Umbilical Cord Mesenchymal Stem Cells (UC-MSC) in the Treatment of Systemic Sclerosis

A Phase I/Ⅱ Clinical Trial for HS_SW01 Cells Injection in the Treatment of Systemic Sclerosis

The goal of this clinical trial is to evaluate the safety and tolerability of human umbilical cord mesenchymal stem cell injection(HS_SW01 Cells injection) in patients with systemic sclerosis, and to further explore its pharmacokinetics(PK), immunological profile and preliminary efficacy.

Participants will be required to sign the informed consent form and will only be assigned to the study and enrolled after undergoing a series of tests and meeting the inclusion and exclusion criteria of the protocol.

Systemic sclerosis (SSc) is a multisystem connective tissue disease involving the skin and internal organs. It is primarily characterized by chronic inflammation of affected tissues with varying degrees of collagen deposition (fibrosis), as well as peripheral and visceral obliterative vasculopathy. SSc is associated with high morbidity and mortality, particularly in patients with involvement of the lungs, heart, gastrointestinal tract, and kidneys. Scleroderma renal crisis, pulmonary arterial hypertension, and interstitial lung disease are the leading causes of death. Current treatments for SSc primarily focus on delaying disease progression and alleviating symptoms, however, their therapeutic effects are limited. As SSc significantly threatens patients' quality of life and survival, there is an urgent need to explore new therapeutic strategies.

Mesenchymal stem cell (MSC) therapy is a novel therapeutic approach that leverages the self-renewal and multidirectional differentiation capabilities of MSCs. When administered to specific sites of tissue injury, MSCs can differentiate into various cell types, thereby exerting therapeutic effects. Human umbilical cord mesenchymal stem cells (hUC-MSCs), a type of multipotent mesenchymal stem cells found in neonatal umbilical cord tissue, exhibit immunomodulatory and immunosuppressive properties, making them an effective and promising potential treatment for systemic sclerosis.

This clinical trial is a multicenter Phase I/II clinical trial, which includes two stages: Phase I dose-escalation and Phase II dose-expansion. The Phase I stage is a multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and tolerability of HS_SW01 cells injection in patients with systemic sclerosis, to further explore its PK, immunogenicity profiles and preliminary efficacy. The Phase II dose-expansion stage is a randomized, double-blind, controlled study designed to evaluate the safety, efficacy, and changes in disease-related biomarkers of HS_SW01 cells injection in patients with systemic sclerosis.

During the Phase I, the trial includes three dose groups: 0.5×10^6 cells/kg, 1.0×10^6 cells/kg, and 2.0×10^6 cells/kg. Using a "3+3" dose-escalation design, each dose group will enroll 4 to 7 subjects in sequential order from the lowest to the highest dose level.

Eligible participants are patients with systemic sclerosis between 18 and 65 years of age inclusive, who satisfy all the inclusion criteria and do not meet any of the exclusion criteria.

Inclusion Criteria:

1. Voluntarily signed informed consent form.

2. Age 18 to 65 years, inclusive, male or female.

3. Diagnosis of systemic sclerosis (SSc) according to the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria.

4. Diagnosis of diffuse cutaneous systemic sclerosis at screening, with disease duration ≤5 years (disease onset defined as the time of initial SSc diagnosis).

5. Prior treatment with at least two of the following: corticosteroids, immunosuppressants, or biologic agents, and a modified Rodnan skin score (mRSS) between 10 and 30, inclusive.

6. Female subjects must meet one of the following:

   1. Of non-childbearing potential, defined as at least one year postmenopausal or surgically sterilized; or
   2. Of childbearing potential and agree to use effective contraception from the signing of informed consent through at least 6 months after the last dose of study drug, with a negative serum pregnancy test at screening.

Exclusion Criteria:

1. At screening, the patient's percent predicted forced vital capacity (FVC) is <50%.

2. Previously diagnosed with moderate or severe pulmonary arterial hypertension, or systolic pulmonary artery pressure >45 mmHg measured by echocardiography at screening.

3. Presence of newly onset or worsening of pre-existing clinical symptoms requiring hospitalization as judged by the investigator prior to screening, including the following:

   ① Myocardial infarction, stroke, scleroderma renal crisis, severe intestinal disease, or uncontrolled severe hypertension (≥160/100 mmHg) with newly onset or worsening of pre-existing clinical symptoms within 6 months.

   ② Unstable ischemic heart disease, uncontrolled cardiac arrhythmia, heart failure (New York Heart Association Class III/IV), left ventricular ejection fraction <50% by echocardiography, renal insufficiency, or renovascular hypertension within 3 months.

4. Presence of other autoimmune connective tissue diseases other than systemic sclerosis at screening, except for patients with secondary Sjögren's syndrome who are permitted to participate in this trial.

5. Any of the following laboratory abnormalities at screening:

   ① Hematologic abnormalities: hemoglobin <90 g/L; white blood cell count <3.0×10^9 /L; absolute neutrophil count <1.5×10^9 /L; platelet count <90×10^9 /L.

   ② Hepatic abnormalities: ALT or AST >3× upper limit of normal (ULN); total bilirubin >3× ULN.

   ③ Renal abnormalities: estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², or any uncontrolled, clinically significant laboratory abnormality that may interfere with data interpretation or subject participation.

6. Positive test for human immunodeficiency virus antibody (anti-HIV-Ab), active syphilis, active hepatitis C (positive for HCV antibody with detectable HCV-RNA), or positive for HBsAg with detectable HBV-DNA at screening; or history of severe active or recurrent bacterial, viral, fungal, parasitic, or other infections at screening.

7. Receipt of inactivated or live-attenuated vaccine within 2 months prior to enrollment.

8. Any of the following within 3 months prior to enrollment:

   ① Major trauma or major surgery (including joint surgery), or need for major surgery during the study period that, in the investigator's opinion, would pose an unacceptable risk to the subject.

   ② Treatment with plasmapheresis or extracorporeal photopheresis.

   ③ Participation in any other interventional clinical trial.

9. Prior treatment with stem cell-based therapy less than 3 months before enrollment.

10. History of any malignancy within 5 years prior to enrollment, except for adequately treated or resected basal cell carcinoma or squamous cell carcinoma of the skin, or cervical carcinoma in situ.

11. Intolerance or contraindication to the study treatment, including any of the following:

    ① Allergy to albumin contained in the excipients of the investigational product.

    ② Absence of peripheral venous access.

12. Heavy smoking, heavy drinking, or drug abuse within 12 months prior to screening or during the screening period:

    ① Heavy smoking defined as an average of ≥5 cigarettes per day within 3 months prior to screening.

    ② Heavy drinking defined as consumption of more than 14 units of alcohol per week within 3 months prior to screening (1 unit = 350 mL of beer, 45 mL of liquor, or 150 mL of wine).

    ③ Drug abuse defined as a history of drug addiction or drug abuse.

13. Plan to father or bear children within at least 6 months following the last dose, or unwilling to use effective contraception with their partner, or plan to donate sperm or eggs.

14. Any other condition that, in the investigator's judgment, makes the subject unsuitable for participation in this study.