to the study site for an Unscheduled Visit. Participants may be asked to return for Unscheduled Visits, as needed for the duration of the study, to provide additional blood, skin swabs, skin tape strips, or skin biopsies,as applicable, for further mechanistic and functional studies, if biosamples are lost or destroyed, or if insufficient yields were obtained at a previous study visit.

Official Title
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Effect of Dupilumab (Anti-IL4Rα) on the Host-Microbe Interface in Atopic Dermatitis, Dupilumab Study

Conditions
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Atopic Dermatitis (AD)

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be able to understand and provide informed consent Chronic AD, (according to the Atopic Dermatitis Research Network [ADRN] Standard Diagnostic Criteria), that has been present for at least 3 years before the Screening Visit EASI score ≥12 at the Screening Visit and ≥16 at the Treatment Initiation Visit Investigator Global Assessment (IGA) score ≥3 (on the 0-4 IGA scale) at the Screening and Treatment Initiation Visits ≥10% body surface area of AD involvement at the Screening and Treatment Initiation Visits Must have active lesions (minimum of 3 of at least 4x4 cm^2 each on the upper or lower extremities, excluding the palms of the hands and soles of the feet) at the Screening and Treatment Initiation Visits Documented recent history (within 6 months before the Screening Visit) of inadequate response to outpatient treatment with topical corticosteroids of medium to high potency (± topical calcineurin inhibitors as appropriate), or for whom topical treatments are otherwise inadvisable Must agree to apply a stable dose of a topical emollient (moisturizer) at least twice daily for at least 7 days before the Treatment Initiation Visit, and must confirm application at the Treatment Initiation Visit Individuals with asthma must adhere to asthma controller medication(s) for the duration of the study including the open-label and follow-up portions Females of childbearing potential must have a negative pregnancy test at the Screening and Treatment Initiation Visits Females with reproductive potential* and sexually active must agree to use FDA approved methods of birth control for the duration of the study, including during the open-label and follow-up portions of the study: --FDA approved methods of birth control include hormonal contraceptives, intrauterine device, double barrier contraception (i.e., condom plus diaphragm), or male partner with documented vasectomy. ---*Menopause is defined as at least 12 consecutive months without menses; if in question, a follicle stimulating hormone of ≥25 U/mL must be documented. Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be documented, as applicable; if documented, women with these conditions are not required to use additional contraception. Males who are sexually active must agree to use an acceptable method of birth control (e.g. barrier methods with vaginal spermicide, surgical sterilization or surgically sterilized partner), or have a female partner practicing an approved birth control method for females as described in Inclusion Criterion above. Willing and able to comply with all clinic visits and study-related procedures Able to understand and complete study-related questionnaires Exclusion Criteria: Inability or unwillingness of an individual to give written informed consent or comply with study protocol Known systemic hypersensitivity to any of the excipients of the dupilumab or placebo study products Known or suspected immunosuppression, including history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent immune-compromised status, as judged by the investigator Known history of human immunodeficiency virus (HIV) infection Ocular disorder that, in the opinion of the investigator, could adversely affect the individual's risk for study participation. Examples include, but are not limited to, individuals with a history of or active case of: herpes keratitis, Sjogren's Syndrome, keratoconjunctivitis sicca or Dry Eye Syndrome that requires daily use of supplemental lubrication, or ocular condition(s) requiring the regular use of ocular corticosteroids or cyclosporine. Parasitic infection, except for vaginal trichomoniasis, within 12 months of the Treatment Initiation Visit, or high risk for contracting parasitic infections (e.g., living in or traveling to endemic areas) Presence of skin comorbidities that may interfere with study assessments History of malignancy within 5 years before the Treatment Initiation Visit except completely treated in situ carcinoma of the cervix, and completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin or melanoma in situ History of non-malignant lymphoproliferative disorders History of alcohol or drug abuse within 2 years before the Screening Visit Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect the individual's participation in the study. Examples include, but are not limited to, individuals with short life expectancy, uncontrolled diabetes (HbA1c ≥9%), cardiovascular conditions (e.g., stage III or IV cardiac failure according to the New York Heart Association classification), severe renal conditions (e.g., individuals on dialysis), hepato-biliary conditions (e.g., Child-Pugh class B or C), neurological conditions (e.g., demyelinating diseases), active major autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic diseases. Any other medical or psychological condition including relevant laboratory abnormalities at screening that, in