Tralokinumab Monotherapy for Moderate to Severe Atopic Dermatitis - ECZTRA 1 (ECZema TRAlokinumab Trial no. 1)

Inclusion Criteria:

1. Written informed consent and any locally required authorisation obtained from thesubject prior to performing any protocol-related procedures, including screeningevaluations.

2. Age 18 and above.

3. Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria for AD (34;Appendix 5).

4. Diagnosis of AD for ≥1 year.

5. Subjects who have a recent history (within 1 year before the screening visit) ofinadequate response to treatment with topical medications or for whom topicaltreatments are otherwise medically inadvisable (e.g., due to important side effectsor safety risks). Inadequate response is defined as failure to achieve and maintain remission or a lowdisease activity state (comparable to IGA 0=clear to 2=mild) despite treatment witha daily regimen of TCS of medium to higher potency (±TCI as appropriate), appliedfor at least 28 days or for the maximum duration recommended by the productprescribing information (e.g., 14 days for super potent TCS), whichever is shorter. Subjects with documented systemic treatment for AD in the past year are alsoconsidered as inadequate responders to topical treatments and are potentiallyeligible for treatment with tralokinumab after appropriate washout. Important side effects or safety risks are those that outweigh the potentialtreatment benefits and include intolerance to treatment, hypersensitivity reactions,significant skin atrophy, and systemic effects, as assessed by the investigator orby the subject's treating physician.

6. AD involvement of ≥10% body surface area at screening and baseline (visit 3).

7. An EASI score of ≥12 at screening and 16 at baseline.

8. An IGA score of ≥3 at screening and at baseline.

9. A Worst Daily Pruritus numeric rating scale (NRS) average score of ≥4 during theweek prior to baseline. Worst Daily Pruritus NRS at baseline will be calculated from daily assessments ofworst itch severity (Worst Daily Pruritus NRS) during the 7 days immediatelypreceding randomisation (Day 6 to 0). A minimum of 4 Worst Daily Pruritus NRS scoresout of the 7 days is required to calculate the baseline average score. For subjectswho do not have at least 4 scores reported during the 7 days immediately precedingthe planned randomisation date, randomisation should be postponed until thisrequirement is met, but without exceeding the 6 weeks maximum duration forscreening.

10. Subjects must have applied a stable dose of emollient twice daily (or more, asneeded) for at least 14 days before randomisation (refer to exclusion criterion no. 8 for limitations regarding emollients).

11. Women of childbearing potential must use a highly effective* form of birth control (confirmed by the investigator) throughout the trial and at least for 16 weeks (5half lives) after last administration of IMP.

• A highly effective method of birth control is defined as one which results in alow failure rate (less than 1% per year) such as bilateral tubal occlusion,intrauterine device (IUD), intrauterine hormone-releasing system (IUS),combined (oestrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation (oral, intravaginal, transdermal),progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), sexual abstinence (when this is in line withthe preferred and usual life style of the subject), vasectomised partner (giventhat the subject is monogamous). The subjects must have used the contraceptivemethod continuously for at least 1 month prior to the pregnancy test atbaseline. A female is defined as not being of child-bearing potential if she ispostmenopausal (at least 12 months with no menses without an alternativemedical cause prior to screening), or surgically sterile (hysterectomy,bilateral salpingectomy or bilateral oophorectomy).

Exclusion Criteria:

1. Concurrent enrolment in another clinical trial where the subject is receiving anIMP.

2. Previous randomisation in tralokinumab trials.

3. Active dermatologic conditions that may confound the diagnosis of AD or wouldinterfere with assessment of treatment, such as scabies, cutaneous lymphoma, orpsoriasis.

4. Known active allergic or irritant contact dermatitis that is likely to interferewith the assessment of severity of AD.

5. Use of tanning beds or phototherapy (narrow band ultraviolet B [NBUVB], ultravioletB [UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]), within 6 weeksprior to randomisation.

6. Treatment with the following medications within 4 weeks prior to randomisation:

• Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate,cyclosporine, azathioprine, mycophenolate mofetil, Janus kinase inhibitorsetc.).

• Systemic corticosteroid use (excludes topical, inhaled, or intranasaldelivery).

• Three or more bleach baths during any week within the 4 weeks.

7. Treatment with the following medications within 2 weeks prior to randomisation

• TCS.

• TCI.

• Topical PDE 4 inhibitor.

