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Recruitment status Open public recruiting
Unique ID issued by UMIN UMIN000029807
Receipt No. R000033876
Scientific Title Cryopreservation and autografting of ovarian tissues for infertility treatment in patients with primary ovarian in sufficiency (POI)
Date of disclosure of the study information 2017/11/16
Last modified on 2019/07/16

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Basic information
Public title Cryopreservation and autografting of ovarian tissues for infertility treatment in patients with primary ovarian in sufficiency (POI)
Acronym Infertility treatment for patients with primary ovarian insufficiency (POI)
Scientific Title Cryopreservation and autografting of ovarian tissues for infertility treatment in patients with primary ovarian in sufficiency (POI)
Scientific Title:Acronym Infertility treatment for patients with primary ovarian insufficiency (POI)
Region
Japan

Condition
Condition POI patients with a chief complaint of infertility.
Patients who are predicted to become POI.
Classification by specialty
Obsterics and gynecology
Classification by malignancy Others
Genomic information YES

Objectives
Narrative objectives1 To develop a safe ovarian tissue cryopreservation and subsequent autografting after thawing as well as a method to achieve successful follicle growths and pregnancies for POI patients.
Basic objectives2 Safety,Efficacy
Basic objectives -Others
Trial characteristics_1 Confirmatory
Trial characteristics_2 Pragmatic
Developmental phase Phase III

Assessment
Primary outcomes Comparison of follicle growth rates after IVA (in vitro activation) treatment with those of base line numbers.
Key secondary outcomes To evaluate the presence of residual follicles, we measure the levels of serum biomarker for early follicles before ovariectomy. Using part of the ovarian tissue, we evaluate the conditions of the follicles and oocytes after thawing structurally and histologically. To evaluate the efficacy and presence of residual follicles, part of the ovarian tissues is used for cultivation, ultrasound/ Far infrared ray scanning and histological examination (follicle count, fibrotic evaluation, antithyroid antibody and inflammatory change) to evaluate the effect of IVA and the presence of residual follicles.
To judge the effect of hCG on induction of angiogenetic factors production after autografting, we collect part of uterine endometrium before autografting and determine the expression levels of related genes and proteins in neovascularization. We further measure serum VEGF levels after hCG administration.
In the case of very rare type of POI, Resistant Ovary Syndrome (ROS), we detect anti-FSH and FSHR antibodies, analyze their responsible genes and ovarian tissue structures, and measure serum levels of CCN growth factors after linear cutting of ovarian cortex..
After IVA, we perform ovarian stimulation by hormonal therapy. Under evaluation of estradiol, progesterone, FSH, LH levels, we stimulate follicle growth for subsequent IVF. We compare the proportions of oocyte retrieval, oocyte maturation, fertilization, high-quality embryos, pregnancy and abortion with those of base line levels.

