Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure

NCT ID: NCT06202547

Last Updated: 2024-01-11

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-02-20
• Study Completion Date: 2025-02-18

Brief Summary

Premature ovarian failure (POF) is a clinical syndrome defined by loss of ovarian activity before the age of 40 years. POF is characterized by menstrual disturbance (amenorrhea or oligomenorrhea) with raised gonadotrophins and low estradiol. The prevalence of POF is 1-2%. Extracellular vesicles (EVs) are membrane-packed vesicles that are secreted by a variety of cell types, including T cells, B cells, dendritic cells, platelets, mast cells, epithelial cells, endothelial cells, neuronal cells, cancerous cells, oligodendrocytes, Schwann cells, embryonic cells, and mesenchymal stromal cells-derived (MSCs). MSCs-EV more stable and induce stronger signaling and are produced in higher concentrations than stem cells. They demonstrate no inherent toxicity, are not associated with any long-term maldifferentiation of engrafted cells or tumor generation, and carry no apparent risk of aneuploidy or immune rejection following in vivo allogenic administration.Several studies have evaluated the safety and possible efficacy of injection MSCs-EV for the treatment of premature ovarian failure in animal models. Based on the available evidence, the study was designed with the aim of investigating the safety and effectiveness of intraovarian injection of MSCs-EV in patients with POF diagnosis.

Detailed Description

Investigating the effect of intraovarian injection of bone marrow-derived extracellular vesicles (MSC-EV) on serum levels of Follicle-Stimulating Hormone (FSH),Anti-Mullerian Hormone (AMH) levels, as well as the return of the menstrual cycle in infertile patients with premature ovarian failure, as well as the evaluation of its possible side effects. A before/after clinical trial (phase I) on 10 patients is designed. Eligible patients will be included in the study if they have written consent. Infertile women who have been diagnosed with premature ovarian failure and have normal body mass index and normal genetic tests are invited to participate in this project. Patients with early amenorrhea and certain immunological and cardiovascular diseases, as well as a history of ovarian masses or abnormal serological tests will not be included in the study. If the patient has undergone hormone replacement therapy (HRT), the HRT will be stopped for at least two months and then the injection cycle will be started.Injection of bone marrow-derived extracellular vesicles with a dose equivalent to 3 times 10 million clonal mesenchymal stem cells in 2 ml will be performed for all patients. Follow-up of patients in order to respond to treatment for 8 months based on evaluation of Follicle-Stimulating Hormone (FSH),Anti-Mullerian Hormone (AMH) levels, return of menstrual cycle, ovarian ultrasound and also check possible complications due to injection (fever, bacteremia, sepsis, Pelvic inflammatory disease, anaphylactic shock and hematoma from the first 24 hours and in the first week) will be done.

Primary Outcome Measures, Safety evaluation, [Time Frame: 8 months]:Early-onset possible side effects (fever, bacteremia, sepsis, PID, anaphylactic shock, and hematoma will be evaluated at the first 24 h and during the first week. Possible second side effects such as ovarian abscesses and benign or malignant neoplasms will be assessed until 8 months after intra-ovarian EV injection.

Secondary Outcome Measures, Feasibility evaluation, [Time Frame: 8 months]: The Serum FSH, Estradiol and AMH levels measurements and Return of menstrual cycle will be evaluated until months after intra-ovarian EV injection. Ultrasonography evaluation will be performed monthly to evaluate the ovarian volume (cc), the antral follicle count, Endometrium thickness, the number and size of the follicles.

Conditions

Premature Ovarian Failure

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

intraovarian injection of MSC-EVs

The patient is anesthetized and placed in a lithotomy position, after preparing and washing the vagina with normal saline, under transvaginal ultrasound guidance (Aloka-40000 vaginal probe, Japan) using needle puncture (Reproline medical Gmbh, Rheinbach/Germany). The injection of 2 ml of extracellular vesicles derived from MSCs (equivalent to 30 million cells) will be performed into one ovary of the patient (the accessible ovary).

Group Type: EXPERIMENTAL

Intra-ovarian injection of bone marrow mesenchymal stromal cells-derived extracellular vesicles

Intervention Type: BIOLOGICAL

he patient is anesthetized and placed in a lithotomy position, after preparing and washing the vagina with normal saline, under transvaginal ultrasound guidance (Aloka-40000 vaginal probe, Japan) using needle puncture (Reproline medical Gmbh, Rheinbach/Germany). The injection of 2 ml of extracellular vesicles derived from MSCs (equivalent to 30 million cells) will be performed into one ovary of the patient (the accessible ovary).

Interventions

Intra-ovarian injection of bone marrow mesenchymal stromal cells-derived extracellular vesicles

he patient is anesthetized and placed in a lithotomy position, after preparing and washing the vagina with normal saline, under transvaginal ultrasound guidance (Aloka-40000 vaginal probe, Japan) using needle puncture (Reproline medical Gmbh, Rheinbach/Germany). The injection of 2 ml of extracellular vesicles derived from MSCs (equivalent to 30 million cells) will be performed into one ovary of the patient (the accessible ovary).

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• Women between 20-38 years old
• Baseline serum level of follicle stimulating hormone (FSH) higher or equal to 25 IU/l at least twice with an interval of 3 or 4 months
• At least one year has passed since secondary amenorrhea and premature ovarian failure (POF) diagnosis
• Normal karyotype and fragile X messenger ribonucleoprotein 1 (FMR1) gene

Exclusion Criteria

• Primary amenorrhea
• Congenital anomaly of the ovary
• Thyroid disease Immune system diseases such as lupus, etc.
• Previous and/or family history of ovarian tumor
• Previous and/or family history of suffering from major diseases in the past and present such as cancer
• Positive serological evidence regarding previous or current hepatitis B and C, Human T-lymphotropic virus 1, Human immunodeficiency virus (HIV), Syphilis Disturbance in the normal range of laboratory tests as levels of Hemoglobin Subunit Alpha 1 (HbA1), Alanine transaminase (ALT), The aspartate aminotransferase (AST), the number of white blood cells (WBCs), The creatinine (Cr), International normalised ratio (INR) , Platelets (Plt), Hematocrit (Hct) tests.
• History of specific systemic disease (rheumatology, endocrine, cardiovascular, etc.)
• Severe endometriosis (stage III and IV)
• Small and non-injectable ovaries Lack of patient satisfaction
• The patient's unwillingness to continue participating in the study

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 38 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Royan Institute

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Faezeh Shekari, Ph.D

Role: PRINCIPAL_INVESTIGATOR

Department of Development of Stem Cell Sciences of Royan Institute

Locations

Royan Institute

Tehran, , Iran

Site Status: RECRUITING

Countries

Iran

Central Contacts

Parvaneh Afsharian, Ph.D

Role: CONTACT

p.afsharian@royan-rc.ac.ir

+9802123562674

Mehri Mashayekhi, M.D

Role: CONTACT

dr.mashayekhy@yahoo.com

+9809123250933

Facility Contacts

Parvaneh Afsharian, Ph.D

Role: primary

p.afsharian@royan-rc.ac.ir

+9802123562674

Other Identifiers

IRCT20080831001141N43

Identifier Type: OTHER

Identifier Source: secondary_id

400000134

Identifier Type: -

Identifier Source: org_study_id