Randomized, Double-Blind, Multicenter Trial of Tocilizumab Versus Placebo in Refractory Chronic Inflammatory Chondrocalcinosis

The primary objective of this study is to demonstrate the efficacy of **IL-6 inhibition** in the treatment of chronic inflammatory forms of chondrocalcinosis that are refractory to standard treatments. This is clinically relevant as it addresses a significant unmet need in managing this condition, potentially offering a new therapeutic option for patients who do not respond to existing therapies.

Secondary objectives include:

• Comparing changes in overall pain from baseline to month 6.
• Assessing the speed of pain resolution, defined as an improvement of more than 80% or pain less than 20 mm.
• Evaluating the response time to treatment, with an improvement of over 50%.
• Determining the number of responding patients with improvement at month 4.
• Comparing the number of relapses during the 6-month study period.
• Analyzing healthcare consumption over 6 months, including hospitalizations related to pain attacks, duration of hospitalizations, analgesic consumption, and time off work.
• Comparing quality of life and disability.
• Evaluating reactions to infusions.
• Comparing the incidence of severe infections.
• Assessing decreases in neutrophils or platelets.
• Comparing hepatic cytolysis.
• Evaluating lipid profiles.
• Determining factors associated with a response to **tocilizumab** among demographic, disease, biological characteristics, and comorbidities.

The clinical trial focuses on individuals diagnosed with **chondrocalcinosis**, specifically targeting those with treatment-refractory chronic inflammatory forms of calcium pyrophosphate (CPP) rheumatism. The study population includes both male and female adults over the age of 18, with no vulnerable populations selected. Participants are required to have a persistent inflammatory pain lasting more than three months or experience at least two arthritis episodes per month, with more than three painful joints and an overall pain visual analog scale (VAS) score greater than 40 mm. The trial excludes individuals who have not failed, shown intolerance, or been unable to repeatedly use standard treatments such as colchicine, NSAIDs, corticosteroids, and anakinra. Women of childbearing potential must use effective contraception for up to three months post-study. The sponsor has not provided the total number of participants involved in the trial. Participants were selected based on their diagnosis according to the ACR/EULAR 2023 classification criteria and their informed consent to participate in the study.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of **tocilizumab** in patients with chronic polyarticular inflammatory forms of **chondrocalcinosis** that are refractory to standard treatments. The trial will involve a comparison between tocilizumab and a placebo, with the primary objective being to demonstrate the efficacy of IL-6 inhibition in this patient population. The study is set to commence recruitment in October 2025 and is expected to conclude by May 2029, with a total duration of approximately 3.5 years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis, and previous treatment failures. The inclusion criteria require participants to be adults over 18 years old with a confirmed diagnosis of **calcium pyrophosphate deposition disease** according to ACR/EULAR 2023 classification criteria, among other conditions. Following the screening, eligible participants will be randomized to receive either the active treatment or placebo via **intravenous infusion**. The treatment period will last for a maximum of 3 months, with infusions administered monthly.

Study visits will occur at baseline, before each infusion at months M1, M2, and M3, and at follow-up visits at M4 and M6, which marks the end of the study. The primary endpoint is the variation in overall pain VAS between initiation and M4, one month after the third infusion. Secondary endpoints include assessments of disease activity, quality of life, and incidence of adverse events. Participants are expected to be involved in the study for approximately 6 months, from the initial screening to the end-of-study visit.

Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent prior to enrollment. The study aims to provide valuable insights into the treatment of **chondrocalcinosis**, potentially improving therapeutic options for patients with this challenging condition.

The clinical trial involves the administration of several **tocilizumab**-based experimental medications, each formulated as a concentrate for solution for infusion. The first experimental medication, Tofidence, is provided at a concentration of 20 mg/mL. It is administered via **intravenous infusion** with a maximum daily dose of 8 mg/kg and a total maximum dose of 24 mg/kg over a treatment period of up to 3 months. The pharmaceutical form is a solution for infusion, and the active substance is derived from a protein of other origin. The product is manufactured by Biogen Netherlands B.V.

Another experimental medication, Avtozma, also contains **tocilizumab** at a concentration of 20 mg/mL. Similar to Tofidence, it is administered through intravenous infusion with the same dosing parameters: a maximum daily dose of 8 mg/kg and a total maximum dose of 24 mg/kg over a 3-month period. The solution for infusion is produced by Celltrion Healthcare Hungary Kft.

RoActemra is another **tocilizumab**-based treatment used in the trial, with a concentration of 20 mg/mL. It follows the same administration and dosing schedule as the other tocilizumab products, with intravenous infusion being the route of administration. The product is manufactured by Roche Registration GmbH.

Tyenne, also containing **tocilizumab** at 20 mg/mL, is administered via intravenous infusion. The dosing schedule is consistent with the other tocilizumab formulations, with a maximum daily dose of 8 mg/kg and a total maximum dose of 24 mg/kg over a 3-month period. This solution for infusion is produced by Fresenius Kabi Deutschland GmbH.

In addition to the experimental medications, the trial includes the use of **sodium chloride** as a non-experimental treatment. Sodium chloride is provided as a solution for infusion with a concentration of 0.9%. It serves as a placebo in the trial, administered via infusion. The maximum daily and total dose is 0.9%, and the treatment period is up to 3 months. Sodium chloride is classified as a chemical substance.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the variation in overall pain Visual Analogue Scale (VAS) between initiation and month 4 (M4), which is one month after the third infusion. This will provide a direct measure of pain reduction over the course of the treatment.

Secondary endpoints include a comprehensive set of parameters to evaluate the broader impact of the treatment. These include the Disease Activity Score (DAS44), the number of swollen and painful joints, overall disease activity VAS, and fatigue VAS. The overall effect on pain will be assessed using the area under the curve (AUC) of global pain VAS from assessments at inclusion, before each infusion at months M1, M2, M3, and at M4 and M6 (end of study). The proportion of patients responding from M2 to M6, defined as an improvement of ≥50% of the initial pain VAS, and the proportion of complete response, defined as an improvement of ≥80% of the initial pain VAS, will also be evaluated.

Additional secondary endpoints include the number of inflammatory flare-ups per month, relapse rate at M6, time to onset of relapse, and biological parameters of inflammation such as sedimentation rate (SV), C-reactive protein (CRP), and **IL-6** levels. Quality of life improvements will be measured using SF-36, HAQ, and EQ-5D-3L questionnaires. The consumption of care over 6 months, including the number of hospitalizations related to CPAP-dependent disease, duration of hospitalizations, duration of time off work, and consumption of analgesics, will be recorded.

Safety and tolerability will be assessed by monitoring the incidence of infusion reactions, neutropenia, thrombocytopenia, hepatic cytolysis, severe infections, and any side effects attributable to treatment. Changes in lipid profile and mean values of neutropenia, thrombocytopenia, transaminases, and lipid profile will also be analyzed. Demographic, disease, biological characteristics, and comorbidities will be evaluated to identify factors linked to a response to **tocilizumab**.