Menstrual Blood Stem Cells in Poor Ovarian Responders

Study Overview
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Brief Summary
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In this controlled trial, poor ovarian responder women will be treated with transplantation of autologous menstrual blood stem cells. The investigators will attempt to assess the safety and efficacy of this procedure for the treatment of infertility in POR patients compared to control group.

Detailed Description
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With economic development, procreation delays have resulted in more women seeking medical help for infertility treatment. Because the quality and quantity of oocytes are affected by physiological age, despite advances in assisted reproductive technology (ART), managing infertility in women with poor ovarian response (POR) remains a daily challenge for physicians. Adult mesenchymal stromal cell (MSC) therapy has gained particular interest in recent years because it may provide a supportive microenvironment for oocyte development from quiescent primordial follicles. Human MSC transplantation has been shown in preclinical studies to host ovaries and restore their function and structure premature ovarian failure (POF) animal models. Because of their encouraging characteristics such as ease of access, high availability, monthly repeatability of sampling, less ethical considerations, lack of tumor-causing potential, protected property, and significant trans-differentiation capacity, endometrial-derived stromal cells have been considered in a wide range of studies since 2007. Menstrual blood-derived stromal cells (MenSCs), on the other hand, are derived from endometrial tissue and can be collected in a non-invasive manner, making them especially useful in the treatment of reproductive disorders. The investigators attempted to assess the safety and efficacy of intraovarian injection of MenSCs for the treatment of infertility in POR patients based on this evidence. The results of this clinical trial's phases I and II indicated that Men-MSCs could be considered as a potential treatment to restore the fertility capability of POR women. Based on these findings, the investigators have designed a Phase III controlled trial of autologous MenSC therapy for patients with POR.

Official Title
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Outcome of Pregnancy in Poor Ovarian Responders by Intraovarian Administration of Autologous Menstrual Blood Derived-Mesenchymal Stromal Cells

Conditions
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Poor Ovarian Response, Infertility, Female

Intervention / Treatment
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* Biological: Autologous Menstrual Blood Stem Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Serum AMH < 0.1 ng/ml (at the screening visit and in the absence of OC or sex-steroid intake) Antral follicular count (AFC) in both ovaries < 4 (at screening visit and in the absence of OC or sex-steroid intake) Positive history of at least1 standard previous IVF-ET or ICSI-ET Normal thyroid hormones (TSH and FT4) Normal level of prolactin, Normal level of fasting blood sugar Normal Liver tests (SGOT, SGPT) Normal level of BUN, creatinine Negative Infectious tests (HIV, HCV, HBS Ag, VDRL) Normal coagulation factors (PT, PTT, BT, CT) Normal serum levels of sodium, potassium, calcium, phosphorus Negative history of endometrioma or other ovarian cysts Negative history of previous ovarian surgery Negative history of cancer Negative history of a known autoimmune disorder. Exclusion Criteria: Positive history of hydrosalpinx or anatomical uterine disorders (In vaginal sonography or HSG) Severe male factors of their husbands (count <15 million/ml)

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MenSCs group<br>Study group, treated with autologous intra-ovarian MenSCs injection and monitored for spontaneous pregnancy for 3 months after intervention. ICSI was used in cases where the pregnancy did not occur naturally. | Biological: Autologous Menstrual Blood Stem Cells<br>* The menstrual blood of patients in the MenSCs treatment group was collected in sterile menstrual cups on the second day of menstruation, and directly transferred to a class B clean room for MSC isolation and culture. All cell quality control studies were performed prior to the International Conference of Harmonization Q2 (ICH Q2) guidelines. The density of the final product was 20×106 cells/ml. 150 μl of the prepared suspension was injected intravaginally into each ovary of the patient under general anaesthesia<br>|
| No Intervention: ICSI group<br>Control group, monitored for spontaneous pregnancy for 3 months after their last ovarian stimulation for ICSI or IVF. ICSI was used in cases where the pregnancy did not occur naturally. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spontaneous pregnancy rate | Number of participants that establish a spontaneous clinical pregnancy after stem cell injection | 3 months after stem cell injection | 
| Pregnancy rate after ICSI | Number of participants that establish a clinical pregnancy after embryo transfer | 4 weeks after embryo transfer | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hormone levels | Change from baseline in Anti-Müllerian hormone (AMH), serum follicle stimulating hormone (FSH), and antral follicle count (AFC) | 2 and 4 months after stem cell injection | 
| Number of oocytes | Mean number of retrieved COCs per protocol | Day 0 after follicle puncture | 
| Number of MII oocytes | Mean number of metaphase II (MII) oocytes per protocol | Day 0 after follicle puncture | 
| Number of embryos | Mean number of embryos | Day 3-5 after follicle puncture | 
| Number of high quality embryos number | Grade A for cleavage stage embryo, >=3BB for blastocyst | Day 3-5 after follicle puncture | 
| Clinical pregnancy rate | The incidence of gestational sac with heartbeat assessed by TVS | 4 weeks after embryo transfer | 
| Biochemical pregnancy rate | Incidence of serum beta-hCG test > 25 mIU/ml | 12-16 days after oocyte pick-up | 
| Live birth rate | Incidence of the birth of at least one live newborn after 22 weeks of gestation | at a follow-up time of 30 days after delivery | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Incidence of adverse and serious adverse events with potential relationship to treatment | at a follow-up time after 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Poor Ovarian Responders, Menstrual Blood Stem cells, Infertility, Cell therapy, ICSI