Safety, Tolerability, and Preliminary Efficacy of Intra-Articular Injection of Mesenchymal Stem Cell-Derived Exosomes for the Treatment of Non-Traumatic Avascular Necrosis of the Femoral Head

Safety, Tolerability, and Preliminary Efficacy of Intra-Articular Injection of Mesenchymal Stem Cell-Derived Exosomes for the Treatment of Non-Traumatic Avascular Necrosis of the Femoral Head: A Single-Arm, Open-Label, Dose-Escalation Clinical Trial

This is a first-in-human, single-arm, open-label, dose-escalation, exploratory Phase I clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of local injection of mesenchymal stem cell-derived exosomes for non-traumatic osteonecrosis of the femoral head (ONFH).

A total of 15 treatment-naïve patients with non-traumatic, non-septic ONFH at ARCO stages I-IIIA, treated at the outpatient clinic of our hospital between June 2026 and June 2027, will be enrolled. Under ultrasound guidance, exosomes will be administered via an anterior approach through a single intra-articular injection into the hip joint. Three dose cohorts will be evaluated: \(4 \times 10^{10}\), \(1.2 \times 10^{11}\), and \(3.6 \times 10^{11}\) particles per administration per hip. The low-dose cohort will include 3 patients, while the medium- and high-dose cohorts will each include 6 patients. The dose-limiting toxicity observation period will extend from the first administration to 14 days after the final administration.

Exosomes will be administered once every 2 weeks at a volume of 3 mL per injection. Three administrations will constitute one treatment course, with a total treatment duration of 4 weeks. The primary endpoints are safety outcomes, including the incidence of adverse events, serious adverse events, and dose-limiting toxicities after administration. Secondary exploratory efficacy endpoints include changes in the Visual Analog Scale (VAS) pain score, Harris Hip Score (HHS), and radiological findings of the femoral head. The follow-up period will be 12 months.

Inclusion Criteria:

1. Age 18-70 years, inclusive, with no restriction on sex.
2. A diagnosis of non-traumatic osteonecrosis of the femoral head (ONFH) confirmed by clinical manifestations and imaging findings, with ARCO stage II or IIIA disease. Patients with advanced femoral head collapse (ARCO stage IIIB or IV) will be excluded.
3. The target hip must be treatment-naïve, defined as no prior hip-specific interventional or injection-based treatment for the affected side.
4. Ability to understand and voluntarily provide written informed consent, with an expectation of completing long-term follow-up.

Exclusion Criteria:

1. Presence of an active infection in the target joint (e.g., septic arthritis or infectious osteomyelitis), or skin disruption, infection, or other abnormalities at the intended injection site.
2. Receipt of intra-articular injection therapy in the affected hip within 3 months before screening, including corticosteroids or sodium hyaluronate.
3. Presence of any active systemic autoimmune disease (e.g., rheumatoid arthritis or systemic lupus erythematosus) or a primary or secondary immunodeficiency disorder.
4. History of malignancy.
5. Clinically significant abnormal laboratory findings during screening, including impaired hepatic or renal function (ALT or AST >1.5 × the upper limit of normal [ULN], or serum creatinine >ULN), or clinically significant abnormalities on complete blood count.
6. Coagulation disorders (PT or APTT >1.5 × ULN), active bleeding risk, or a requirement for long-term anticoagulant therapy that cannot be interrupted.
7. Severe systemic chronic disease not adequately controlled with medication, such as severe heart failure or uncontrolled severe hypertension or diabetes mellitus.
8. Severe alcohol dependence or a history of substance or corticosteroid abuse that, in the investigator's judgment, cannot be controlled during the trial and may substantially compromise treatment adherence or efficacy assessment.
9. Participation in another clinical trial within 3 months before screening, or previous treatment with stem cells, exosomes, or other cell- or biologic-based therapies.
10. Known hypersensitivity to any component of the investigational product.
11. Women who are pregnant or breastfeeding, or patients who plan to conceive during the trial or within 6 months after the last administration.