Effects of tralokinumab treatment of atopic dermatitis on skin barrier function.

A phase II, monocenter , open, investigator initiated clinical trial investigating the effects of Tralokinumab treatment of atopic dermatitis on skin barrier physiology and function.

Inclusion Criteria:

1. Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations

2. Age ≥ 18 years at time of study entry.

3. Diagnosis of chronic atopic dermatitis for at least 1 year prior to enrollment based on American Academy Criteria

4. Subjects who have a recent history (within 1 year before the screening visit) of inadequate response to treatment with topical medications. 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.

5. Eczema Area and Severity Index (EASI) score ≥12 at screening (Week0 minus 7d) and baseline visit (Week0)

6. Investigator Global Assessment (IGA) ≥3 at screening and baseline visit

7. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.

8. Female participants who are not capable of bearing children or who use a method of contraception that is medically approved by the health authority of the respective country at screening

   This includes:

   • A woman who is not capable of bearing a child is defined as follows: post-menopausal (12 months natural (spontaneous) amenorrhea or 6 months spontaneous amenorrhea with serum-FSH-values (follicle-stimulating hormone) of >40 mIU/mL); 6 weeks after a bilateral ovariectomy with or without hysterectomy or sterilization by means of tubal ligation
   • A woman capable of bearing child is defined as follows: a woman who is physiologically capable of becoming pregnant, including women whose occupation, lifestyle or sexual orientation exclude sexual intercourse with a male partner and women whose partners have been sterilized by vasectomy or other measures.
   • Medically-approved methods of contraception can include the following: hormonal contraceptives or, intrauterine device and double barrier method. Acceptable preventive measures can include total abstinence at the discretion of the investigator, in cases where compliance is ensured because of the study participant's age, occupation, lifestyle or sexual orientation. Periodical abstinence (e.g. calendar, ovulation, symptothermal methods or abstinence until the 4th day after the ovulation) as well as coitus interruptus are not acceptable methods of contraception.
   • A reliable method of contraception (CTFG guideline) must be used for the entire duration of the study.

9. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

1. Subject is unable to provide written informed consent or comply with the protocol

2. Concurrent enrolment in another clinical trial where the subject is receiving an IMP or participation in another clinical trial with investigational product during the last 30 days before inclusion or 7 half-lives of previously used trial medication, whichever is longer.

3. Previous enrollment in a Tralokinumab clinical trial.

4. Active dermatologic conditions that may confound the diagnosis of AD or would interfere with assessment of treatment, such as scabies, cutaneous lymphoma, or psoriasis.

5. Known active allergic or irritant contact dermatitis that is likely to interfere with the assessment of severity of AD.

6. Subject with mild atopic dermatitis (EASI<12 and IGA<3) or is not a candidate or is not eligible for Tralokinumab treatment, because of a known or suspected allergy or reaction to any component of the IMP formulation or other possible contraindications like trypanophobia

7. Having used immunosuppressive/immunomodulating therapy (Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate, cyclosporine, azathioprine, mycophenolate mofetil, Janus kinase inhibitors), systemic corticosteroid use (excludes topical, inhaled, or intranasal delivery, bleach baths) during any week within the 4 weeks or tanning beds or phototherapy (narrow band ultraviolet B [NBUVB], ultraviolet B [UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]), within 4 weeks before the baseline visit

8. Treatment of selected skin areas (non-lesional skin at volar forearm and extensor forearm, lesional skin) with topical corticosteroid or topical calcineurin inhibitor 1 week prior to baseline visit and throughout the study.

9. Treatment of skin areas of examination with emollients 24 hours prior to baseline visit and throughout the study.

10. Involvement in the planning and/or conduct of the study.

11. Dementia or significantly altered mental status that would prohibit the understanding or rendering of information, consent and compliance with the requirements of the protocol and patients who are legally institutionalized.

12. Pregnancy and breastfeeding are exclusion factors. The effects of Tralokinumab on the developing human fetus are unknown. Enrolled patients must agree to use adequate contraception prior to study entry, the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

13. Medication that is known to interfere with any of the agents applied in the trial.

14. Receipt of live attenuated vaccines 30 days prior to the date of baseline and during the trial including the safety follow-up period.

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

15. Receipt of any marketed biological therapy (i.e. immunoglobulin, anti-IgE) including dupilumab or investigational biologic agents:

    1. Any cell-depleting agents including but not limited to rituximab: within 6 months prior to baseline or until lymphocyte count returns to normal whichever is longer.
    2. Other biologics: within 3 months or 5 half-lives, whichever is longer prior to baseline.

16. Receipt of any investigational non-biologic agent within 5 half-lives prior to baseline.

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

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

19. History of any active skin infection within 1 week prior to baseline.

20. History of a clinically significant infection within 4 weeks prior to baseline which, in the opinion of the investigator or sponsor, 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:

    1. A systemic infection.
    2. A serious skin infection requiring parenteral (intravenous or intramuscular) antibiotics, antiviral, or antifungal medication.

21. History of a helminthic 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.

22. History of anaphylaxis following any biological therapy.

23. History of immune complex disease.

24. History of cancer:

    1. Subjects who have had basal cell carcinoma, localized 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.
    2. 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.

25. History of tuberculosis requiring treatment within the 12 months prior to screening. Evaluation will be according to local guidelines as per local standard of care.

26. 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.

27. 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.

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

    1. Affect the safety of the subject throughout the trial.
    2. Influence the findings of the trial or their interpretations.
    3. Impede the subject's ability to complete the entire duration of trial.

29. Any clinically significant abnormal findings in physical examination, vital signs, hematology or clinical chemistry 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.

30. 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.

31. Pregnant, breastfeeding, or lactating women.

32. Employees of the trial site or any other individuals directly involved