HydroxyChloroquine as steroid-sparing Agent in Extra-pulmonary SARcoidosis. A multicenter, prospective, placebo-controlled, randomized trial. CAESAR

The primary objective of this study is to evaluate the **steroid-sparing** effect of hydroxychloroquine as an add-on therapy in patients with non-severe extra-pulmonary sarcoidosis requiring systemic treatment. This is clinically relevant as it aims to reduce the dependency on corticosteroids, which are associated with significant side effects, thereby potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Assessing and comparing the evolution of organ-specific responses using the extrapulmonary Physician Organ Severity Tool (ePOST).
• Evaluating the global response in terms of complete, partial, stable, or relapse (or progression) response.
• Assessing the evolution of the need for local steroid treatments, including type, frequency, and dosage, to calculate cumulative doses.
• Evaluating the efficacy of hydroxychloroquine in maintaining relapse-free survival over a prolonged period (up to 24 months).
• Assessing the potential reduction of steroid-related toxicity through clinical and biological indices.
• Evaluating the safety of hydroxychloroquine and patient adherence, including monitoring through electroretinogram, autofluorescence, or OCT, and tracking adverse events.
• Assessing changes in quality of life using the SF36 questionnaire.

The clinical trial focuses on evaluating the **steroid-sparing effect** of hydroxychloroquine as an add-on therapy in patients with non-severe extra-pulmonary sarcoidosis requiring systemic treatment. The study population includes both male and female participants, aged 18 years and older, who have been diagnosed with non-severe sarcoidosis-related conditions such as ENT involvement, ocular, skin, osseous, joint involvement, hypercalcemia, or peripheral nervous system involvement, all requiring systemic treatment. Participants must be able to provide informed consent and be affiliated with the National French social security system. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **steroid-sparing** effect of **hydroxychloroquine** as an add-on therapy in patients with non-severe extra-pulmonary **sarcoidosis** requiring systemic treatment. This is a multicenter, prospective, placebo-controlled, randomized trial. The trial will involve a double-blind methodology to ensure unbiased results. The estimated duration of the trial is from September 2023 to September 2028, with participant involvement expected to last up to 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease severity, and ability to provide informed consent. Following the screening, participants will be randomized to receive either **hydroxychloroquine** or a placebo, in addition to their standard treatment with **prednisone**. Study visits will occur at baseline (M0), and at months 1, 3, 6, 12, 18, and 24. These visits will include assessments of organ-specific response, global clinical response, and the frequency and dosage of local steroid treatments. Safety evaluations will include monitoring for steroid-associated side effects and **hydroxychloroquine** safety through eye evaluations and EKGs.

The primary endpoint is the percentage of patients in remission and off **prednisone** at month 9, without relapse until month 12. Secondary endpoints include organ-specific response, global clinical response, relapse rate, and quality of life assessments. Participants may be withdrawn from the study if they experience serious adverse events, such as those leading to hospitalization or death, or if they fail to adhere to the study protocol. The trial aims to provide valuable insights into the potential benefits of **hydroxychloroquine** as a steroid-sparing agent in the management of extra-pulmonary **sarcoidosis**.

The clinical trial involves the use of several treatments, including **PREDNISONE**, **PLAQUENIL 200 mg**, and a placebo. **PREDNISONE** is administered in the form of a tablet, with the active substance being prednisone, a chemical compound. The dosage is calculated based on the participant's weight, with a maximum daily dose of 70 mg/kg and a total maximum dose of 12,600 mg/kg. The administration route is oral, and the treatment period is limited to a maximum of 6 months. **PREDNISONE** is categorized under corticosteroids and is not a pediatric formulation.

**PLAQUENIL 200 mg, comprimé pelliculé** contains the active substance **HYDROXYCHLOROQUINE SULFATE** and is provided as a film-coated tablet. The maximum daily dose is 400 mg, with a total maximum dose of 146 g. The administration is oral, and the treatment duration can extend up to 12 months. This medication is used as a test treatment in the trial and is not formulated for pediatric use. The product is manufactured by SANOFI-AVENTIS FRANCE and is classified under the ATC code P01BA02, which corresponds to hydroxychloroquine.

The placebo used in the trial is composed of non-active substances, including hydrogénophosphate de calcium dihydraté, stéarate de magnésium, and amidon de maïs, provided by various suppliers. The placebo does not have a specific pharmaceutical form or active substance and serves as a comparator treatment to evaluate the efficacy of the experimental medications. The administration details and dosing schedules for the placebo are not specified in the provided data.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint is the percentage of patients in remission and off **prednisone** at month 9, without relapse until month 12. This will be evaluated at month 12 (M12). Secondary endpoints include organ-specific response, which will be assessed using the extrapulmonary Physician Organ Severity Tool (ePOST) at multiple timepoints: M0, M1, M3, M6, M12, M18, and M24. Global clinical response will also be evaluated by the physician as complete, partial, stable, or relapse at the same timepoints.

Additional secondary endpoints involve the type, frequency, and dosage of local steroid treatments, allowing for cumulative dose calculations at specified intervals. The relapse rate will be monitored until M24, with remission defined by either complete or partial response, and relapse defined as the persistence or recurrence of existing manifestations or the occurrence of new sarcoidosis manifestations requiring substantial treatment modification. Frequencies of steroid-associated side effects will be monitored clinically and biologically, with the Glucocorticoid Toxicity Index (GTI) calculated at the designated timepoints.

Hydroxychloroquine (HCQ) safety will be assessed through initial and annual eye evaluations, including electroretinogram, autofluorescence, or OCT, and monitoring of adverse events (AEs). Electrocardiograms (EKG) will be performed before study initiation and at M1, M3, M6, M12, M18, and M24. An AE will be considered serious if it leads to HCQ cessation, hospitalization, or death. Patient adherence will be controlled by patient notebooks, pharmacy count of unused tablets, and serial dosages of blood HCQ levels at M6 and M12. Quality of life will be assessed using the SF36 questionnaire at the specified timepoints.