Efficacy and Safety of Methotrexate Versus Placebo in Adults With Atopic Dermatitis.

Inclusion Criteria:

• Woman of childbearing potential must have a negative pregnancy test at the ScreeningVisit and must agree to use highly effective methods of contraception while takingthe investigational medicinal product (IMP) and for 6 months after the last IMPadministration. Men must agree to use a condom during intercourse while taking theIMP and for 3 months after the last IMP administration. They must also agree to notdonate sperm for the time period starting at the Screening Visit, throughout theentire trial period, and for at least 3 months after the last IMP administration.

• Diagnosis of atopic dermatitis (AD) at least 12 months prior to the Screening Visit,diagnosed as defined by the Hanifin and Rajka criteria for AD 4.

• Moderate to severe AD, defined as the following criteria at the Baseline Visit:Eczema Area and Severity Index (EASI) ≥ 16, Investigator Global Assessment (IGA) ≥ 3, Dermatology Life Quality Index (DLQI) ≥ 10

• Eligible for systemic treatment, ie, documented history (within 12 months prior toBaseline Visit) of inadequate response to treatment with topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI)s or documented systemic treatment forAD (such as cyclosporine (CYC), azathioprine and/or mycophenolate mofetil).Inadequate response to TCS or TCI is defined as failure to obtain or maintain aremission or a low activity disease (IGA ≥ 2) despite a daily treatment with a class 2 or class 3 TCS or TCI for 28 days (or the maximal authorised duration according tothe Summary of Product Characteristics (SmPC))

• Treated with a stable dose of topical emollient, for at least 7 consecutive daysprior to the Baseline Visit

• Chest X-ray without clinically relevant abnormalities performed within the last 6months prior to the Baseline Visit

• Capable of giving signed informed consent, which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol

• Willing and able to comply with the protocol requirements for the duration of thetrial

• Covered by health care insurance in accordance with local requirements

Exclusion Criteria:

• Pregnant or breast-feeding women, or planning to become pregnant, or to breastfeedduring the trial

• Previously treated with MTX

• Presenting a known hypersensitivity to MTX or folic acid as well as to any of theexcipients

• Presenting ulcers of the oral cavity and known active gastrointestinal ulcer disease

• Presenting with known blood dyscrasia (haemoglobin < 8.0 g/dL or white blood cellcount < 4000/mm3 or platelet count < 100000/mm3)

• Presenting liver impairment and/or aspartate transaminase (AST) or alanineaminotransferase (ALT) > 2 times the upper limit of normal (ULN), or bilirubin > 5mg/dL (85.5 μmol/L), or a positive result in the FibrotestTM at the Screening Visit

• Presenting drug or alcohol abuse within the last 12 months

• Presenting renal impairment (creatinine clearance less than 60 mL/min)

• Presenting serious, acute or chronic infections such as tuberculosis, hepatitis B orC, HIV positive, or other immunodeficiency syndromes

1. A positive test result at Screening for hepatitis B surface antigen (HBsAg)and/or core antibodies (anti-HBc) excludes the patient from trialparticipation. Patients with positive surface antibodies (anti-HBs) and ahistory of hepatitis B virus (HBV) vaccination may be included.

2. A positive test result at Screening for hepatitis C (positive hepatitis C virus (HCV) antibody test confirmed with positive hepatitis C RNA test) excludes thepatient from trial participation, even if they have received appropriate andeffective treatment, due to the risk of reactivation.

3. If the interferon-gamma release assay shows a positive result at the ScreeningVisit the patient may only be included in the trial if the tuberculosis islatent and all of the following 3 conditions are true: (i) Chest X-ray does notshow evidence suggestive of active tuberculosis. (ii) There are no clinicalsigns and symptoms of pulmonary and/or extra-pulmonary tuberculosis. (iii)Documented receipt of one of the following prophylactic treatment regimens:Oral daily isoniazid for 6 months or Oral daily rifampin for 4 months orIsoniazid and rifapentine weekly for 3 months. The IMP can only be administeredto a participant with a positive test result in the interferon-gamma releaseassay (or an indeterminate result if only 1 test is done, or 2 indeterminateresults if a second test is done after the first indeterminate test result)after the approval of a tuberculosis specialist.

• Presenting uncontrolled infection, hospitalisation due to uncontrolled infection ortreatment with intravenous antibiotics for infection within 2 months prior to theBaseline Visit

• Presenting a history of malignancy, including solid tumours and haematologicmalignancies, except non-melanoma skin cancer (epithelial cell carcinoma or basalcell carcinoma) and cervical carcinoma in situ that have been treated with noevidence of recurrence during the past 5 years

• Currently experiencing or having a history of other concomitant skin conditions thatwould interfere with evaluation of AD (eg. psoriasis, lupus erythematosus, eczemaherpeticum)

• Treated with an investigational drug within 8 weeks or within 5 half-lives (ifknown), whichever is longer, before the Baseline

• Treated with TCS, calcineurin inhibitors or phosphodiesterase-4 inhibitors such ascrisaborole within 1 week prior to the Baseline Visit

• Treated with oral corticosteroids, azathioprine, mycophenolate mofetil, CsA (Ciclosporin A) or any other systemic immunosuppressor / immunomodulator within 4weeks before the Baseline Visit

• Treated by specific allergen immunotherapy started within 3 months before theBaseline Visit 17

• Treated with a monoclonal antibody (including but not limited to dupilumab ortralokinumab) within the last 3 months or 5 times the half-life of the respectivemonoclonal antibody (whichever is the longer period) or with any JAK (Janus kinase)inhibitors (including but not limited to ruxolitinib, baricitinib, tofacitinib,upadicitinib, or abrocitinib) within the last 4 weeks prior to the Baseline Visit

• Treated with any parenteral corticosteroid within 6 weeks prior to the BaselineVisit

• Treated with ultraviolet therapy within 4 weeks prior to the Baseline Visit

• Received a live (attenuated) vaccine within 4 weeks before the Baseline Visit orplanning to be vaccinated with live vaccine during the trial. Please note: Since MTXmay have an effect on the immune system, vaccination with live vaccines must not beperformed during MTX administration

• Having a planned surgery during the trial

• Presenting a clinically significant medical disease that is uncontrolled despitetreatment that, in the opinion of the Investigator, is likely to impact the abilityto participate in the trial or to impact the trial efficacy or safety assessments

• Presenting any additional condition that, in the opinion of the Investigator, mayinterfere with the assessment or may put the participant at risk

• Protected by the law (adult under guardianship, or hospitalised in a public orprivate institution for a reason other than this trial, or incarcerated)

• Persons performing mandatory military service, persons deprived of liberty, personswho, due to a judicial decision, cannot take part in clinical trials, and persons,who due to their age, disability or state of health are reliant on care and for thatreason accommodated in residential care institutions, that is accommodationsproviding an uninterrupted assistance for persons who necessitate such assistance,are in a situation of subordination or factual dependency and therefore may requirespecific protective measures