8. Initiation of treatment of AD with prescription emollients or emollients containingadditives such as ceramide, hyaluronic acid, urea, or filaggrin degradation productsduring the screening period (subjects may continue using stable doses of suchemollients if initiated before the screening visit).

9. Receipt of live attenuated vaccines 30 days prior to the date of randomisation andduring the trial including the safety follow-up period.

• Receipt of inactive/killed vaccinations (e.g. inactive influenza) are allowed,provided they are not administered within 5 days before/after any study visit.

10. Receipt of any marketed (i.e. immunoglobulin, anti-IgE) or investigational biologicagent, including dupilumab:

• Any cell-depleting agents including but not limited to rituximab: within 6months prior to randomisation, or until lymphocyte count returns to normal,whichever is longer.

• Other biologics: within 3 months or 5 half-lives, whichever is longer, prior torandomisation.

11. Receipt of any investigational non-biologic agent within 5 half-lives prior torandomisation.

12. Receipt of blood products within 4 weeks prior to screening.

13. Major surgery within 8 weeks prior to screening, or planned in-patient surgery orhospitalisation during the trial period.

14. Known or suspected allergy or reaction to any component of the IMP formulation.

15. History of any active skin infection within 1 week prior to randomisation.

16. History of a clinically significant infection within 4 weeks prior to randomisationwhich, in the opinion of the investigator or sponsor's medical expert, maycompromise the safety of the subject in the trial, interfere with evaluation of theIMP, or reduce the subject's ability to participate in the trial. Clinicallysignificant infections are defined as:

• a systemic infection.

• a serious skin infection requiring parenteral (intravenous or intramuscular)antibiotics, antiviral, or antifungal medication.

17. A helminth parasitic infection within 6 months prior to the date informed consent isobtained that has not been treated with, or has failed to respond to, standard ofcare therapy.

18. History of anaphylaxis following any biologic therapy.

19. History of immune complex disease.

20. History of cancer:

• Subjects who have had basal cell carcinoma, localised squamous cell carcinomaof the skin or in situ carcinoma of the cervix are eligible provided that thesubject is in remission and curative therapy was completed at least 12 monthsprior to the date informed consent was obtained.

• Subjects who have had other malignancies are eligible provided that the subjectis in remission and curative therapy was completed at least 5 years prior tothe date informed consent was obtained.

21. Tuberculosis requiring treatment within the 12 months prior to screening. Evaluationwill be according to local guidelines as per local standard of care.

22. History of any known primary immunodeficiency disorder including a positive humanimmunodeficiency virus (HIV) test at screening, or the subject taking antiretroviralmedications as determined by medical history and/or subject's verbal report.

23. History of chronic alcohol or drug abuse within 12 months prior to screening, or anycondition associated with poor compliance as judged by the investigator.

24. History of attempted suicide or is at significant risk of suicide (either in theopinion of the investigator or defined as a "yes" to suicidal ideation questions no. 4 or 5 or answering "yes" to suicidal behaviour on the Columbia-Suicide SeverityRating Scale [C-SSRS] Screening version).

25. Any disorder, including but not limited to, cardiovascular, gastrointestinal,hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic,haematological, immunological, psychiatric, or major physical impairment that is notstable, in the opinion of the investigator, and could:

• Affect the safety of the subject throughout the trial.

• Influence the findings of the trial or their interpretations.

• Impede the subject's ability to complete the entire duration of trial.

26. Any clinically significant abnormal findings in physical examination, vital signs,electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis during thescreening period, which in the opinion of the investigator, may put the subject atrisk because of his/her participation in the trial, or may influence the results ofthe trial, or the subject's ability to complete entire duration of the trial.

27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.0 timesthe ULN (upper limit of normal) at screening.

28. Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb),hepatitis B core antibody (HBcAb) or hepatitis C virus antibody (anti-HCV) serologyat screening. Subjects with positive HBsAb may be randomised provided they arehepatitis B vaccinated and have negative HBsAg and HBcAb.

29. Subjects who are not willing to abstain from donating blood and/or plasma from thetime of informed consent and for 16 weeks (5 half-lives) after last dose of IMP.

30. Subjects who are legally institutionalised.

31. Pregnant, breastfeeding, or lactating women.

32. Employees of the trial site or any other individuals directly involved with theplanning or conduct of the trial, or immediate family members of such individuals.