Efficacy and Safety of Dupilumab in Combination With Tofacitinib in Moderate to Severe Adult AD Patients

Inclusion Criteria:

1. Have the ability to understand the content of the research and voluntarily sign theICF.

2. 18 years old≤ age ≤ 60 years old (calculated from the date of signing the ICF), maleor female.

3. The diagnosis of AD at screening meets the consensus criteria for dermatology in theUnited States (2014) (see Appendix), and the disease has been in condition for ≥half a year before screening, and all of the following conditions are met atscreening and randomization: A. EASI score ≥ 12 points at screening and randomization; B. IGA score ≥ 3 points atscreening and randomization (0-4 points IGA scale, 3 points are moderate, 4 pointsare severe); C. AD involvement of BSA ≥10% at screening and randomization; D. Weeklyaverage of daily peak pruritus NRS score at randomization ≥ 4 points.

4. Subjects of childbearing potential and their partners agree to use effectivecontraceptive measures throughout the study period (from signing the ICF to 3 monthsafter the last study drug administration) .

5. Able to communicate well with the investigator and comply with the follow-uprequirements of the protocol.

Exclusion Criteria:

Subjects with any of the following cannot be enrolled in this study:

1. Allergy to any ingredient in dupilumab or tofacitinib, or allergy or intolerance toother oral JAK inhibitors.

2. Use of any of the following medications or treatments:

3. Received treatment with other oral JAK inhibitors within 1 month prior tobaseline, or lack of efficacy/intolerance to other oral JAK inhibitors in thepast, including but not limited to baricitinib, upadatinib and abuxitinib;

4. Use of excessive pilumab within 6 weeks prior to baseline;

5. Within 3 months (or within 5 drug half-lives, whichever is longer) prior tobaseline, use of other systemic biologics other than dupilumab that are knownor likely to affect AD (such as IL-13 receptor antibody [tracilumab], IL-31Rαantibody [nimolizumab], etc.);

6. Within 4 weeks (or within 5 half-lives, whichever is longer) prior to baseline,have used any kind of systemic therapy for AD: immunosuppressants (such ascyclosporine, methotrexate, azathioprine, mycophenolate mofetil, etc.),glucocorticoids, PDE-4 inhibitors, etc.;

7. Treatment with phototherapy (narrowband ultraviolet B [NBUVB], ultraviolet B [UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]), tanning bed, orany other luminescent device within 4 weeks prior to baseline;

8. Allergen-specific immunotherapy (desensitization therapy) within 6 months priorto baseline;

9. Vaccination with any live vaccine or live attenuated vaccine within 12 weeksprior to baseline; or anticipated need to receive a live or live attenuatedvaccine during the study, including at least 12 weeks after the last dose ofthe investigational drug;

10. Treatment with any drug or medical device clinical study within 3 months priorto baseline or within 5 half-lives of the drug (whichever is longer, if known),or currently enrolled in another interventional study.

11. Laboratory abnormalities that meet any of the following criteria during thescreening period:

12. Hemoglobin < 90.0 g/L;

13. White blood cell count< 2.5×109/L;

14. Neutrophil count< 1.5×109/L;

15. Lymphocyte count<0.8×109/L;

16. Platelet count< 100×109/L;

17. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or totalbilirubin (TBIL) >2×ULN;

18. Serum creatinine> 1.2 times ULN; h Any clinically significant other laboratorytest abnormalities (as judged by the investigator) that may interfere with theevaluation of the results of this study.

19. Have a history or abnormality of any of the following:

20. Presence of other cutaneous comorbidities other than AD that may interfere withstudy assessments;

21. Subject has active/severe concomitant disease/symptoms (e.g., unstable chronicasthma, etc.) that may require systemic hormonal therapy or interfere withstudy participation, or requires active and frequent monitoring;

22. Have a history of 2 or more episodes of herpes zoster, or have a history ofdisseminated (even a single episode) of herpes zoster, or disseminated (even asingle episode) of herpes simplex infection;

23. Active tuberculosis or γ-interferon release assay at screening (e.g.,QUANTIFERON-TB® GOLD, T-SPOT. TB TEST OR OTHER γ-INTERFERON RELEASE ASSAYEQUIVALENT INDEX) IS POSITIVE

24. Hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or syphilis infection:

25. Active skin infection, non-skin infection, or other persistent/chronicinfection or invasive infection, which meets the following conditions: 1) skininfection: including bacterial, fungal or viral infection, requiring systemictreatment within 4 weeks prior to the baseline visit, or superficial skininfection within 1 week prior to the baseline visit, or may affect theevaluation of AD lesions; 2) Non-skin infection: need to be given systemicnon-gastrointestinal anti-infective therapy within 4 weeks before the baselinevisit, or need to receive oral anti-infective therapy within 2 weeks before thebaseline visit; 3) Persistent/chronic infection: such as chronic recurrentinfection and/or active viral infection such as chronic pyelonephritis,bronchiectasis or osteomyelitis, which is judged by the investigator to beunsuitable for participating in this study; 4) Invasive infection: knownhistory of invasive infection (e.g., listeriosis and histoplasmosis).

26. Patients who have had thromboembolism (including deep vein thrombosis,pulmonary embolism, arterial thrombosis, etc.) in the past, or other high-riskgroups prone to thromboembolism (such subjects are not suitable forparticipation in this study as judged by the investigator based on clinicalevaluation);

27. Has any of the following history/abnormalities of cardiovascular disease: 1)moderate to severe congestive heart failure (New York Heart Association ClassIII or IV); 2) Cerebrovascular accident, myocardial infarction, coronary arterystent implantation; 3) poorly controlled or refractory hypertension (systolicblood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥100 mmHg after drugcontrol); 3) There are significant abnormalities in the ECG examination, andparticipation in the clinical study may pose unacceptable risks to the subjectas judged by the investigator, including but not limited to severe arrhythmias,QT interval (QTcF) corrected for heart rate using Fridericia's formula, >480 ms (see Appendix 10 for the calculation formula); 4) Other cardiovascular-relatedabnormalities/medical history, which, in the judgment of the investigator, arenot suitable for participation in this study.

28. Has a history of gastrointestinal perforation (except appendicitis orpenetrating injury), diverticulitis;

29. Conditions that may interfere with drug absorption, including, but not limitedto, short bowel syndrome, gastrectomy, or specific types of bariatric surgery (e.g., gastric bypass); Subjects with a history of gastric banding/segmentationwere not excluded;

30. Those who have a history of lymphoproliferative disorders, or have relevantsymptoms/signs that have not been ruled out of lymphoproliferative disorders;

31. History of any malignancy, with the exception of successfully treatednon-melanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix;

32. Organ transplant patients, who require continuous use of immunosuppressants;

33. History of drug or alcohol abuse within 6 months prior to screening;

34. Have a history of nodules or masses (e.g., pulmonary nodules, thyroid nodules,incomplete resection), malignancy cannot be ruled out or there is a possibilityof malignant progression, and close observation is required as assessed by aspecialist (at least once every six months); p Have undergone major surgery within 8 weeks prior to baseline; q Has other clinically significant medical conditions that may affect the subject'sparticipation in this study or make the subject no longer suitable to receive aninvestigational drug product as a candidate (such as any disease that, in thejudgment of the investigator, would put the subject at risk for safety byparticipating in the study, or any disease during the study that would affect theefficacy or safety analysis if the disease/condition worsens).

35. Pregnant or lactating women, or women who plan to become pregnant or breastfeedingduring the study.

36. Any reason that, in the opinion of the investigator, would preclude the subject'sparticipation in the study.