Base
Study type Interventional

Study design
Basic design Parallel
Randomization Non-randomized
Randomization unit
Blinding Open -no one is blinded
Control Active
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms 4
Purpose of intervention Treatment
Type of intervention
Maneuver
Interventions/Control_1 IVA
1.we measure serum molecular markers before surgeries to evaluate the effect of hippo signal inhibition and presence of residual follicles.
2.whole or part of one ovary is removed under laparoscopic surgery. ovarian cortex is isolated and cut into small tissues (
1x1cm,1-2mm thickness )
before vitrification.to induce secondary follicle growth, in situ incision of ovarian cortex is performed on the residual ovary.
3.To determine follicle numbers in ovarian tissues,we count follicles under histological analyses. part of ovarian tissues is used for cultivation,ultrasound,far infrared ray scanning and histological examination.
4.After thawing,ovarian strips are fragmented into 1-2mm cubes and cultured with IVA
medium containing a PTEN inhibitor (bpV)
and PI3K activators (740YP,phospharidic acid, and /or propranolol) for 48h.
5.After culture,the activated ovarian cubes are washed with medium without IVA drugs.The ovarian cubes are transplanted beneath serosa of Fallopian tubes and to the residual ovary and Douglas'pouch.
6.We treat patients with estrogen for 2 weeks before autografting. After grafting,hCG is administered to induce production of
angiogenesis factor to help vascularization and survival of grafts.To judge the effect of hCG, part of endometrium is collected to measure related gene and protein levels before autografting. Angiogenesis factor levels are measured after hCG.
7.We measure molecular markers to evaluate the effect of Hippo signal inhibition after grafting. We treat the patients with
gonadotropin for ovarian stimulation for IVF-ET.Ovarian stimulation continues for one to two years. If ovarian stimulation is not effective, we perform another autografting.
Interventions/Control_2 Fresh IVA
For patients who have high possibility to have residual follicles, we perform fresh IVA. In fresh IVA, we remove their ovaries and culture the ovarian tissues with IVA medium for 48 hours without cryopreservation. After culture, we perform autograft of ovarian tissues under the same method of IVA. Remaining ovarian tissues are vitrified using the same method. Other methods and outcome measures are same as IVA.
Interventions/Control_3 Drug-free IVA
For patients who are predicted to become
POI but still have irregular menstruation,
we fragmented the ovarian tissue into
small cubes and autograft them immediately without culture to stimulate secondary follicle growth leading to increase in the number of retrieved oocytes.
1.Excise one side of whole ovary or partial ovarian tissues under laparoscopic surgery. After removal of medulla tissues to prepare ovarian cortex,the ovarian cortex was dissected into 3x3cm with 1-2mm thickness of tissue stripes and further fragmented into 1-2mm cubes.To measure the number of secondary follicles in the dissected ovarian tissue,10% of volume of the tissue is fixed and then each developmental stage of follicles are counted under histological analyses.
2.The ovarian cubes are auto-transplanted beneath of the serosa of both Fallopian
tubes,remaining ovaries and/or Douglus'
pouch.We also directly cut ovarian cortex of the contra lateral ovary to induce physical stimulation.
3.Remaining ovarian tissues are vitrified using the same method.Other methods and outcome measures are are same as IVA.
Interventions/Control_4 Resistant Ovary Syndrome(ROS) is a very rare type of POI. In contrast to regular POI, ROS patients still have higher number of residual follicles in their ovaries. However, the follicles do not respond to endogenous and exogenous FSH stimulation, resulting in failure to grow. Based on our previous studies, physical stimulation to ovaries induces the production of CCN growth factors, leading to ovarian follicle stimulation. Thus, we perform in situ incision of ovarian cortex as a less invasive approach for ROS patients. When in situ incision of ovarian cortex is not effective, we perform Drug-free IVA. In some cases of ROS patients, auto-antibodies such as anti-FSH/FSHR antibody are found as causes of the disease, we use steroid hormone treatment to suppress the production of auto-antibodies. Using blood tests, we measure the levels of auto-antinodies. We analyze responsible genes for ROS, and perform histological analysis of ovarian structure. We also measure the levels of CCN growth factors after the surgery.
Correct serum from the patients before surgery to measure molecular markers to ensure suppression of Hippo signaling.
We directly cut ovarian cortex or scratch ovarian cortex to induce physical stimulation to the ovary. To measure the number of secondary follicles in the dissected ovarian tissue, 10% of volume of the tissue is fixed and then each developmental stage of follicles are counted under histological analyses.
Correct serum from the patients after surgery to measure molecular markers to ensure suppression of Hippo signaling. After grafting, patients receive ovarian stimulation using gonadotropin drugs to stimulate follicle growth and retrieve oocytes. Mature oocytes are fertilized by in vitro fertilization and preimplantation embryos are transplant into uterus. The treatment continues for 1-2 years. If first auto-transplantation is not successful and patients have cryopreserved ovarian tissues, patients can repeat these procedures.
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit

Not applicable
Age-upper limit
48 years-old >
Gender Female
Key inclusion criteria 1. POI patients
2. Patients with all followng criteria
1) Over 40 yeras-old
2) Low responder diagnosed by previous ovarian stimulation (less than 3 oocytes retreival)
3) Abnormal ovarian resreve (AFC: <5-7, AMH: 0.5-1.1 ng/ml)

Key exclusion criteria 1. Patients over reproductive age
2. Patients with high risk for laparoscopy.
3. Patients without permission of pregnancy due to complications
4.Patients judged to be inappropriate for the study by the physicians.
Target sample size 200

Research contact person
Name of lead principal investigator
1st name Bunpei
Middle name
Last name Ishizuka
Organization Rose Ladies Clinic
Division name Division of clinical treatment
Zip code 158-0082
Address 2-3-18 Todoroki, Setagaya-ku,Tokyo
TEL 03-3703-0116
Email ishizuka@marianna-u.ac.jp

Public contact
Name of contact person
1st name Eri
Middle name
Last name Ozasa
Organization Rose Ladies Clinic
Division name Department of information and research
Zip code 158-0082
Address 2-3-18 Todoroki, Setagaya-ku,Tokyo
TEL 03-3703-0116
Homepage URL http://roseladiesclinic.jp/
Email eriozasa@gmail.com

Sponsor
Institute Rose Ladies Clinic
Institute
Department

Funding Source
Organization None
Organization
Division
Category of Funding Organization Self funding
Nationality of Funding Organization

Other related organizations
Co-sponsor St. Marianna University / Stanford University
Name of secondary funder(s)

IRB Contact (For public release)
Organization Biomedical Ethics Committee of the Rose Ladies Clinic
Address 2-3-18 Todoroki, Setagaya-ku, Tokyo
Tel 03-3703-0116
Email ishii_junri@hotmail.co.jp

Secondary IDs
Secondary IDs NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions ローズレディースクリニック 
Rose Ladies Clinic

Other administrative information
Date of disclosure of the study information
2017 Year 11 Month 16 Day

Related information
URL releasing protocol
Publication of results Unpublished

Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Unpublished
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status Open public recruiting
Date of protocol fixation
2017 Year 06 Month 01 Day
Date of IRB
2017 Year 06 Month 29 Day
Anticipated trial start date
2017 Year 08 Month 01 Day
Last follow-up date
2027 Year 08 Month 01 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other
Other related information Unpublished

Management information
Registered date
2017 Year 11 Month 02 Day
Last modified on
2019 Year 07 Month 16 Day


Link to view the page
URL(English) https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033876

Research Plan
Registered date File name

Research case data specifications
Registered date File name

Research case data
Registered date File name


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