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

Autologous Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure Patients. Pilot Study ASCOT-2

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.

Study Overview

• Status: Unknown
• Conditions: Premature Ovarian Failure (POF)
• Intervention / Treatment: Drug: G-CSF; Combination product: ASCOT

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mónica Romeu, Doctor; Phone Number: 244116 +34961244000; Email: monicaromeuvillarroya@gmail.com
• Study Contact Backup: Name: Susana Martínez, Doctor; Phone Number: 244116 +34961244000; Email: susamc12@hotmail.com

Study Locations

• Spain
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico la Fe-IIS la Fe
    • Principal Investigator: Sonia Herraiz, PhD
    • Sub-Investigator: Nuria Pellicer de Castellví, Doctor
    • Sub-Investigator: Inés Gómez, Doctor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: G-CSF; Only receives G-CSF subcutaneously five days for stem cell mobilization	Drug: G-CSF; G-CSF subcutaneously during five days; Other Names: Granulocyte colony stimulating factor
Experimental: ASCOT; Receives G-CSF subcutaneously five days and then plasmapheresis for hematopoietic stem cell collection and catheterism for infusion in ovarian artery	Drug: G-CSF; G-CSF subcutaneously during five days; Other Names: Granulocyte colony stimulating factor; Combination product: ASCOT; G-CSF subcutaneously during five days, aphaeresis to hematopoietic stem cell collection and catheterism for ovarian artery infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antral follicle count (AFC)	every antral follicle is measured	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Menses recovery	Spontaneous menstrual cycle restoration and its characteristics	6 months
serum follicle stimulating hormone (FSH) and estradiol	serum extraction for biological measurements	6 months
ovarian reserve dynamics	ultrasound observation of follicular development	6 months
Controlled Ovarian Hyperstimulation (COH) response	ovarian response to gonadotropins	6 months
pregnancy rate	pregnancy rate spontaneous and after COH	2 years
Number of good quality embryos	Morphological criteria and developmental potential	6 months
Number of participants with treatment-related adverse events	Secondary effects of the received interventions following hematological and gynecological medical criteria	6 months

Collaborators and Investigators

• Sponsor: Instituto de Investigacion Sanitaria La Fe
• Investigators: Principal Investigator: Antonio Pellicer, Professor, Iis la Fe

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2018
• Primary Completion (Anticipated): June 1, 2020
• Study Completion (Anticipated): June 1, 2022

Study Registration Dates

• First Submitted: May 2, 2018
• First Submitted That Met QC Criteria: May 22, 2018
• First Posted (Actual): May 24, 2018

Study Record Updates

• Last Update Posted (Actual): May 24, 2018
• Last Update Submitted That Met QC Criteria: May 22, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: ovarian reserve
• Additional Relevant MeSH Terms: Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Primary Ovarian Insufficiency; Menopause, Premature; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Lenograstim
• Other Study ID Numbers: 2017/0251

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No