Inclusion Criteria (Parts A & B):

• Male or female, ≥ 12 years of age.
• A documented diagnosis of EoE by endoscopic biopsy prior to screening, as demonstrated by intraepithelial eosinophilic infiltration (peak cell count ≥ 15 eos/hpf) from at least one esophageal region and performed after at least 8 weeks of  treatment with a high-dose PPI regimen. If the patient discontinued PPI therapy, the biopsy must have been performed within 2 weeks of the date of discontinuation.
• If a prior (historical) endoscopic biopsy meeting these criteria is not available (or no prior biopsy is available), patients who meet other clinical and laboratory eligibility criteria will undergo treatment with a high-dose PPI regimen for at least 8 weeks during the screening period before their baseline endoscopy/biopsies. 
  • Note: If the patient is already using an acceptable high dose PPI regimen at the time of the screening visit, the baseline endoscopy may be scheduled at any point during the screening period after 8 weeks of treatment have been documented.
• Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial eosinophilic infiltration (peak cell count ≥ 15 eos/hpf) in at least 2 of the 3 biopsied esophageal regions (proximal, mid, or distal).
• History (by patient report) of an average of at least 2 episodes of dysphagia (with intake of solids) per week in the 4 weeks prior to screening.
• At least 4 episodes of dysphagia in the 2 weeks prior to baseline, documented via eDiary, at least 2 of which require liquids, coughing or gagging, vomiting, or medical attention to obtain relief.
• Completed at least 11 of 14 days of DSQ eDiary data entry in the 2 weeks prior to the baseline visit (visit 3).
• Baseline DSQ score ≥ 10.
• Able to understand and complete study-related questionnaires.
• Willing and able to comply with clinic visits and study-related procedures.
• Provide informed consent signed by study patient or legally acceptable representative. For adolescents, parent or legal guardian must provide signed informed consent (patients must also provide separate informed assent to enroll in the study, and the assent documented either in a separate informed assent form [IAF] or in the informed consent form [ICF] signed by the parent(s)/legal guardian [as appropriate based on local regulations and requirements]).

Exclusion Criteria (Parts A and B):

