Comparative Efficacy and Safety of Infliximab Versus Tocilizumab in Refractory or Relapsing Takayasu Arteritis: A Multicenter Randomized Trial

The primary objective of this study is to evaluate the efficacy of **Infliximab** compared to **Tocilizumab** in achieving a clinical response in patients with refractory or relapsing **Takayasu arteritis**. Specifically, the goal is to achieve, by treatment arm, at least 70% of patients with a prednisone (or prednisolone) dose of ≤ 0.1 mg/kg per day and inactive disease status during the last three months at six months post-treatment. This is clinically relevant as it aims to reduce the dependency on corticosteroids while maintaining disease remission, which is crucial for minimizing long-term side effects associated with steroid use.

Secondary objectives include:

• Estimating the incidence of relapse between three and six months post-treatment in each arm.
• Estimating the incidence of treatment failure at three months post-treatment in each arm.
• Estimating the incidence of revascularization procedures required due to the disease at six and twelve months post-treatment in each arm.
• Estimating the cumulative dose of prednisone (or prednisolone) at six and twelve months post-treatment in each arm.
• Estimating the incidence of adverse events at six and twelve months post-treatment in each arm.
• Estimating the mean change in SF-36 quality-of-life values from Day 1 of treatment to six and twelve months post-treatment in each arm.
• Estimating the proportion of new vascular lesions at six and twelve months post-treatment in each arm, measured by angio-computerized tomography or magnetic resonance imaging angiography.

The clinical trial focuses on individuals diagnosed with **Takayasu arteritis**, a rare inflammatory disease affecting large blood vessels. The study population includes both male and female participants aged 15 years and older, with a weight range of 40 to 120 kg. Participants are required to have active disease as per the international criteria of the National Institute of Health and must be experiencing refractory or relapsing disease or symptomatic severe arterial involvement. The trial population is selected based on specific inclusion criteria, including the use of at least one immunosuppressive agent, and the ability to provide written informed consent. Participants must have a negative HIV serology, negative hepatitis C RNA, and hepatitis B surface antigen within the last three months. Additionally, they must be willing to comply with the treatment and follow-up procedures outlined in the study protocol. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a multicenter, randomized, double-blind, controlled study designed to evaluate the efficacy and safety of **infliximab** compared to **tocilizumab** in patients with refractory or relapsing **Takayasu arteritis**. The trial is set to run from February 2021 to February 2026, with an estimated duration of 24 months for each participant. The study involves intravenous administration of the investigational products, with **infliximab** administered as a powder for infusion and **tocilizumab** as a concentrate for solution for infusion. The maximum treatment period for **infliximab** is 22 weeks, while for **tocilizumab**, it is 24 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, and disease status. The inclusion criteria require a diagnosis of **Takayasu arteritis**, active disease according to NIH criteria, and a history of refractory or relapsing disease. Participants must also be willing to use adequate contraceptive measures and provide informed consent. The screening visit will include assessments such as chest X-ray or CT, tuberculosis evaluation, and serology tests for HIV and hepatitis.

Following the screening, eligible participants will be randomized to receive either **infliximab** or **tocilizumab**. The primary endpoint is the proportion of patients achieving a prednisone dose of ≤0.1 mg/kg per day with sustained inactive disease at six months post-treatment. Secondary endpoints include the incidence of relapse, treatment failure, and adverse events, as well as changes in quality of life and the occurrence of new vascular lesions.

Participants will attend follow-up visits at three and six months post-treatment initiation to monitor disease activity, medication adherence, and any adverse events. The end-of-study visit will occur at 12 months post-treatment initiation, where final assessments will be conducted. Participant involvement is expected to last up to 24 months, with conditions for early termination including non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events.

The clinical trial involves the administration of **Infliximab**, an experimental medication formulated as a **powder for infusion**. The active substance, infliximab, is administered via **intravenous use**. The dosing regimen specifies a maximum daily dose of 5 mg/kg, with a total maximum dose of 2500 mg over a treatment period of up to 22 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the protocol.

In addition to infliximab, the trial includes the use of **RoActemra**, which contains the active substance **tocilizumab**. This medication is provided as a **concentrate for solution for infusion** and is also administered intravenously. The maximum daily dose for tocilizumab is 800 mg, with a total maximum dose of 5600 mg over a treatment period of up to 24 weeks. The pharmaceutical form and administration route are designed to optimize the therapeutic effect while maintaining participant safety. Compliance with the dosing schedule is closely monitored throughout the trial.

Both infliximab and tocilizumab are utilized as test treatments in this study, with no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments being employed. The trial aims to evaluate the efficacy and safety of these medications in patients with refractory or relapsing **Takayasu arteritis**. The study's objective is to achieve a significant reduction in disease activity while minimizing the use of corticosteroids, such as prednisone or prednisolone, to a dose of ≤ 0.1 mg/kg per day.

Efficacy in the clinical trial evaluating the use of **Infliximab** and **Tocilizumab** in patients with refractory or relapsing Takayasu arteritis will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients at 6 months post-treatment who maintain a prednisone (or prednisolone) dosage of ≤ 0.1 mg/kg per day and exhibit sustained inactive disease from month 3 (M3) to month 6 (M6), while continuing the same biological therapy from the start of treatment. This will be measured among the randomized patients within the same treatment arm.

Secondary endpoints include the incidence of relapse as defined by the National Institute of Health (NIH) criteria between M3 and M6, the incidence of treatment failure at M3, and the proportion of patients maintaining the specified prednisone dosage and inactive disease status using a modified NIH score from M3 to M6. Additional secondary measures involve the incidence of relapse and treatment failure according to modified NIH criteria, incidence of revascularization procedures up to M6 and M12, cumulative doses of prednisone at M6 and M12, incidence of adverse events of grades III or IV at M6 and M12, mean change in quality of life as assessed by the SF-36 questionnaire from Day 1 to M6 and M12, and the proportion of new vascular lesions at M6 and M12 as assessed by angio-CT or MR angiography.