Phase Ⅰ/Ⅱa Trial Evaluating Intravenous hUC-MSCs Injection for Safety, Tolerability and Efficacy in Patients With POI

Premature ovarian insufficiency (POI) is defined as ovarian dysfunction occurring in women before the age of 40, which is mainly characterized by menstrual abnormalities (amenorrhea, oligomenorrhea or polymenorrhea), elevated gonadotropin levels (FSH > 25 U/L), and fluctuating decline in estrogen levels. The incidence of POI is age-specific: 1 in 250 women develops POI before 35 years of age, and 1 in 100 women develops POI before 40 years of age. The incidence rate of POI in China is 2.8%, showing an upward trend year by year with a younger onset age.

hormone replacement therapy (HRT) relieves symptoms caused by low estrogen through estrogen supplementation. Sequential estrogen-progestogen therapy is recommended for POI patients with an intact uterus. Since patients with POI require long-term HRT, natural or nearly natural estrogens and progestogens can be selected to minimize adverse effects on the mammary gland, metabolism, cardiovascular system and other systems. Nevertheless, HRT still increases the risks of breast cancer, heart disease and stroke.

Studies have demonstrated that mesenchymal stem cells can home to ovarian stroma, regulate the balance of Th1/Th2 cytokines and the expression of endometrial natural killer cells, alleviate inflammatory responses, inhibit apoptosis of ovarian granulosa cells and reduce ovarian interstitial fibrosis, thereby improving the ovarian microenvironment. Meanwhile, these cells can secrete growth factors including VEGF, IGF-1 and HGF, promote proliferation of various ovarian cells and angiogenesis, repair ovarian structure and restore ovarian ovarian function. This study aims to evaluate the safety, tolerability and efficacy of intravenously administered hUC-MSCs in the treatment of patients with POI.

Inclusion criteria

• Aged 18 to 40 years at the time of signing the informed consent form (exclusive of the boundary values);
• Meet the diagnostic criteria specified in the Expert Consensus on Clinical Diagnosis and Treatment of Premature Ovarian Insufficiency (2023 Edition): oligomenorrhea (menstrual cycle longer than 35 days) or amenorrhea for more than 4 months, with basal serum follicle-stimulating hormone (FSH) > 25 U/L (tested on Days 2-4 of the menstrual cycle or during amenorrhea, at least twice with an interval of ≥4 weeks);
• Satisfy one of the following two criteria:

• Total number of antral follicles (AFC) with a diameter of 2-10 mm in bilateral ovaries < 5;
• Serum anti-Müllerian hormone (AMH) ≤ 7.85 pmol/L (equivalent to 1.1 ng/mL);
• Have received standardized hormone replacement therapy (HRT) at a stable dose for ≥3 months prior to drug administration with stable hormone levels, and maintain stable HRT per medical advice throughout the trial (within 24 weeks after enrollment);
• Have no fertility requirements;
• Agree to use effective contraceptive measures throughout the trial period (such as complete abstinence, condoms, cervical caps plus spermicides, intrauterine devices, etc.);
• Negative serum β-hCG test result during the screening period (to rule out pregnancy);
• Fully understand the trial information and sign the informed consent form.

Exclusion criteria

• Subjects with primary amenorrhea;
• Subjects with thyroid disorders (hypothyroidism/hyperthyroidism or thyroid malignant tumors) or resistant ovary syndrome (ROS);
• Subjects with abnormal female karyotypes (e.g., Turner syndrome, Fragile X syndrome);
• Positive serology tests (HBV antibody, HCV antibody, HIV antibody, syphilis). Exceptions: HBV carriers, patients with stable HBV after drug treatment (HBV DNA titer ≤500 IU/mL or copies <1000 copies/mL), and patients with cured HCV (negative HCV RNA test) may be enrolled if deemed eligible by the investigator;
• Subjects receiving or planning to use the following medications during the trial: oral or systemic corticosteroids, danazol, anticoagulants, Chinese herbal medicines or botanical supplements that may affect hormone levels or ovarian function;
• History of hypersensitivity to human serum albumin;
• Pregnant or breastfeeding subjects;
• Participation in another clinical trial within the past 3 months, or receipt of other cell therapies (excluding blood transfusion);
• History of malignant tumors;
• Subjects with contraindications or cautions for estrogen use, including known or suspected breast cancer, endometrial cancer, other known or suspected sex hormone-dependent malignancies, active venous or arterial thromboembolic diseases within the last 6 months, undiagnosed abnormal genital bleeding, severe hepatic or renal insufficiency [serum aspartate aminotransferase (AST) >3×ULN, serum alanine aminotransferase (ALT) >3×ULN, estimated glomerular filtration rate (eGFR) <60 mL/min], etc.;
• Uncontrolled diabetes, hypertension (>150/100 mmHg), heart disease, etc.;
• Any other conditions judged by the investigator to render the subject unsuitable for participation in this study.