A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy of Methotrexate as Remission Maintenance Therapy after Remission-Induction Therapy with Tocilizumab and Glucocorticoids in Subjects with Giant Cell Arteritis

The primary objective of this study is to assess the efficacy of **methotrexate** (metex®) on sustained remission in patients with **giant cell arteritis** (GCA). This is clinically relevant as achieving and maintaining remission is crucial in preventing disease-related complications and improving patient outcomes.

Secondary objectives include:

• Assessing the need for rescue therapy with prednisone.
• Evaluating the number of flares or relapses during maintenance therapy with metex®.
• Evaluating the impact of metex® maintenance therapy on patient-reported and investigator-reported outcomes.
• Assessing the impact of metex® on visual symptoms and other ischemic complications related to GCA.
• Assessing vasculitic involvement and changes in intima-media values of temporal and axillary arteries in patients with or without flares.
• Analyzing the influence of study treatment on patients with aortitis in MRI of the aorta.
• Analyzing the influence of study treatment on local and systemic inflammation.
• Evaluating the safety of methotrexate.

The clinical trial focuses on evaluating the efficacy of metex® in achieving sustained remission in patients with **giant cell arteritis** (GCA). The study population comprises both male and female subjects aged 18 years and older. Participants are required to have a confirmed diagnosis of GCA and must have previously been treated with glucocorticoids and tocilizumab. Eligible individuals are those in whom the discontinuation of tocilizumab therapy has been decided by their treating rheumatologist, and they must have been in stable remission, defined by the absence of GCA symptoms and normal CRP levels, for at least one month prior to screening. Participants must be willing and able to self-administer methotrexate or a placebo subcutaneously. The trial does not include a vulnerable population, and both genders are represented. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel group study** to evaluate the efficacy of **methotrexate** as remission maintenance therapy in subjects with **giant cell arteritis** (GCA). The trial aims to assess the efficacy of methotrexate on sustained remission of GCA following remission-induction therapy with tocilizumab and glucocorticoids. The study is expected to span a duration of 12 months, with an estimated recruitment start date of August 1, 2022, and an estimated end date of August 1, 2025.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), a confirmed diagnosis of GCA, and previous treatment with glucocorticoids and tocilizumab. The screening will ensure that patients are in stable remission, defined by the absence of GCA symptoms and normal CRP levels, and have been off glucocorticoids for at least one month. Following randomization, participants will be required to self-administer methotrexate or placebo subcutaneously.

Throughout the trial, follow-up visits will be conducted to monitor the primary endpoint, which is the time to relapse during the 12-month treatment period. Secondary endpoints include cumulative prednisone doses, the number of flares per patient, patient-reported outcomes, investigator-reported outcomes, and the occurrence of adverse events. The end-of-study visit will conclude the participant's involvement, assessing the overall efficacy and safety of the treatment.

Participant involvement is expected to last for the entire 12-month treatment period unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial is conducted under the framework of a Phase 4 study, ensuring rigorous scientific and ethical standards are maintained throughout the research process.

The clinical trial involves the administration of **methotrexate** as the experimental medication. Methotrexate is provided in the form of a solution for injection, specifically in pre-filled syringes. The concentration of the solution is 50 mg/ml. The maximum daily dose of methotrexate administered to participants is 17.5 mg, with the total dose not exceeding 17.5 mg per administration. The treatment period is set for a maximum of 12 weeks. Methotrexate is classified under the ATC code L01BA01, indicating its role as a cytostatic agent. The administration route is via injection, and the pharmaceutical form is a ready-to-use solution, ensuring ease of administration and compliance monitoring. The product is manufactured by MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH (WEDEL) and is authorized in Germany under the marketing authorization number 70930.00.00.

In addition to the experimental treatment, the study includes the use of **sodium chloride** as a non-experimental treatment. Sodium chloride is utilized as a placebo in this trial. The pharmaceutical form, dosage, and administration details for sodium chloride are not specified in the provided data. However, it is typically used in clinical trials to maintain blinding and ensure that the placebo group receives a treatment that is indistinguishable from the active medication in terms of appearance and administration method. Compliance with the administration of both methotrexate and sodium chloride is monitored throughout the study to ensure adherence to the dosing schedule and to maintain the integrity of the trial results.

The efficacy of **methotrexate** as a remission maintenance therapy in patients with Giant Cell Arteritis (GCA) will be assessed through a randomized, double-blind, placebo-controlled, parallel group study. The primary endpoint for evaluating efficacy is the time to relapse during the 12-month treatment period. Secondary endpoints include cumulative prednisone doses at months 6, 12, and 18, the number of flares per patient during the treatment period, and the time to first, second, and third relapse after randomization. Additionally, the percentage of patients experiencing a relapse at months 6 and 18 after discontinuation of tocilizumab will be measured.

Patient-reported outcomes will be collected using instruments such as the SF-36, FACIT-Fatigue, Patient Global Assessment of Disease Activity (PGA), and patient assessment of pain. Investigator-reported outcomes will include the Evaluator Global Assessment of disease activity (EGA). The study will also monitor the occurrence of symptoms and signs related to GCA, the number of vasculitic vessels, and changes in intima-media values. The prevalence of aortitis at baseline and at months 12 and 18 will be assessed, along with the proportion of subjects with increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels at every visit. The occurrence of adverse events, serious adverse events, and glucocorticoid-related adverse events will also be documented.