the opinion of the investigator, suggests a new and/or insufficiently understood disease, may present an unreasonable risk to the study participant as a result of his/her participation in this clinical trial, may make individual's participation unreliable, or may interfere with study assessments. This includes hypersensitivity to local anesthetics (e.g., lidocaine or Novocain), bleeding disorders, treatment with anticoagulants or other conditions that make the biopsy procedure inadvisable. Planned major surgical procedure during the screening period or study treatment (i.e. Screening through Day 112) Member of the investigational team or his/her immediate family Pregnant or breast-feeding women, or women planning to become pregnant or breastfeed during the study including the open-label and follow up portions of the study Individuals unwilling to use adequate birth control, if of reproductive potential and sexually active. Adequate birth control is defined as agreement to consistently practice an approved method of contraception for the duration of the study, including the open-label and follow up portions of the study. History of keloid formation History of serious life-threatening reaction to latex, tape, or adhesives Prior treatment with dupilumab Individuals with asthma who have required use of a systemic corticosteroid within 3 months prior to the Treatment Initiation Visit or who require a dose greater than 880 mcg/day of fluticasone propionate or equivalent inhaled corticosteroid to maintain asthma control Treatment with biologics as follows: Any cell-depleting agents, including but not limited to rituximab, within 6 months before the Treatment Initiation Visit, or until lymphocyte and CD 19+ lymphocyte count returns to normal, whichever is longer Infliximab, adalimumab, golimumab, certolizumab pegol, abatacept, etanercept, anakinra within 16 weeks before the Treatment Initiation Visit for any indication, or Other biologics within 5 half-lives (if known) or 16 weeks before the Treatment Initiation Visit, whichever is longer Treatment with a live (attenuated) vaccine within 12 weeks before the Treatment Initiation Visit or planning to receive a live vaccine during the study (through Day 182) Use of an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before the Treatment Initiation Visit Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks before the Treatment Initiation Visit, or superficial skin infections within 1 week before the Treatment Initiation Visit The following treatments within 4 weeks before the Treatment Initiation Visit, or any condition that, in the opinion of the investigator, will likely require such treatment(s) during the screening period and study treatment (i.e., Screening through Day 112): Systemic corticosteroids Immunosuppressive/immunomodulating drugs (e.g., cyclosporine, mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, or methotrexate) Use of phototherapy (such as narrow band ultraviolet B [NBUVB], ultraviolet B [UVB], ultraviolet A1 [UVA1], psoralen + UVA [PUVA]) or a tanning booth/parlor within 4 weeks of the Treatment Initiation Visit Treatment with bleach bath within 3 weeks before the Treatment Initiation Visit Use of a chlorinated hot tub within 3 weeks before the Treatment Initiation Visit Treatment with topical corticosteroids, phosphodiesterase inhibitors (crisaborole), or calcineurin inhibitors (tacrolimus or pimecrolimus) within 1 week before the Treatment Initiation Visit Initiation of treatment of AD with prescription moisturizers or moisturizers containing ceramide, hyaluronic acid, urea, or filaggrin during the screening period (participants may continue using stable doses of such moisturizers if initiated before the Screening Visit) Planned or anticipated use of any prohibited medications or procedures during the screening period and study treatment (i.e., Screening through Day 112)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Dupilumab w/OLE<br>Participants will receive a loading dose of dupilumab (two 300 mg subcutaneous (subcut) injections (total of 600 mgs)) on Day 0, followed by 300 mg dose of dupilumab by subcut injection every 2 weeks (Days 14 and 28). Open Label Extension (OLE): Participants will begin a 10 week OLE on Day 42, beginning with a loading dose of two subcut administered injections (one 300 mg dose of dupilumab and one dose of placebo, in order to protect prior masking/blind).Participants will then maintain a regimen of 300 mg of dupilumab by subcut injection every two weeks through Day 98. The subcut injections will be administered in the abdomen (except for the 2 inches (5 cm) around the navel-not allowed), thighs, or upper arms. Injection sites will be rotated with each dose. | Drug: Dupilumab<br>* Dupilumab, an interleukin (IL)-4 receptor alpha (IL-4Rα) antagonist, is indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. (FDA approved on March 28, 2017.)<br>* Other names: IL4Ra mAb;Drug: Placebo<br>* Placebo will contain the identical formulation as the dupilumab formulation without the active mAb and will be given by exactly the same route and schedule through Day 28.<br>* Other names: Dupilumab placebo;|
