Evaluation of Subcutaneous Methotrexate Efficacy and Safety Compared to Placebo in Adults with Moderate to Severe Atopic Dermatitis

The primary objective of this phase 3, randomized, double-blind, placebo-controlled trial is to demonstrate the superiority of subcutaneous **methotrexate** (MTX) over placebo in achieving an improvement of at least 75% in the Eczema Area and Severity Index (EASI 75 response) by the 16th week of treatment in adult participants with moderate to severe atopic dermatitis. This objective is clinically relevant as it aims to establish MTX as a more effective treatment option for reducing the severity of atopic dermatitis, potentially improving patient outcomes and quality of life.

Secondary objectives include: - Comparing the efficacy of MTX (SC) versus placebo at various timepoints in participants with moderate to severe atopic dermatitis. - Evaluating the safety and tolerability profiles of MTX (SC) compared to placebo. - Assessing the quality of life of participants treated with MTX (SC) versus placebo at different timepoints. - Evaluating the maintenance of efficacy of MTX versus placebo during the extension phase. These objectives are crucial for understanding the broader impact of MTX on patient health and its potential as a long-term treatment strategy.

The clinical trial involves adult participants diagnosed with **moderate to severe atopic dermatitis**. The study population includes both male and female subjects aged 18 years or older. Participants are required to have a documented history of inadequate response to topical corticosteroids or calcineurin inhibitors, or previous systemic treatment for atopic dermatitis. All participants must be covered by health care insurance and capable of providing informed consent. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants are expected to maintain a stable dose of topical emollient for at least seven consecutive days prior to the baseline visit. Additionally, women of childbearing potential must have a negative pregnancy test and agree to use highly effective contraception methods, while men must agree to use condoms and refrain from donating sperm during and after the trial period. The trial population was selected based on their eligibility for systemic treatment and their ability to comply with the protocol requirements throughout the trial duration.

The clinical trial is designed as a **randomized**, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous **methotrexate** in comparison to a placebo in adult participants with moderate to severe **atopic dermatitis**. The trial is structured into two parallel groups and aims to demonstrate the superiority of methotrexate over placebo by achieving an improvement of at least 75% in the Eczema Area and Severity Index (EASI 75 response) by the 16th week of the trial. The trial is expected to commence recruitment on November 1, 2023, and is estimated to conclude by November 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, health insurance coverage, and a confirmed diagnosis of atopic dermatitis. The trial will include several follow-up visits at weeks 4, 8, 12, and 16 to monitor primary and secondary endpoints, including EASI, SCORAD, IGA, NRS, and POEM scores, as well as adverse events and changes in vital signs and laboratory values. The end-of-study visit will occur at week 24, or later if participants are involved in an extension phase. The total duration of participant involvement is anticipated to be up to 24 weeks, with conditions for early termination including non-compliance with the protocol or withdrawal of consent.

Participants will be required to adhere to specific protocol requirements, including the use of effective contraception for women of childbearing potential and men, and maintaining a stable dose of topical emollient prior to the baseline visit. The trial will ensure that all participants are capable of providing informed consent and are willing to comply with the study's requirements throughout its duration. The trial's primary endpoint is the EASI 75 response at week 16, with secondary endpoints assessing various clinical scores and adverse events at multiple time points. The study will be conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **methotrexate**, which is provided in the form of a solution for injection in a pre-filled pen. The maximum daily dose of methotrexate is 20 mg, with a total maximum dose of 480 mg over the treatment period. The administration route is subcutaneous injection, and the treatment period is set for a maximum of 24 weeks. The pre-filled pen has been modified with a yellow transparent label for blinding purposes.

Another experimental medication used in the trial is **tacrolimus**, which is formulated as an ointment. The maximum daily dose is 1 mg, and the administration is via cutaneous use. The treatment period for tacrolimus is also set for a maximum of 24 weeks.

**Desoximetasone** is included as an auxiliary treatment in the form of a cream. The maximum daily dose is 0.05%, and it is administered through cutaneous use. The treatment period is consistent with the other medications, set at a maximum of 24 weeks.

**Folic acid** is provided in two forms: as a coated tablet and as a standard tablet. The coated tablet, known as Acidum folicum Léčiva, contains 10 mg of folic acid per tablet. The maximum daily dose is 10 mg, with a total maximum dose of 240 mg over the treatment period. The administration route is oral, and the treatment period is up to 24 weeks. Folic acid is also referred to as vitamin B9 in the study.

The trial also includes a **placebo** as a comparator treatment. The placebo is used to evaluate the efficacy and safety of the experimental treatments in a double-blind manner. The placebo does not contain any active substances and is administered in a manner consistent with the experimental treatments to maintain blinding.

The efficacy of the clinical trial will be assessed primarily through the **Eczema Area and Severity Index (EASI 75 response)** at the Trial Week 16 Visit. This endpoint measures the improvement from baseline of at least 75% in participants with moderate to severe atopic dermatitis. Secondary endpoints include various scores and responses such as EASI, SCORAD, IGA, NRS, and POEM at different time points, including Trial Week 4, Week 8, Week 12, and Week 16. Additionally, changes in DLQI, SCORAD, WPAI:GH, HADS, EQ-5D-5L, and ADCT scores from baseline to these time points will be evaluated. The trial will also monitor adverse events, treatment-related adverse events, serious adverse events, and serious adverse reactions from the Screening Visit until the Trial Week 16/24 Visit, with specific time points depending on participation in the extension phase. Changes in vital signs and laboratory values will also be assessed. The efficacy parameters will be collected and analyzed using validated scales and patient-reported outcomes at the specified time points to ensure a comprehensive evaluation of the treatment's impact on the disease.