Comparative Efficacy of Autologous Hematopoietic Stem Cell Transplantation Versus Immunosuppressive Therapy in Early Diffuse Cutaneous Systemic Sclerosis

The primary objective of this study is to determine the optimal treatment strategy for early **diffuse cutaneous systemic sclerosis** (dcSSc) by comparing the effects of upfront autologous hematopoietic stem cell transplantation (HSCT) with immunosuppressive medication. The focus is on evaluating survival rates and the prevention of major organ failure, as measured by the Global Rank Composite Score, which serves as the primary endpoint. This is clinically relevant as it aims to establish a more effective initial treatment approach for patients with early dcSSc, potentially improving long-term outcomes and quality of life.

Secondary objectives include:

• Evaluating whether disease activity correlates with immunological parameters, such as skin immunopathology, immune reconstitution, and autoantibodies, in both treatment arms. Additionally, the study will assess the cost-effectiveness of HSCT as a first-line treatment compared to usual care and identify factors associated with treatment response.
• Assessing the safety of the treatment approaches.
• Investigating the impact on skin thickening, visceral involvement, functional status, sexual functioning, and quality of life.
• Determining the cost-effectiveness of the treatment strategies.

The clinical trial involves a total of **10 participants** diagnosed with **diffuse cutaneous systemic sclerosis** according to the ACR/EULAR criteria. The study population includes both male and female subjects, aged between 18 and 65 years. Participants were selected based on specific inclusion criteria, including fulfilling the 2013 ACR-EULAR classification criteria and having a disease duration of 3 years or less from the onset of first non-Raynaud's symptoms, with a modified Rodnan skin score (mRSS) of 15 or greater, or clinically significant organ involvement. The trial also considers individuals with a disease duration of 1 year or less and diffuse cutaneous disease with mRSS greater than 10 and high-risk ANA for organ-based disease and/or acute phase response. The trial population includes a vulnerable group, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed to evaluate the optimal treatment strategy for **diffuse cutaneous systemic sclerosis** by comparing hematopoietic stem cell transplantation (HSCT) as upfront therapy against immunosuppressive medication. This study is structured as an international, multicenter, open-label, randomized controlled trial. The trial is expected to span from October 30, 2020, to January 15, 2028, with participants involved for a maximum of 24 months. The primary endpoint is the Global Rank Composite Score, which assesses multiple disease manifestations simultaneously. Secondary endpoints include progression-free survival, treatment-related mortality, and treatment toxicity, among others.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-65 years), disease duration, and clinical involvement. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and adverse events. These visits will occur at specified intervals, including assessments at 6, 12, 18, and 24 months, to evaluate the area under the curve of the CRISS over time. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.

Participant involvement may be terminated early if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial employs a combination of **anhydrous cyclophosphamide**, **filgrastim**, **mycophenolate mofetil**, and **anti-T lymphocyte immunoglobulin for human use, rabbit** as part of the treatment regimen, with administration routes including injection, subcutaneous use, oral, and intravenous infusion. The study aims to provide valuable insights into the efficacy and safety of HSCT as a treatment for early diffuse cutaneous systemic sclerosis, potentially influencing future therapeutic approaches.

The clinical trial involves the administration of several treatments, including **anhydrous cyclophosphamide**, which is utilized as an experimental medication. Cyclophosphamide is administered in the form of an injection, with a pharmaceutical form code of PHF00231MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 750 mg/m² and a total maximum dose of 9000 mg/m² over a treatment period of up to 12 months. The administration route is via injection, and participant compliance is monitored throughout the trial.

**Filgrastim** is another treatment used in the study, serving as an auxiliary medication. It is administered subcutaneously, with a pharmaceutical form code of PHF802. The dosage is determined by body weight, with a maximum daily dose of 0.02 mg/kg and a total maximum dose of 0.07 mg/kg over a treatment period of up to 5 days. Filgrastim is a protein-based medication, and its administration is closely monitored to ensure adherence to the dosing schedule.

**Mycophenolate mofetil** is included as an auxiliary treatment in the trial. It is administered orally, with a pharmaceutical form code of PHF00170MIG. The maximum daily dose is 3 grams, with a total maximum dose of 2190 grams over a treatment period of up to 24 months. As a chemical substance, mycophenolate mofetil requires careful monitoring of participant compliance to ensure the effectiveness of the treatment regimen.

**Anti-T lymphocyte immunoglobulin for human use, rabbit** is utilized as a test medication in the trial. It is administered via intravenous infusion, with a pharmaceutical form code of PHF00230MIG. The dosage is based on body weight, with a maximum daily dose of 2.5 mg/kg and a total maximum dose of 7.5 mg/kg over a treatment period of up to 3 days. This structurally diverse, blood-derived substance necessitates precise administration and monitoring to maintain participant safety and treatment efficacy.

Efficacy in the clinical trial titled "Upfront autologous hematopoietic stem cell transplantation versus immunosuppressive medication in early diffuse cutaneous systemic sclerosis" will be assessed using several parameters. The primary endpoint is the Global Rank Composite Score (GRCS), which is an analytic tool that accounts for multiple disease manifestations simultaneously. Secondary endpoints include progression-free survival, treatment-related mortality, treatment toxicity, the area under the curve (AUC) of the CRISS over time, change over years in clinical parameters, and event-free survival at two years follow-up.

Progression-free survival is defined as the time in days from randomization until any relative changes from baseline are documented. Treatment-related mortality is any death during the study period that cannot be attributed to disease progression, as determined by the consensus opinion of the DSMB. Treatment toxicity will be assessed using WHO CTCAE v5.0 toxicity parameters and infections according to the Bone Marrow Transplant Clinical Trials Network (BMT-CTN) grading, in consecutive 3-month periods following randomization until five years follow-up. The AUC of the CRISS measures the 'predicted probability of being improved' over 2 and 5 years, calculated based on repeated measures at 6, 12, 18, and 24 months. Event-free survival is defined as the time from randomization until death due to any cause or the development of persistent major organ failure.