Tralokinumab Monotherapy for Moderate to Severe Atopic Dermatitis - ECZTRA 1 (ECZema TRAlokinumab Trial no. 1)
Condition: Atopic Dermatitis
MeSH terms: Dermatitis, Atopic; Dermatitis; Eczema
Intervention: Tralokinumab; Placebo
Intervention description: Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. It is presented as a liquid formulation for subcutaneous (SC) administration; Placebo contains the same excipients, in the same concentration only lacking tralokinumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking description: Neither the subject nor any of the investigator or LEO staff who are involved in the treatment or clinical evaluation and monitoring of the subjects will be aware of the treatment received. The packaging and labelling of the IMPs will contain no evidence of their identity.
Since tralokinumab and placebo are visually distinct and not matched for viscosity, IMP will be handled and administered by a qualified, unblinded HCP at the site who will not be involved in the management of trial subjects and who will not perform any of the assessments.
Enrollment: 802.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Primary objective:

      To evaluate the efficacy of tralokinumab compared with placebo in treating moderate to severe
      atopic dermatitis (AD).

      Secondary objectives:

      To evaluate the efficacy of tralokinumab on severity and extent of AD, itch, and health
      related quality of life compared with placebo.

      Maintenance objective:

      To evaluate maintenance of effect with continued tralokinumab dosing up to 52 weeks compared
      to placebo for subjects achieving clinical response at Week 16.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Written informed consent and any locally required authorisation obtained from the
             subject prior to performing any protocol-related procedures, including screening
             evaluations.

          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) of
             inadequate response to treatment with topical medications or for whom topical
             treatments are otherwise medically inadvisable (e.g., due to important side effects or
             safety risks).

             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 TCS of medium to higher potency (±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.

             Subjects with documented systemic treatment for AD in the past year are also
             considered as inadequate responders to topical treatments and are potentially eligible
             for treatment with tralokinumab 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
             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 the week
             prior to baseline.

             Worst Daily Pruritus NRS at baseline will be calculated from daily assessments of
             worst itch severity (Worst Daily Pruritus NRS) during the 7 days immediately preceding
             randomisation (Day 6 to 0). A minimum of 4 Worst Daily Pruritus NRS scores out of the
             7 days is required to calculate the baseline average score. For subjects who do not
             have at least 4 scores reported during the 7 days immediately preceding the planned
             randomisation date, randomisation should be postponed until this requirement is met,
             but without exceeding the 6 weeks maximum duration for screening.

         10. Subjects must have applied a stable dose of emollient twice daily (or more, as needed)
             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 (5 half
             lives) after last administration of IMP.

               -  A highly effective method of birth control is defined as one which results in a
                  low 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 contraception associated 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 with the preferred and
                  usual life style of the subject), vasectomised partner (given that the subject is
                  monogamous). The subjects must have used the contraceptive method continuously
                  for at least 1 month prior to the pregnancy test at baseline. A female is defined
                  as not being of child-bearing potential if she is postmenopausal (at least 12
                  months with no menses without an alternative medical 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 an IMP.

          2. Previous randomisation in tralokinumab trials.

          3. Active dermatologic conditions that may confound the diagnosis of AD or would
             interfere with assessment of treatment, such as scabies, cutaneous lymphoma, or
             psoriasis.

          4. Known active allergic or irritant contact dermatitis that is likely to interfere with
             the assessment of severity of AD.

          5. Use of tanning beds or phototherapy (narrow band ultraviolet B [NBUVB], ultraviolet B
             [UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]), within 6 weeks prior
             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 inhibitors etc.).

               -  Systemic corticosteroid use (excludes topical, inhaled, or intranasal delivery).

               -  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 containing
             additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products
             during the screening period (subjects may continue using stable doses of such
             emollients if initiated before the screening visit).

          9. Receipt of live attenuated vaccines 30 days prior to the date of randomisation and
             during 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 biologic
             agent, including dupilumab:

               -  Any cell-depleting agents including but not limited to rituximab: within 6 months
                  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 to
                  randomisation.

         11. Receipt of any investigational non-biologic agent within 5 half-lives prior to
             randomisation.

         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 or
             hospitalisation 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 randomisation
             which, in the opinion of the investigator or sponsor's medical expert, may compromise
             the safety of the subject in the trial, interfere with evaluation of the IMP, or
             reduce the subject's ability to participate in the trial. Clinically significant
             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 is
             obtained that has not been treated with, or has failed to respond to, standard of care
             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 carcinoma of
                  the skin or in situ carcinoma of the cervix are eligible provided that the
                  subject is in remission and curative therapy was completed at least 12 months
                  prior to the date informed consent was obtained.

               -  Subjects who have had other malignancies are eligible provided that the subject
                  is in remission and curative therapy was completed at least 5 years prior to the
                  date informed consent was obtained.

         21. Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation
             will be according to local guidelines as per local standard of care.

         22. History of any known primary immunodeficiency disorder including a positive human
             immunodeficiency virus (HIV) test at screening, or the subject taking antiretroviral
             medications 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 any
             condition associated with poor compliance as judged by the investigator.

         24. History of attempted suicide or is at significant risk of suicide (either in the
             opinion 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 Severity Rating
             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 not
             stable, 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 the
             screening period, which in the opinion of the investigator, may put the subject at
             risk because of his/her participation in the trial, or may influence the results of
             the trial, or the subject's ability to complete entire duration of the trial.

         27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.0 times
             the 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) serology at
             screening. Subjects with positive HBsAb may be randomised provided they are hepatitis
             B vaccinated and have negative HBsAg and HBcAb.

         29. Subjects who are not willing to abstain from donating blood and/or plasma from the
             time 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 the
             planning or conduct of the trial, or immediate family members of such individuals.