| Placebo Comparator: Placebo Comparator w/OLE<br>Participants will receive a loading dose of placebo (two placebo subcutaneous (subcut) injections) on Day 0 followed by one dose of placebo by subcut injections every 2 weeks (Days 14 and 28). Open Label Extension (OLE): Participants will begin a 10 week OLE on Day 42, beginning with a loading dose of dupilumab (two 300 mg subcut injections (total of 600 mgs)-protection of prior masking/blind maintained). Participants will then maintain a regimen of 300 mg of dupilumab by subcut injection every two weeks through Day 98. The subcut injections will be administered in the abdomen (except for the 2 inches (5 cm) around the navel-not allowed), thighs, or upper arms. Injection sites will be rotated with each dose. | Drug: Dupilumab<br>* Dupilumab, an interleukin (IL)-4 receptor alpha (IL-4Rα) antagonist, is indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. (FDA approved on March 28, 2017.)<br>* Other names: IL4Ra mAb;Drug: Placebo<br>* Placebo will contain the identical formulation as the dupilumab formulation without the active mAb and will be given by exactly the same route and schedule through Day 28.<br>* Other names: Dupilumab placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Staphylococcus Aureus Abundance on Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | Staphylococcus aureus (S. aureus) abundance was measured by microbial DNA (femA qPCR) on lesional skin at Day 28, measurement is expressed in relative Colony Forming Units (rCFU)/cm^2). The abundance of S. aureus is summarized as the geometric mean ratio (and corresponding 95% confidence interval) between the dupilumab and placebo arms. The geometric mean ratio is reported from an ANCOVA model with fixed effects for clinical site, disease severity at Day 0 (as measured by EASI >21.1 [severe] or ≤21.1 [non-severe]) and S. aureus abundance at Day 0. | Day 28 (Post treatment initiation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Staphylococcus Aureus Abundance on Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | Staphylococcus aureus (S. aureus) abundance was measured by microbial DNA (femA qPCR) on lesional skin at Days 0, 3, 7, 14, 21, 42, 77 and 112. The abundance of S. aureus is summarized as the geometric mean ratio (GMR) and corresponding 95% confidence interval between the dupilumab and placebo arms. The GMR is reported from a linear mixed model for repeated measures with fixed effects for S. aureus abundance on lesional skin at Day 0, treatment arm, clinical site, disease severity at Day 0 as measured by EASI ≥ 21.1 or < 21.1, time point of measurement (as a categorical variable), and an interaction term between treatment arm and pre-specified time point(s). A linear mixed model similar to the model specified above was fit for every time point measured. The model was used to estimate the GMR between treatment arms at Days 77 and 112 and the ratio within treatment arm between Day 77 and Day 42 and between Day 112 and Day 42. | Day 0 (Prior to treatment), 3, 7, 14, 21, 42, 77 and 112 | 
| Staphylococcus Aureus Abundance on Non-lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | Staphylococcus aureus (S. aureus) abundance was measured by microbial DNA (femA qPCR) on non-lesional skin at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112. The abundance of S. aureus is summarized as the geometric mean ratio (GMR) and corresponding 95% confidence interval between the dupilumab and placebo arms. The GMR is reported from a linear mixed model for repeated measures with fixed effects for S. aureus abundance on non-lesional skin at Day 0, treatment arm, clinical site, disease severity at Day 0 as measured by EASI ≥ 21.1 or < 21.1, time point of measurement (as a categorical variable), and an interaction term between treatment arm and pre-specified time point(s). A linear mixed model similar to the model specified above was fit for every time point measured. The model estimated the GMR between treatment arms at Days 77 and 112 and the ratio within treatment arm between Day 77 and Day 42 and between Day 112 and Day 42. | Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112 | 
| Transepidermal Water Loss (TEWL) of Non-lesional and Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | TEWL assessment is a noninvasive in vivo measurement of water loss across the stratum corneum that is used to characterize skin barrier function. Basal TEWL =baseline measure (prior to tape stripping). An increase in TEWL values shows damage to the skin barrier function. Basal TEWL was measured on non-lesional and lesional skin. Basal TEWL is summarized as the mean difference between the dupilumab and placebo arms. The mean difference is reported from two linear mixed models for repeated measures (lesional and non-lesional) with fixed effects for treatment arm, basal TEWL at Day 0, clinical site, and disease severity at Day 0 as measured by EASI ≥ 21.1 or < 21.1 at Days 3, 7, 14, 21, 28, and 42. Two linear mixed models similar to the models specified above were fit for every time point measured. The model was used to estimate the mean difference between treatment arms at Days 77 and 112 and the ratio within treatment arm between Day 77 and Day 42 and between Day 112 and Day 42. | Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112 | 
| Transepidermal Water Loss (TEWL) Area Under the Curve (AUC) on Non-Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | TEWL skin barrier assessment was assessed prior to tape stripping and repeated after 5, 10, and 15 tape strips. TEWL AUC was calculated using the trapezoidal rule and represents skin barrier integrity. An increase in TEWL values shows damage to the skin barrier function. TEWL AUC was measured on non-lesional skin at Days 0, 7, 14, 21, 28, 42, 77 and 112. The mean difference (between Groups) is reported from a linear mixed model for repeated measures with a random effect for participant and fixed effects for treatment arm, TEWL AUC at Day 0, clinical site, and disease severity at Day 0 as measured by EASI ≥ 21.1 or < 21.1 at Days 7, 14, 21, 28, and 42. A linear mixed model similar to the model specified above was fit for every time point measured. The model was used to estimate the mean difference between treatment arms at Days 77 and 112 and the mean difference within treatment arm between Day 77 and Day 42 and between Day 112 and Day 42. | Day 0 (Prior to treatment), 7, 14, 21, 28, 42, 77 and 112 | 
