Clinical trial NCT03389893: Effect of Dupilumab (Anti-IL4Rα) on the Host-Microbe Interface in Atopic Dermatitis
Official title: Effect of Dupilumab (Anti-IL4Rα) on the Host-Microbe Interface in Atopic Dermatitis, Dupilumab Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Atopic Dermatitis (AD)
Keywords: randomized double-masked (blind) placebo-controlled trial
T helper 2 (Th2) effect
cutaneous microbial community
skin barrier
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Regeneron Pharmaceuticals
name: Sanofi
name: Atopic Dermatitis Research Network
name: Rho Federal Systems Division, Inc.
First posted: 2018-01-04
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Staphylococcus Aureus Abundance on Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up
timeFrame: Day 28 (Post treatment initiation)
Secondary outcomes:
measure: Staphylococcus Aureus Abundance on Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up
timeFrame: Day 0 (Prior to treatment), 3, 7, 14, 21, 42, 77 and 112
measure: Staphylococcus Aureus Abundance on Non-lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up
timeFrame: Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112
measure: 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
timeFrame: Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112
measure: 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
timeFrame: Day 0 (Prior to treatment), 7, 14, 21, 28, 42, 77 and 112
measure: Transepidermal Water Loss (TEWL) Slope on Non-Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up
timeFrame: Day 0 (Prior to treatment), 7, 14, 21, 28, 42, 77 and 112
measure: 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
timeFrame: Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112
measure: Investigator Global Assessment (IGA) Score Within Each Treatment Group, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up
timeFrame: Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112
measure: SCORing Atopic Dermatitis (SCORAD) Score Within Each Treatment Group, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up
timeFrame: Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112
measure: 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
timeFrame: Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112
Other outcomes:
measure: EXPLORATORY: Composition of Bacterial Taxa
timeFrame: Day 0 (Prior to treatment), 16 weeks
measure: EXPLORATORY: Abundance of Bacterial Taxa in Lesional and Non-lesional Skin
timeFrame: Day 0 (Prior to treatment), 16 weeks
measure: EXPLORATORY: Gene Expression in the Skin Transcriptome in Non-lesional Skin
timeFrame: Day 0 (Prior to treatment) and 7
measure: EXPLORATORY: Gene Expression in the Skin Transcriptome in Lesional Skin
timeFrame: Day 0 (Prior to treatment), 7, and 21
measure: EXPLORATORY: Lipid Profiles of Non-Lesional and Lesional Skin
timeFrame: Day 0 (Prior to treatment), 16 weeks
measure: EXPLORATORY: Expression of S. Aureus Superantigens and Toxins on Lesional and Non-Lesional Skin
timeFrame: Day 0 (Prior to treatment), 16 weeks
measure: EXPLORATORY: Confocal Imaging of Tight Junctions and Relationship to LCs in the Epidermis From Non-Lesional Skin
timeFrame: Days 0 (Prior to treatment), 7 and 21
measure: EXPLORATORY: Percent of Coagulase-Negative Staphylococci [CoNS] Isolates That Kill S. Aureus on Lesional and Non-Lesional Skin
timeFrame: Day 0 (Prior to treatment), 16 weeks
measure: EXPLORATORY: Peripheral Blood Mononuclear Cells (PBMCs) Immunoprofiling
timeFrame: Days 0 (Prior to treatment), 14 and 28
measure: EXPLORATORY: Levels of Serum Biomarkers (e.g. Th2 Biomarkers)
timeFrame: Day 0 (Prior to treatment), 16 weeks
measure: EXPLORATORY: Levels of Serum Anti-Drug Antibodies (ADA)
timeFrame: Day 0 (Prior to treatment), 16 weeks
measure: EXPLORATORY: The Presence of Single Nucleotide Polymorphisms (SNPs)
timeFrame: Day 0 (Prior to treatment)
Locations:
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Rochester
name: Lisa A. Beck, MD
role: STUDY_CHAIR
References: