Inclusion Criteria:

• Male or female, 18 to 75 years.
• Chronic AD, according to American Academy of Dermatology Consensus Criteria (Eichenfield, 2014), that has been present for at least 3 years before the screening visit .
• EASI score ≥16 at the screening and baseline visits.
• IGA score ≥3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at screening and baseline visits.
• ≥ 10% BSA of AD involvement at the screening and baseline visits.
• Baseline peak Pruritus NRS score for maximum itch intensity ≥4.
  • NOTE:  Baseline peak Pruritus NRS score for maximum itch intensity will be determined based on the average of daily NRS scores for maximum itch intensity (the daily score ranges from 0 to 10) during the 7 days immediately preceding randomization. A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average score. For patients who do not have at least 4 daily scores reported during the 7 days immediately preceding  the planned randomization date, randomization should be postponed until this requirement is met, but without exceeding the 35-day maximum duration for screening.
• Documented recent history (within 6 months before the screening visit) of inadequate response to topical AD medication(s) or for whom topical treatments are medically inadvisable (e.g., intolerance, because of important side effects, or safety risks).
  • NOTE:  Inadequate response is defined as failure to achieve and maintain remission or a low disease activity state (comparable to IGA 0=clear to 2=mild) despite treatment with a daily regimen of topical corticosteroids (TCS) of medium to higher potency (± topical calcineurin inhibitor [TCI] as appropriate), applied for at least 28 days or for the maximum duration recommended by the product prescribing information (e.g., 14 days for super-potent TCS), whichever is shorter.
• Patients with documented systemic treatment for AD (e.g., systemic immunosuppressant drugs like cyclosporine, methotrexate, corticosteroids, etc.) in the past 6 months are also considered to be inadequate responders to topical treatments and are potentially eligible for treatment with REGN3500 after appropriate washout.  Important side effects or safety risks are those that outweigh the potential treatment benefits and include intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and systemic effects, as assessed by the investigator or by the patient’s treating physician.  Acceptable documentation includes contemporaneous chart notes that record topical medication prescription and treatment outcome, or investigator documentation based on communication with the patient’s treating physician. If documentation is inadequate, potential patients may be offered a course of treatment with a daily regimen of TCS of medium or higher potency (±TCI as appropriate), applied for at least 28 days during the screening period, or for the maximum duration recommended by the product prescribing information, whichever is shorter. Patients who demonstrate inadequate response during this period, as defined above, will be eligible for inclusion in the study following appropriate washout.
• Have applied a stable dose of topical bland emollient (moisturizer) at least twice daily for at least the 7 consecutive days immediately before the baseline visit (i.e., baseline/randomization visit would be the eighth day; see exclusion criterion 7 regarding restrictions on the kind of emollients permitted during the study).
• Willing and able to comply with all clinic visits and study-related procedures.
• Provide informed consent signed by study patient or legally acceptable representative.
• Able to understand and complete study-related questionnaires.

Exclusion Criteria:

• Participation in a prior anti-IL-33 class medication clinical study.
• Body mass index <16 kg/m2.
• Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before the baseline visit.
• 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:  
  • Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, cyclosporine, mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, methotrexate, etc.);
  • Phototherapy for AD.
• Treatment with TCS, TCI, or topical crisaborole within 1 week before the baseline visit.  Treatment with biologics as follows:
  • Any cell-depleting agents including but not limited to rituximab: within 6 months before the baseline visit, or until lymphocyte count returns to normal, whichever is longer;
  • Other biologics (including dupilumab): within 5 half-lives (if known) or 16 weeks prior to baseline visit, whichever is longer.
• Initiation of treatment of AD with prescription moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products during the screening period (patients may continue using stable doses of such moisturizers if initiated before the screening visit).
• Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the baseline visit.
• Planned or anticipated use of any prohibited medications and procedures during study treatment.
• Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit.
• Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline visit, or superficial skin infections within 1 week before the baseline visit.
  • NOTE: patients may be re-screened after infection resolves.
• Known or suspected history of immunosuppression, including history of invasive opportunistic infections (eg, tuberculosis [TB]*, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution: or unusually frequent, recurrent, or prolonged infections, per investigator judgment.
  • * Patients with a positive TB QuantiFERON test result at screening will be excluded from the study.
• History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening.
• Positive with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus antibody (HCV Ab) at the screening visit.
• At baseline, presence of any conditions listed as criteria for study drug discontinuation.
• Presence of skin comorbidities that may interfere with study assessments.
• History of cancer, with the exceptions of:
  • Patients with adequately treated basal cell carcinoma or carcinoma in situ of the cervix;
  • Patients with other malignancies that have been successfully treated for >10 years prior to screening where, in the judgement of both the investigator and the treating physician, appropriate follow-up has revealed no evidence of recurrence through time of screening.
• Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection, unless clinical and (if necessary) laboratory assessment have ruled out active infection before randomization.
• History of alcohol or drug abuse within 2 years of the screening visit.
• Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect the patient’s participation in the study. Examples include, but are not limited to, patients with short life expectancy, patients with uncontrolled diabetes (hemoglobin A1c [HbA1c] ≥9%), patients with uncontrolled cerebrocardiovascular conditions (e.g., myocardial infarction, unstable arterial hypertension, unstable angina, cerebrovascular accident, and stage III or IV cardiac failure according to the New York Heart Association classification), severe renal conditions (e.g., patients on dialysis), hepatobiliary 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. The specific justification for patients excluded under this criterion will be noted in study documents (chart notes, case report forms [CRFs], etc.).
• Any other medical or psychological condition (including relevant laboratory abnormalities at screening) that, in the opinion of the investigator, may suggest a new and/or insufficiently understood disease, may present an unreasonable risk to the study patient as a result of his/her participation in this clinical study, may make patient’s participation unreliable, or may interfere with study assessments. The specific justification for patients excluded under this criterion will be noted in study documents (chart notes, CRFs, etc.).
• Planned or anticipated major surgical procedure during the patient’s participation in this study.
• Patient is a member of the investigational team or his/her immediate family.
• Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study.
• Women of childbearing potential (WOCBP)* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 20 weeks after the last dose of study drug. Highly effective contraceptive measures include:
  • stable use of oral contraceptives associated with inhibition of ovulation (such as contraceptives containing estrogen/progesterone or high dose progesterone) initiated 2 or more menstrual cycles prior to screening;
  • intrauterine device (IUD); intrauterine hormone-releasing system (IUS);
  • bilateral tubal ligation;
  • vasectomized partner with confirmed sterility (ie, patient’s medical record);
  • and/or sexual abstinence†, ‡;
  • contraception for male patients is not required§.
    • * Postmenopausal women must be amenorrheic for at least 12 months (without an alternative medical cause) in order not to be considered of childbearing potential. Amenorrheic status should be confirmed by demonstrating follicle-stimulating hormone levels (FSH) consistent with postmenopausal status according to laboratory ranges. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
    • † Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
    • ‡ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.
    • § Based on the known target biology of the study drugs and the extremely low levels of study drug expected to reach the fetus via seminal fluid, the use of contraception in treated males to prevent female partner and/or fetal exposure is considered unnecessary.
• Known sensitivity to doxycycline and/or tetracycline or to any of the components of the investigational product formulation.
• Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities will be excluded from this study (as required by country regulations).