Autologous Bone Marrow-derived Mesenchymal Stem Cells for Atrophic Endometrium in Patients With Repeated IVF Failures

Open Randomized Trial of Clinical Efficiency and Safety of Cell Product of Autologous Bone Marrow-derived Mesenchymal Stem Cells for Reparative Treatment of Destructively Changed Endometrium in Patients With Repeated IVF Failures

Investigators will examine safety and efficiency of the cell product of autologous bone marrow-derived mesenchymal stem cells (MSC) for patients with repeated IVF failures and hypoplastic or/and fibrosis process of endometrium

Study Overview

• Status: Completed
• Conditions: Infertility, Female; Asherman Syndrome; Infertility of Uterine Origin
• Intervention / Treatment: Biological: bone marrow-derived MSC and HRT; Other: hormonal replacement therapy

Detailed Description

Sixty patients eligible for the study will be divided to two groups (experimental and control) according to randomization (envelope) procedure in 1:1 ratio.

For patients of the main group bone marrow stem cells will be extracted from the crest of the ilium using standard methodology. After extraction and cultivation final product of autologous bone marrow-derived mesenchymal stem cells will be transplanted to endometrial cavity on menstrual cycle day 5-6. Meanwhile patients will receive three cycles of hormonal replacement therapy (4 mg Progynova (Bayer Pharma, Germany) daily on menstrual cycle day 5-25 in combination with 20 mg Duphaston (Abbott Healthcare Products, B.V., Netherlands) daily from day 15 to day 25. On day 20 of hormonal replacement therapy (HRT) of the last (third) cycle Pipelle-biopsy of endometrium will be performed. Obtained material will be analyzed by immunohistochemistry with the assessment of estrogen and progesterone receptors, VEGFa, GM-CSF, CD133+, CD34 and CD56. Ultrasound characteristics of endometrial quality will be registered on day 9-10 and day 19-21 of every cycle. When morphological and echographic parameters of endometrium are found satisfactory for embryo transfer, the HRT for endometrial preparation for frozen/thawed embryo transfer cycle will be initiated. If acceptable endometrial characteristics are not achieved, patients could be offered to undergo repeated (not more than 3) transplantation of MSC procedures.

Control group will receive three standard cycles of HRT following hysteroscopy before frozen/thawed embryo transfer. If endometrial characteristics are found unsatisfactory, gestational surrogacy might be offered.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

• Russian Federation
  • Saint Petersburg, Russian Federation, 199034
    • D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 44 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Repeated IVF attempts with high and good quality embryo transfer in fresh and frozen IVF cycles;
• Age 20-44 years;
• Endometrial thickness less than 6 mm in 2 or more of HRT cycles for endometrial preparation for embryo transfer
• Hysteroscopic evidence of fibrosis processes of uterine cavity with the absence of positive dynamics of HRT in 3 months following operation;
• Signed informed consent.

Exclusion Criteria:

• Contraindication for pregnancy;
• Absence of cryopreserved embryos, stored at clinic's cryobank;
• BMI > 30 kg/m2;
• Impaired carbohydrate metabolism according to glucose tolerance test;
• Thrombosis in anamnesis;
• Oncological diseases in anamnesis;
• Diagnosed inherited thrombophilia;
• Uterine fibroids of more than 4 cm or more than 2 fibroids of 2.5 cm diameter;
• Nodal form of adenomiosis;
• Ovarian cysts more than 4 cm in diameter.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: bone marrow-derived MSC and HRT; endometrial injection of autologous cell product of MSC with hormonal replacement therapy before frozen/thawed ET	Biological: bone marrow-derived MSC and HRT; Transplantation procedure to endometrial cavity is performed with ultrasound guidance on menstrual cycle day 5-6 through uterine cervix using cater for embryo transfer with 1 ml of suspension containing 5 millions of autologous bone marrow-derived mesenchymal stem cells; Three cycles of HRT following MSC transplantation;; Pipelle-biopsy of endometrium on day 20 of hormonal replacement therapy of the last (third) cycle;; Frozen/thawed embryo transfer 3-6 months after transplantation.
Active Comparator: hormonal replacement therapy; standard endometrial preparation for frozen/thawed ET	Other: hormonal replacement therapy; standard treatment of hypoplastic endometrium or Asherman's syndrome: Three cycles of HRT preceding frozen/thawed embryo transfer;; Frozen/thawed embryo transfer.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of endometrial receptivity	combination of endometrial thickness on ultrasound and immunohistochemistry of endometrium assessed at the biopsy day of the third cycle of HRT	3-6 month after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical pregnancy rate	presence of intrauterine gestational sac at transvaginal ultrasound at 5-6 weeks of gestation or 5-6 weeks after starting the intervention; measured per frozen/thawed embryo transfer	3-4 weeks after embryo transfer
Treatment-Emergent Adverse Events	Incidence of adverse events: side reactions, abdominal discomfort and patient's tolerance (Safety and Tolerability)	3-6 month after randomization

Collaborators and Investigators

• Sponsor: D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductology

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2017
• Primary Completion (Actual): March 16, 2019
• Study Completion (Actual): December 28, 2019

Study Registration Dates

• First Submitted: May 23, 2017
• First Submitted That Met QC Criteria: May 23, 2017
• First Posted (Actual): May 25, 2017

Study Record Updates

• Last Update Posted (Actual): January 2, 2020
• Last Update Submitted That Met QC Criteria: December 31, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Stem cell; Repeated IVF failure
• Additional Relevant MeSH Terms: Infertility; Infertility, Female; Gynatresia
• Other Study ID Numbers: MSC-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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