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

A Phase 3, Randomised, 2-arm, Parallel-group, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Subcutaneous Methotrexate Versus Placebo in Moderate to Severe Atopic Dermatitis.

Atopic dermatitis is an ongoing condition that causes skin irritation, redness, and itchiness. Treatments are usually topical - applied to the skin (e.g., moisturisers or medicated creams) - but a wider variety of systemic treatments (that target the whole body) are needed for those whose condition does not improve with topical treatments. Methotrexate, a drug approved for similar conditions such as arthritis and psoriasis, has been shown to improve atopic dermatitis. This randomised, controlled clinical trial will investigate how effective.

Inclusion Criteria:

• Woman of childbearing potential must have a negative pregnancy test at the Screening Visit and must agree to use highly effective methods of contraception while taking the investigational medicinal product (IMP) and for 6 months after the last IMP administration. Men must agree to use a condom during intercourse while taking the IMP and for 3 months after the last IMP administration. They must also agree to not donate sperm for the time period starting at the Screening Visit, throughout the entire 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 to Baseline Visit) of inadequate response to treatment with topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI)s or documented systemic treatment for AD (such as cyclosporine (CYC), azathioprine and/or mycophenolate mofetil). Inadequate response to TCS or TCI is defined as failure to obtain or maintain a remission 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 to the Summary of Product Characteristics (SmPC))
• Treated with a stable dose of topical emollient, for at least 7 consecutive days prior to the Baseline Visit
• Chest X-ray without clinically relevant abnormalities performed within the last 6 months prior to the Baseline Visit
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
• Willing and able to comply with the protocol requirements for the duration of the trial
• Covered by health care insurance in accordance with local requirements

Exclusion Criteria:

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

• Previously treated with MTX

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

• 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 cell count < 4000/mm3 or platelet count < 100000/mm3)

• Presenting liver impairment and/or aspartate transaminase (AST) or alanine aminotransferase (ALT) > 2 times the upper limit of normal (ULN), or bilirubin > 5 mg/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 or C, 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 trial participation. Patients with positive surface antibodies (anti-HBs) and a history 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 the patient from trial participation, even if they have received appropriate and effective treatment, due to the risk of reactivation.
  3. If the interferon-gamma release assay shows a positive result at the Screening Visit the patient may only be included in the trial if the tuberculosis is latent and all of the following 3 conditions are true: (i) Chest X-ray does not show evidence suggestive of active tuberculosis. (ii) There are no clinical signs 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 or Isoniazid and rifapentine weekly for 3 months. The IMP can only be administered to a participant with a positive test result in the interferon-gamma release assay (or an indeterminate result if only 1 test is done, or 2 indeterminate results 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 or treatment with intravenous antibiotics for infection within 2 months prior to the Baseline Visit

• Presenting a history of malignancy, including solid tumours and haematologic malignancies, except non-melanoma skin cancer (epithelial cell carcinoma or basal cell carcinoma) and cervical carcinoma in situ that have been treated with no evidence of recurrence during the past 5 years

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

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

• Treated with TCS, calcineurin inhibitors or phosphodiesterase-4 inhibitors such as crisaborole 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 4 weeks before the Baseline Visit

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

• Treated with a monoclonal antibody (including but not limited to dupilumab or tralokinumab) within the last 3 months or 5 times the half-life of the respective monoclonal 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 Baseline Visit

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

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

• Having a planned surgery during the trial

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

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

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

• Persons performing mandatory military service, persons deprived of liberty, persons who, 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 that reason accommodated in residential care institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such assistance, are in a situation of subordination or factual dependency and therefore may require specific protective measures