| Transepidermal Water Loss (TEWL) Slope on Non-Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | The skin tape strip collection was comprised of 1 set of 15 strips from non-lesional skin and was collected as part of the TEWL skin barrier assessment. The TEWL values measured at every 5 tape strips were used to model the TEWL slope. TEWL slope assesses skin barrier integrity. An increase in TEWL values shows damage to the skin barrier function. TEWL slope is summarized as the mean difference (and corresponding 95% confidence interval) between the dupilumab and placebo arms. The mean difference in slope for each Day is reported from a linear mixed model for repeated measures with a fixed effects for basal TEWL prior to tape stripping, treatment arm, clinical site, disease severity at Day 0 as measured by EASI ≥ 21.1 or < 21.1, tape strip number, and an interaction term between treatment arm and tape strip number. | Day 0 (Prior to treatment), 7, 14, 21, 28, 42, 77 and 112 | 
| Eczema Area and Severity Index (EASI) Score Within Each Treatment Group, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | EASI is a composite score (range: 0-72) measuring physical signs of atopic dermatitis, including area of involvement and severity. Severity components include: erythema, papulation, excoriation and lichenification [0=absent, 1=mild, 2=moderate, 3=severe] for each body region (head/neck, trunk, arms, legs). Area of involvement (%) is assessed for each body region. Area and severity of each body region is weighted based on size of region, and region scores are added for the total score. Scores ≤7 are considered mild, >7 and ≤21 are considered moderate, and >21 are considered severe. The mean EASI score in each treatment arm is reported from a linear mixed model for repeated measures with fixed effects for EASI at Day 0, treatment arm, clinical site, time point of measurement, and an interaction term between treatment arm and pre-specified time point(s), Additionally, a similar model was fit using all time points. | Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112 | 
| Investigator Global Assessment (IGA) Score Within Each Treatment Group, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | Investigator Global Assessment (IGA) score is a subjective scale measuring disease severity. Based on a 5-point scale from 0 (completely clear) to 4 (severe). Defined score of 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe. The mean IGA score in each treatment arm is reported from a linear mixed model for repeated measures with fixed effects for IGA at Day 0, treatment arm, clinical site, disease severity at Day 0 as measured by EASI ≥ 21.1 or < 21.1, time point of measurement, and an interaction term between treatment arm and pre-specified time point(s). Additionally, a similar model was fit using all time points. | Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112 | 
| SCORing Atopic Dermatitis (SCORAD) Score Within Each Treatment Group, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | SCORAD is a composite index comprising a) the amount/extent of body surface area affected, b) subjective symptom visual analog assessments of itch and sleep loss [itch: 0 (no itch) to 10 (worst itch imaginable) / sleep loss: 0 (no sleep loss) to 10 (worst imaginable sleep loss)], and c) 6 disease intensity assessments [dryness, erythema, edema/papulation, excoriation, lichenification and oozing/crusting, each graded from 0-3: 0 (none), 1 (mild), 2 (moderate) and 3 (severe). The score ranges from 0 (no AD present) to 103 (severe). The mean SCORAD score in each treatment arm is reported from a linear mixed model for repeated measures with fixed effects for SCORAD at Day 0, treatment arm, clinical site, disease severity at Day 0 as measured by EASI ≥ 21.1 or < 21.1, time point of measurement, and an interaction term between treatment arm and pre-specified time point(s). Additionally, a similar model was fit using all time points. | Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112 | 
| Pruritus Numerical Rating Scale (Pruritus NRS) Score Within Each Treatment Group, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up | Pruritus NRS scale is an assessment tool that is used to report the average intensity of a participant's pruritus (itch) during a 24-hour recall period. Participants were asked to report the average itch experienced during the past 24 hours on a scale of 0 - 10 [0= no itch; 10= worst imaginable itch]). The mean Pruritus NRS score in each treatment arm is reported from a linear mixed model for repeated measures with fixed effects for Pruritus NRS at Day 0, treatment arm, clinical site, disease severity at Day 0 as measured by EASI ≥ 21.1 or < 21.1, time point of measurement, and an interaction term between treatment arm and pre-specified time point(s). Additionally, a similar model was fit using all time points. | Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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randomized double-masked (blind) placebo-controlled trial, T helper 2 (Th2) effect, cutaneous microbial community, skin barrier