Efficacy of Rituximab in Reducing Glucocorticoid Exposure in Patients with Newly Diagnosed Polymyalgia Rheumatica: A Randomized Controlled Trial

The primary objective of the study is to evaluate the **efficacy** of treatment with **rituximab** in patients with newly diagnosed **polymyalgia rheumatica** compared to placebo. This is clinically relevant as it aims to determine whether rituximab can effectively reduce the need for glucocorticoid exposure, which is a common treatment for polymyalgia rheumatica but is associated with significant side effects. The study does not list any secondary objectives.

The clinical trial focuses on patients with **Polymyalgia Rheumatica**, specifically those newly diagnosed within less than 12 weeks, as per the 2012 EULAR/ACR classification criteria. The study population includes both male and female participants, with an age range that encompasses adults and older adults. Participants are required to have been on glucocorticoid treatment for less than 8 weeks, with a glucocorticoid dose equivalent to prednisolone of less than 30 mg per day. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria ensure that the study population is representative of individuals who are newly diagnosed and have not yet undergone extensive treatment. Lifestyle factors such as diet and physical activity are not specified as considerations for this trial.

The clinical trial is designed to evaluate the efficacy of **rituximab** in patients with newly diagnosed **polymyalgia rheumatica**. This is a randomized, double-blind, placebo-controlled trial, categorized as a phase III/IV therapeutic use study. The trial aims to compare the proportion of patients achieving glucocorticoid-free remission one year after treatment with rituximab versus placebo. The study is expected to commence recruitment in February 2023 and conclude by April 2026, with an overall duration of approximately three years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of polymyalgia rheumatica within the last 12 weeks and glucocorticoid treatment of less than eight weeks. The trial will include follow-up visits at specified intervals to monitor the primary and secondary endpoints, including glucocorticoid-free remission at various time points, disease relapse rates, and changes in patient-reported outcomes. The end-of-study visit will assess the long-term effects of the treatment and collect final data on the endpoints.

The expected length of participant involvement is up to two years, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The trial will ensure rigorous monitoring to maintain the integrity of the data and participant safety throughout the study period. The use of rituximab will be administered intravenously, with a maximum daily dose of 1000 mg and a total dose not exceeding 1500 mg over the treatment period. The study will adhere to ethical standards and regulatory requirements to ensure the validity and reliability of the findings.

The clinical trial involves the administration of **rituximab**, an experimental medication, to evaluate its efficacy in patients with newly diagnosed polymyalgia rheumatica. **Rituximab** is provided in the form of a **solution for infusion**. The active substance, **rituximab**, is a protein of non-human origin. The medication is administered **intravenously**. The dosing regimen includes a maximum daily dose of 1000 mg and a total maximum dose of 1500 mg over the treatment period. The maximum treatment period is specified as 1 unit of time, which is typically interpreted as one day in clinical settings. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** will be used as a comparator to assess the efficacy of **rituximab**. The placebo will be administered in a manner identical to the experimental medication, ensuring that the study remains double-blind. This means that neither the participants nor the investigators will know which treatment the participants are receiving, thereby minimizing bias. The placebo will also be delivered intravenously, matching the administration route of **rituximab**. The use of a placebo is critical in determining the true effect of the experimental treatment by providing a baseline for comparison.

The efficacy of rituximab in the treatment of newly diagnosed **polymyalgia rheumatica** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients achieving glucocorticoid-free remission one year after treatment with rituximab compared to placebo. Secondary endpoints include the proportion of patients in glucocorticoid-free remission at week 21, and the proportion of patients maintaining low-dose glucocorticoid remission (≤5 mg/day) at various timepoints, including week 21, week 52, 1.5 years, and 2 years. Additional secondary endpoints involve the assessment of the PMR Activity Score (PMR-AS) at each visit, the number of disease relapses or recurrences up to week 52, and the proportion of patients experiencing a relapse or recurrence at week 52.

Further secondary endpoints include the time from baseline to glucocorticoid-free remission and to relapse, the cumulative glucocorticoid dose at 52 weeks, 1.5 years, and 2 years, and the proportion of patients requiring retreatment with rituximab or placebo. The study will also evaluate the proportion of patients initiating other treatments such as methotrexate, leflunomide, tocilizumab, or sarilumab, and will assess sex differences in glucocorticoid remission frequencies and adverse events. Patient-reported outcomes related to pain, fatigue, stiffness, and physical function will be monitored, alongside medical consumption and productivity loss. The modified glucocorticoid toxicity index, excluding bone mineral density scans, will be used to assess changes in toxicity. The frequency and types of adverse events, particularly those related to glucocorticoids and rituximab, will be recorded during the 52-week study period.