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

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.

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)