• Body weight ≤ 40 kg.
• Prior participation in a dupilumab clinical trial, or past or current treatment with dupilumab.
• Initiation or change of a food-elimination diet regimen or re-introduction of a previously eliminated food group in the 6 weeks prior to screening. Patients on a food-elimination diet must remain on the same diet throughout the study.
• Other causes of esophageal eosinophilia or the following conditions: hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).
  • Note: Patients with eosinophilic gastroenteritis are eligible, provided they meet other eligibility criteria.
• Active Helicobacter pylori infection.
• History of achalasia, Crohn’s disease, ulcerative colitis, celiac disease, and prior esophageal surgery.
• Any esophageal stricture unable to be passed with a standard, diagnostic, 9 to10 mm upper endoscope or any critical esophageal stricture that requires dilation at screening.
• History of bleeding disorders or esophageal varices.
• Treatment with swallowed topical corticosteroids within 8 weeks prior to baseline.
• Initiation, discontinuation, or change in the dosage regimen of the following medications within 8 weeks prior to the baseline endoscopy:
  • Proton pump inhibitors (except for patients who require a PPI trial prior to baseline endoscopy);
  • Leukotriene inhibitors;
  • Nasal and/or inhaled corticosteroids;
  • Patients on a stable dose of these medications for at least 8 weeks prior to the baseline endoscopy may be included in the study, but must not change the dose during the study.
• Initiation, discontinuation, or change in the dosage regimen of SC immunotherapy (SCIT). 
  • Patients on a stable dose of these medications for at least 1 year prior to visit 1 may be included in the study, but must not change the dose during the study.
• Treatment with sublingual immunotherapy (SLIT).
• Treatment with oral immunotherapy (OIT) within 6 months prior to visit 1.
• The following treatments within 3 months prior to screening, or any condition that, in the opinion of the investigator, is likely to require such treatment(s) during the study:
  • Systemic immunosuppressant/immunomodulating drugs, including but not limited to systemic corticosteroids, omalizumab, cyclosporine, mycophenolate-mofetil, interferon-gamma [IFN-γ], Janus kinase inhibitors, azathioprine, and methotrexate.
  • Note: One-time use of a corticosteroid as a part of the anesthetic preparation used during each endoscopy procedure is allowed.
• Treatment with an investigational drug within 2 months or within 5 half-lives (if known), whichever is longer, prior to visit 1.
• Planned or anticipated use of any prohibited medications and procedures during the study.
• Planned or anticipated major surgical procedure during the study.
• Treatment with a live (attenuated) vaccine within 4 weeks prior to the baseline visit
• Active parasitic infection or suspected parasitic infection, unless clinical and (if necessary) laboratory assessments have ruled out active infection before randomization
• Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before baseline visit.
  • Note: patient may be re-screened after the infection resolves.
• Known or suspected immunodeficiency disorder, including history of invasive opportunistic infections (eg, tuberculosis [TB], non-tuberculous mycobacterial infections, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency, or prolonged infections suggesting an immune-compromised status, as judged by the investigator.
  • Tuberculosis testing will be performed on a country-by-country basis according to local guidelines if required by regulatory authorities or ethics committees (ECs).
• Known history of human immunodeficiency virus (HIV) infection.
• Established diagnosis of hepatitis B viral infection at the time of screening or positive for hepatitis B surface antigen (HBsAg) at the time of screening:
  • Patients who have gained immunity for hepatitis B virus infection after vaccination (patients who are HBsAg negative, hepatitis B surface antibody [HBsAb] positive, and hepatitis B core antibody [HBcAb] negative are eligible for the study);
  • Patients with positive HBcAb are eligible for the study only if hepatitis B virus DNA level is undetectable.
• Established diagnosis of hepatitis C viral (HCV) infection at the time of screening Patients positive for hepatitis C Ab are eligible for the study only if HCV RNA is negative.
• On current treatment for hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis, or hepatic failure, or has evidence of liver disease as indicated by persistent (confirmed by repeated tests ≥ 2 weeks apart) elevated  .transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) more than 3 times the upper limit of normal [ULN] during the screening period).
• Any of the following abnormal lab values at screening:
• Platelets <100 ×103/μL;
• Neutrophils <1.5 × 103/μL;
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2.
  • Note: If an abnormal value is detected at screening, a repeat test should be performed to confirm the abnormality. Only if the repeat test confirms the abnormality would the patient be categorized as a screen failure. eGFR will be calculated using the Modification of Diet in Renal Disease (MDRD) equation in adult patients and using the Bedside Schwartz formula in patients < 18 years of age.
• 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 short life expectancy, uncontrolled diabetes, cardiovascular conditions (e.g., NYHA Class III or IV cardiac failure), severe renal conditions (e.g., severe nephrotic syndrome), 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 endocrinologic, 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 [CRF], etc.).
• History of malignancy within 5 years prior to screening, except completely treated in situ carcinoma of the cervix and completely treated non-metastatic squamous or basal cell carcinoma of the skin.
• History of alcohol or drug abuse within 6 months prior to screening.
• Any other medical or psychological condition including relevant laboratory abnormalities at screening that, in the opinion of the investigator, 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 trial, 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.
• Patient or his/her immediate family is a member of the investigational team.
• Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study
• Women of childbearing potential* 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 12 weeks after the last dose. Highly effective contraceptive  easures include:
  • Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
  • Intrauterine device; intrauterine hormone-releasing system;
  • Bilateral tubal ligation;
  • Vasectomized partner;
  • And/or sexual abstinence†, ‡.
  • * Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of childbearing potential. 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 are not acceptable methods of contraception. Female condom and male condom should not be used together.
• Known systemic hypersensitivity to dupilumab or the excipients of the drug product.

Exclusion Criteria (Part C - the Open-Label Treatment Period):

• Patients who, during the double-blind treatment period, developed a serious adverse event (SAE) and/or adverse event (AE) deemed related to study drug, which in the opinion of the investigator could indicate that continued treatment with study drug may present an unreasonable risk for the patient.
• Patients who, during the double-blind treatment period, were prematurely withdrawn because of a protocol violation, poor compliance, or inability to complete required study assessments.
• Patients who became pregnant during the double-blind treatment period.
• Patients who are prematurely discontinued from study drug due to an AE (patients who are prematurely discontinued from study drug due to lack of effectiveness are eligible to enter Part C).
• Patients who did not undergo endoscopy with biopsies prior to receiving rescue treatment.
• Systemic hypersensitivity to dupilumab or the excipients of the drug product based on participation in Part A or Part B.