CITAR - Comparison of the efficacy and safety of early use of IL-6R blockade with tocilizumab in combination with short-term glucocorticoids versus glucocorticoids alone for the treatment of arthritis induced by cancer immunotherapy by check point inhibitors: a randomized, open, multicentre, proof of concept, superiority, controlled clinical trial

The primary objective of this clinical trial is to evaluate whether the early use of **IL6R blockade** with tocilizumab, in combination with short-term glucocorticoids, demonstrates superior efficacy in controlling arthritis induced by cancer immunotherapy with immune checkpoint inhibitors, compared to glucocorticoids alone. This is assessed by achieving Clinical Disease Activity Index (CDAI) low disease activity or remission at week 16. The clinical relevance of this objective lies in potentially improving treatment outcomes for patients with arthritis secondary to cancer immunotherapy, offering a more effective therapeutic strategy.

Secondary objectives include:

• Assessing the efficacy of the combination therapy in controlling arthritis at week 24.
• Evaluating the ability of the combination therapy to induce remission in immune checkpoint inhibitor-induced arthritis.
• Determining the efficacy in achieving sustained low disease activity or remission, with and without low-dose cortisone.
• Evaluating the potential for achieving glucocorticoid-free low disease activity or remission.
• Assessing improvements in patient-reported outcomes.
• Investigating the association with longer progression-free survival and overall survival.
• Evaluating the impact on the number of missed treatment cycles.
• Assessing the safety profile of the combination therapy compared to glucocorticoids alone.

The clinical trial involves **participants** who are adults aged 18 years and older, with no upper age limit specified. Both male and female subjects are included in the study population. Participants are individuals with histologically or cytologically confirmed cancer who have developed arthritis as a secondary condition due to treatment with immune checkpoint inhibitors. The trial does not focus on a vulnerable population. Participants must have at least two clinically defined joints involved and a Clinical Disease Activity Index (CDAI) greater than 10. The general health status of participants is assessed using the Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS), with eligible participants having a status of 0-1, although a status of 2 is permissible if due to ongoing immune-related adverse events. Women of child-bearing potential are required to have a negative pregnancy test at inclusion and must agree to use highly effective contraception during the treatment and for up to three months after the last dose of the investigational medicinal product. The total number of participants is not provided, as the sponsor has not disclosed this information. Participants may already be on glucocorticoids for arthritis treatment, provided the duration does not exceed one week. The selection process for the trial population is based on these specific inclusion criteria, ensuring a targeted and relevant cohort for the study's objectives.

The clinical trial is designed to evaluate the efficacy and safety of early use of **tocilizumab** in combination with short-term **glucocorticoids** compared to glucocorticoids alone for the treatment of arthritis induced by cancer immunotherapy with immune checkpoint inhibitors. This is a randomized, open-label, multicenter, proof-of-concept, superiority, controlled trial. The trial is expected to conclude by December 31, 2026, with recruitment having commenced on January 16, 2023. Participants will be randomly assigned to one of two arms: Arm A, receiving glucocorticoids alone, and Arm B, receiving tocilizumab in combination with glucocorticoids. The primary endpoint is the percentage of patients achieving a Clinical Disease Activity Index (CDAI) of ≤10 at week 16.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, cancer diagnosis, and arthritis development due to immune checkpoint inhibitors. Participants must have at least two joints involved and a CDAI >10. Follow-up visits will occur at regular intervals to assess disease activity, treatment adherence, and any adverse events. The end-of-study visit will evaluate the overall efficacy and safety outcomes, including secondary endpoints such as CDAI at week 24, improvement in pain, general health, and quality of life, as well as progression-free and overall survival.

Participant involvement is anticipated to last up to 24 weeks, with the treatment period capped at 12 weeks. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide valuable insights into the management of arthritis secondary to cancer immunotherapy, potentially influencing future therapeutic strategies.

The clinical trial involves the administration of **Prednisolone**, a glucocorticoid, in two different dosages as part of the comparator treatment. **Prednisolone** is provided in tablet form, with two available strengths: 5 mg and 2.5 mg, both manufactured by Pfizer AB. The tablets are intended for **oral use**. The maximum daily dose for **Prednisolone** is 0.3 mg/kg, with a total maximum dose of 0.3 mg/kg per day. The treatment period for **Prednisolone** is set at a maximum of 12 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The experimental treatment in this trial is **Tocilizumab**, marketed as RoActemra, which is an IL-6 receptor antagonist. **Tocilizumab** is administered as a 162 mg solution for injection, provided in a pre-filled pen for **subcutaneous** administration. The maximum daily dose of **Tocilizumab** is 162 mg, with a total maximum dose of 162 mg per day. The treatment duration for **Tocilizumab** is also limited to 12 weeks. The administration of **Tocilizumab** will be closely monitored to ensure proper dosing and participant compliance.

No placebo or additional non-experimental treatments are utilized in this study. The trial aims to compare the efficacy and safety of early use of IL-6R blockade with **Tocilizumab** in combination with short-term glucocorticoids versus glucocorticoids alone for the treatment of arthritis induced by cancer immunotherapy by checkpoint inhibitors. The study is designed as a randomized, open, multicentre, proof of concept, superiority, controlled clinical trial.

Efficacy in this clinical trial will be assessed by evaluating the **Clinical Disease Activity Index (CDAI)**, which serves as the primary endpoint. The primary endpoint is defined as the percentage of patients in both treatment arms (arm A and arm B) achieving a CDAI score of ≤10 at week 16. Secondary endpoints include the percentage of patients with a CDAI score of ≤10 at week 24, a CDAI score of ≤2.8 at weeks 16 and 24, and a CDAI score of ≤10 with Prednisolone doses of 0-5 mg/day and 0 mg/day at weeks 16 and 24. Additional secondary endpoints involve improvements in pain, general health, fatigue, functional status, and quality of life, as measured by the Visual Analogue Scale (VAS) and the Health Assessment Questionnaire (HAQ) and EQ5D questionnaire, respectively, at weeks 16 and 24. Progression-free survival, overall survival, and the total number of missed treatment cycles with immune checkpoint inhibitors (ICI) at week 24 will also be evaluated. The occurrence of adverse events (AEs) and serious adverse events (SAEs) from baseline to week 24 will be monitored.