Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure (ASCOT-2)

Instituto de Investigacion Sanitaria La Fe

Status and phase: Unknown; Phase 4

Conditions: Premature Ovarian Failure (POF)

Treatments: Combination Product: ASCOT; Drug: G-CSF

Study type: Interventional

Funder types: Other

Identifiers

NCT03535480

2017/0251

Details and patient eligibility

About

This study aims to recover ovarian function in POF/POI patients. With this pueprose we designed a study protocol including two arms: ASCOT arm, were patients receive the stem cell mobilization treatment with Granulocyte colony stimulating factor (G-CSF) followed by apheresis and ovarian artery catheterism to selectively infuse the stem cells into the ovary and the G-CSF arm including patients that receive the mobilization treatment but not the ovarian artery catheterism to selectively infuse the cells into the ovary.

Full description

Ovarian aging appears early in life as a decline in function at 30s leading to a complete ovarian failure around 51 years of age in women. Women in modern society have delayed the age of childbearing due to socioeconomic changes and patient´s age has become the main determinant of infertility, since it is well known that both quantity and quality of the oocytes from aging patients are seriously impaired. Nevertheless, the low ovarian reserve is not only associated with age. Primary ovarian insufficiency (POI) is a cause of infertility in women, affecting 1% of the population. It is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women younger than 40 years of age. Impairment of ovarian function in POI can be mixed up with a low ovarian reserve or poor ovarian response although represent different clinical entities and patients.

Thus, interventions to recover damaged gonads in POI patients should be developed in order to enhance their reproductive potential. Clinically, bone marrow (BM) transplant in patients with POI due to chemotherapy treatment rescues ovarian functions as demonstrated by several spontaneous pregnancies. Previous research demonstrates that autologous stem cell ovarian transplantation (ASCOT) improves ovarian reserve (AMH and AFC) in 81% of women. Three of the eleven included patients achieve 5 pregnancies and 3 healthy babies have born. Response is highly variable between patients and molecular mechanisms still unknown. New approach is mandatory to elucidate them.

Results obtained in our premature ovarian failure (POF) animal model (included chemotherapy, CT ovarian injury) demonstrate that bone marrow stem cells restore ovulation by means of increasing vascularization, proliferation and diminishing apoptosis within the ovarian niche. These ovarian niche improvements promotes follicular development, increased number of antral and preovulatory follicles and corpus luteum.

POF model is ideal to demonstrate effectivity of ASCOT technique as they represent the worst possible scene. Any improvement in those patients should be significant.

Trying to be less invasive, we designed a study protocol including two arms: ASCOT arm as previously described and Granulocyte colony stimulating factor (G-CSF) arm including patients that receive the treatment but not the apheresis nor the ovarian artery catheterism to selectively infuse the cells into the ovary.

Enrollment: 20 estimated patients

Sex: Female

Ages: 18 to 38 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• ≤ 38 years old
• Oligo/Amenorrhea at least 4 months.
• Serum FSH > 25 IU/l, AMH < 5picomols (pM)
• Standard criteria for autologous bone marrow transplantation of our hospital.

Exclusion criteria

• Ovarian endometriosis
• Any ovarian surgery considered as risk factor of poor reserve.
• Genetic factors associated with poor ovarian reserve (Turner syndrome, FMR1 premutations...)
• Acquired poor ovarian reserve (Chemotherapy, radiotherapy...)
• BMI ≥ 30kg/m2.
• Iodine allergy
• Kidney failure
• Severe male factor

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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20 participants in 2 patient groups

G-CSF

Experimental group

Description:

Only receives G-CSF subcutaneously five days for stem cell mobilization

Treatment:

Drug: G-CSF

ASCOT

Experimental group

Description:

Receives G-CSF subcutaneously five days and then plasmapheresis for hematopoietic stem cell collection and catheterism for infusion in ovarian artery

Treatment:

Combination Product: ASCOT

Drug: G-CSF