Evaluation of Hydroxychloroquine Sulfate and Low-Dose Corticosteroid Efficacy in Pulmonary Sarcoidosis: A Randomized Controlled Trial

The primary objective of this study is to demonstrate the **non-inferiority** of hydroxychloroquine combined with low-dose corticosteroids compared to medium-dose corticosteroid therapy in improving respiratory function at 6 months in patients with pulmonary **sarcoidosis**. This is clinically relevant as it may offer a treatment option with potentially fewer side effects while maintaining efficacy in managing respiratory symptoms associated with sarcoidosis.

Secondary objectives include:

• To demonstrate the superiority of hydroxychloroquine combined with low-dose corticosteroids versus medium-dose corticosteroid therapy at 3, 6 months, and 1 year on general quality of life, respiratory quality of life, fatigue, treatment side effects, and treatment adherence.
• To demonstrate the non-inferiority of hydroxychloroquine combined with low-dose corticosteroids versus medium-dose corticosteroid therapy at 3, 6 months, and 1 year on respiratory function using additional tools, respiratory symptoms, and the activity and flares of thoracic and extra-thoracic sarcoidosis.

The clinical trial focuses on individuals diagnosed with **sarcoidosis**, specifically targeting those with pulmonary involvement. The study population includes both male and female participants aged between 18 and 80 years. Participants are required to have a confirmed diagnosis of pulmonary sarcoidosis as per the ATS 2020 AJRCCM diagnostic criteria, which includes a compatible presentation and the presence of non-necrotizing granulomas in one or more tissues, while excluding other granulomatous diseases. The trial does not involve a vulnerable population. Participants must exhibit lung activity on imaging and meet specific respiratory function criteria, such as a forced vital capacity (FVC) of 80% or less of the predicted value, or a significant decline in FVC, accompanied by respiratory symptoms like cough, dyspnea, or chest pain. Women of childbearing potential are required to use effective contraception until eight months post-treatment. The sponsor has not provided information regarding the total number of participants. The selection process ensures that participants have provided informed consent and have social security coverage. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations.

The clinical trial is designed to evaluate the efficacy of **hydroxychloroquine** combined with low-dose corticosteroid therapy in patients with pulmonary **sarcoidosis**. This is a randomized, controlled trial with a double-blind design to ensure unbiased results. The trial aims to demonstrate the non-inferiority of the combination therapy compared to medium-dose corticosteroid therapy in improving respiratory function over a period of six months. The trial is expected to run from June 2022 to December 2027, with participant involvement lasting 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 (18-80 years), diagnosis of pulmonary sarcoidosis, and specific respiratory symptoms. Following the screening, participants will be randomized into treatment groups. Regular follow-up visits will occur at three-month intervals to monitor respiratory function, treatment adherence, and side effects. The primary endpoint is the change in forced vital capacity (FVC) percentage from baseline to six months. Secondary endpoints include quality of life assessments, side effects, and additional respiratory function tests.

The end-of-study visit will occur at the conclusion of the 24-month treatment period, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to adhere to the treatment protocol, or if the investigator deems it necessary for their safety. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **hydroxychloroquine sulfate** as an experimental medication. This compound is chemically derived and is administered in the form of **PHF00082MIG**. The maximum daily dosage is 400 mg, with a total maximum dose of 67,200 mg over a treatment period of 24 weeks. The route of administration is oral, and the medication is not formulated for pediatric use. The trial aims to evaluate the efficacy of hydroxychloroquine sulfate in combination with low-dose corticosteroids in the treatment of pulmonary sarcoidosis.

**Prednisolone** is another experimental medication used in this trial. It is a chemically synthesized corticosteroid, administered orally in the form of **PHF00245MIG**. The maximum daily dose is 40 mg, with a total maximum dose of 3,010 mg over a 24-week period. Prednisolone is used in combination with hydroxychloroquine sulfate to assess its effectiveness in improving respiratory function in patients with pulmonary sarcoidosis.

The comparator treatment in this study is **prednisone**, a chemically derived corticosteroid. It is administered orally in tablet form, with a maximum daily dose of 20 mg and a total maximum dose of 1,960 mg over the course of 24 weeks. Prednisone serves as the standard-of-care therapy against which the experimental combination of hydroxychloroquine sulfate and low-dose corticosteroids is compared. The trial's objective is to demonstrate the non-inferiority of the experimental combination therapy in comparison to medium-dose corticosteroid therapy.

The efficacy of the treatment in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the difference in forced vital capacity (FVC) percentage of predicted value between baseline and 6 months. This will be measured to evaluate the improvement in respiratory function, which is the main objective of the trial. Secondary endpoints include a variety of measures to assess the overall impact of the treatment on patients' health and quality of life. These include the General Quality of Life assessed by the Short Form 36 item (SF-36) questionnaire, and the Respiratory Quality of Life measured by the St George's Respiratory Questionnaire (SGRQ).

Additional secondary endpoints involve the assessment of fatigue using the Fatigue Assessment Scale (FAS), and the evaluation of treatment side effects, such as digestive issues, allergic reactions, and ocular effects for **hydroxychloroquine**; and weight changes, blood pressure, and other metabolic parameters for corticosteroids. Treatment adherence will be monitored using the GIRERD self-questionnaire. Respiratory function will be further evaluated through measures of FVC, Forced Expiratory Volume in 1 second (FEV1), Carbon Monoxide Diffusing Capacity (DLCO), oxygen saturation, and the 6-minute walk test (6MWT). Respiratory symptoms will be assessed using dyspnea scores and scales, including mMRC, Baseline and Transition Dyspnea Index (BDI-TDI), and Dyspnea-12, as well as the Cough and Sputum Assessment Questionnaire (CASA-Q).

Other secondary endpoints include the activity and flares of thoracic and extrathoracic sarcoidosis, assessed using the Wasog sarcoidosis organ assessment instrument, and the response to treatment evaluated by the extra-Pulmonary physician Organ Severity Tool (ePOST) and the Sarcoidosis-Disease Activity Index (S-DAI). Biological activity will be assessed by measuring serum angiotensin-converting enzyme (ACE) levels, calcium, and lymphocyte count in complete blood count. These assessments will be conducted at various time points throughout the trial to ensure comprehensive evaluation of the treatment's efficacy.