Efficacy and Safety of Hydroxychloroquine in Early Systemic Sclerosis: A Double-Blind, Randomized, Placebo-Controlled, Add-On Trial

The primary objective of this study is to evaluate the **efficacy** and **safety** of hydroxychloroquine compared to placebo in the treatment of early **systemic sclerosis** (SSc). This is conducted at an oral dose of 6 mg/kg daily, up to a maximum of 400 mg/day, in conjunction with standard therapies for SSc, which may include immunosuppressive and/or vasoactive treatments. The clinical relevance of this objective lies in the potential to improve therapeutic outcomes for patients with early SSc, a condition characterized by immunological, vascular, and fibrotic abnormalities.

Secondary objectives include: - Evaluating the effectiveness of adding hydroxychloroquine to standard therapy for SSc on various clinical parameters such as the ESScGAI, capillaroscopic parameters, CSURI Index, VAS pain, Morning Stiffness (MS), FACIT Fatigue Index, and Raynaud Condition Score (RCS). - Assessing the tolerability and variation of clinical, laboratory, and biomarker parameters from baseline.

The clinical trial involves participants diagnosed with **Systemic Sclerosis (SSc)**, a rare autoimmune disease characterized by immunological, vascular, and fibrotic abnormalities. The study population includes both male and female subjects, aged 18 years and older, with a disease duration of 5 years or less from the first non-Raynaud’s symptom. Participants are required to have stable SSc standard treatment for at least four weeks prior to the screening visit. The trial population was selected based on the 2013 ACR/EULAR criteria for classification of SSc, and subjects must be either naïve to hydroxychloroquine treatment or have completed a wash-out period of at least 16 weeks. The sponsor has not provided the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring comprehensive evaluation across diverse patient profiles.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy and safety of **hydroxychloroquine** in patients with early **systemic sclerosis** (SSc). The trial will involve the administration of hydroxychloroquine at an oral dose of 6 mg/kg daily, up to a maximum of 400 mg per day, in conjunction with standard therapies for SSc, which may include immunosuppressive and/or vasoactive treatments. The study is expected to span a duration of 52 weeks, with participant involvement beginning from the screening visit and continuing through to the end-of-study visit.

Participants will undergo a series of study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of SSc according to the 2013 ACR/EULAR criteria, age of 18 years or older, and a disease duration of 5 years or less from the first non-Raynaud's symptom. Following the screening, eligible participants will be randomized to receive either hydroxychloroquine or placebo. The primary endpoint will be assessed at week 52, focusing on changes from baseline in the American College of Rheumatology Combined Response Index for Systemic Sclerosis (CRISS). Secondary endpoints will include assessments of the European Systemic Sclerosis Global Disease Activity Index (ESScGDAI), Visual Analogue Scale (VAS) for pain, morning stiffness duration, FACIT fatigue index, Raynaud Condition Score (RCS), and nailfold capillaroscopy parameters at specified intervals throughout the study.

Participants are expected to remain in the study for the full 52-week period unless conditions arise that necessitate early termination, such as adverse events, withdrawal of consent, or non-compliance with study protocols. The trial aims to provide comprehensive data on the potential benefits of hydroxychloroquine as an add-on therapy in the management of early systemic sclerosis, contributing valuable insights into its role in improving patient outcomes in this rare and complex autoimmune disease.

The clinical trial involves the administration of **hydroxychloroquine sulfate** as the experimental medication. The pharmaceutical form of this medication is a coated tablet, marketed under the name PLAQUENIL 200 mg compresse rivestite. Each tablet contains 200 mg of hydroxychloroquine sulfate. The medication is administered orally, with a dosage regimen of 6 mg/kg daily, not exceeding a maximum of 400 mg per day. The treatment period extends up to 52 weeks. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, randomized, placebo-controlled trial. The placebo is provided in tablet form, referred to as Placebo tablets LFM. The placebo tablets are designed to be indistinguishable from the active medication in appearance and are administered orally at the same frequency as the experimental drug. This ensures that the study maintains its double-blind nature, with neither the participants nor the investigators aware of the treatment assignments.

Participants in the trial may also receive standard-of-care therapies for early **systemic sclerosis** (SSc), which may include immunosuppressive and/or vasoactive treatments. These non-experimental treatments are administered according to the current medical guidelines and are not influenced by the trial protocol. The combination of hydroxychloroquine sulfate or placebo with standard therapies aims to evaluate the efficacy and safety of the experimental medication in conjunction with established treatment regimens for SSc.

The efficacy of **hydroxychloroquine** in the treatment of early systemic sclerosis (SSc) will be assessed through a double-blind, randomized, placebo-controlled, add-on trial. The primary endpoint for evaluating efficacy is the change from baseline in the American College of Rheumatology Combined Response Index for Systemic Sclerosis (CRISS) at week 52. Secondary efficacy endpoints include changes from baseline in the European Systemic Sclerosis Global Disease Activity Index (ESScGDAI) at week 52, Visual Analogue Scale (VAS) for pain at weeks 26 and 52, morning stiffness duration at weeks 26 and 52, the FACIT fatigue Index at weeks 26 and 52, Raynaud Condition Score (RCS) scale at weeks 26 and 52, and Naifold Capillaroscopy (NC) main parameters and CSURI (Capillaroscopic Skin Ulcer Risk Index) at week 52.

These efficacy parameters will be measured and collected at specified timepoints throughout the trial, utilizing validated scales and indices. The trial is designed to compare the efficacy of hydroxychloroquine, administered at an oral dose of 6 mg/kg daily (up to 400 mg/day), against a placebo, in conjunction with standard therapies for SSc. The assessments will be conducted at various intervals, with the final evaluation occurring at the end of the 52-week treatment period.