UMIN-CTR Clinical Trial

Basic information
Public title	Future fertility preservation strategies for patients with ovarian endometrioma undergoing laparoscopic cystectomy: Cryopreservation, activation and autografting of ovarian tissues.
Acronym	Future fertility preservation strategies for patients with ovarian endometrioma undergoing laparoscopic cystectomy.
Scientific Title	Future fertility preservation strategies for patients with ovarian endometrioma undergoing laparoscopic cystectomy: Cryopreservation, activation and autografting of ovarian tissues.
Scientific Title:Acronym	Future fertility preservation strategies for patients with ovarian endometrioma undergoing laparoscopic cystectomy.
Region	Japan

Condition
Condition	Ovarian endometrioma
Classification by specialty	Obsterics and gynecology
Classification by malignancy	Others
Genomic information	YES

Objectives
Narrative objectives1	Endometriosis affect 10% of reproductive age women and 50% of infertile women. Ovarian cystectomy is preferred procedure for excision of endometriosis lesion and improvement of endometriosis-associated symptoms, however, a potential risk of post-surgical reduction in the ovarian reserve is concerned. Recently, a new infertility treatment by ovarian tissue cryopreservation, in vitro activation (IVA) and autografting procedure is reported to improve fertility outcomes in cases of extremely low ovarian reserve women. In this study, we aimed to apply the procedure of ovarian tissue cryopreservation, IVA and autografting for women with endometrioma undergoing laparoscopic cystectomy and evaluate the effectiveness for improving their future fertility outcome.
Basic objectives2	Efficacy
Basic objectives -Others
Trial characteristics_1	Confirmatory
Trial characteristics_2	Pragmatic
Developmental phase	Phase III

Assessment
Primary outcomes	Primary outcomes are to compare the postoperative pregnancy rate and birthrate between the cases with or without ovarian tissue cryopreservation when performing laparoscopic cystectomy for ovarian endometrioma.
Key secondary outcomes	1.Basic information: age, medical history, diameter of the ovarian cyst, unilateral/bilateral lesion, preoperative hormone therapy, serum hormone level (E2, P4, FSH, LH, AMH, inhibin B), tumor marker level (C125, CA19-9). 2.Initial surgical findings (Laparoscopic cystectomy, partial resection and cryopreservation of ovarian tissue): operative duration, blood loss, weight of excised cyst, pathological findings, tumor diameter, unilateral/bilateral lesion, revised American Society of Reproductive Medicine (rASRM) score, obtained site of ovarian tissue for cryopreservation (distance from ovarian hilum and endometriosis lesion). 3. Clinical course from initial surgery to second surgery (In vitro activation and laparoscopic autografting of ovarian tissue): age trying to conceive, prophylactic hormone therapy, endometrioma recurrence, serum hormone level (E2, P4, FSH, LH, AMH), protocol used and outcomes of infertility treatment. 4. Second surgical findings: operative duration, blood loss, endometrioma recurrence, rASRM score, number of autografting ovarian tissue pieces, autografting site of ovarian tissue. Using part of the ovarian tissue, we measure a variety of molecular markers to evaluate the efficacy of Hippo signaling suppression, and we perform ultrasound/ Far infrared ray scanning and histological examination (follicle count, fibrotic evaluation, and inflammatory change) to evaluate the effect of IVA and the presence of residual follicles. We measure the serum angiogenesis factors to evaluate the angiogenic response of autografting ovarian tissue. 5. Clinical course after laparoscopic autografting of ovarian tissue: We measure vesicular ovarian follicle count and serum hormone level (E2, P4, FSH, LH, AMH). We record infertility treatment outcomes including number of oocytes retrieved, percentage of mature oocytes, fertility rate, acquisition rate of good-morphology embryos, cycle cancellation rate, pregnancy rate, birthrate and miscarriage rate.

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	2
Purpose of intervention	Treatment
Type of intervention	Maneuver
Interventions/Control_1	Laparoscopic cystectomy, ovarian tissue cryopreservation, and autografting at the desire for pregnancy. 1. Part of unilateral or bilateral normal ovarian tissue are harvested when performing laparoscopic cystectomy for ovarian endometrioma. The tissue size for harvest is determined depending on their ovarian reserve, the degree of adhesion, and the size of ovarian cyst (one to six pieces of 1cm ovarian cortex are made). The obtained ovarian cortex tissues are cryopreserved. Using 10x1x1mm cube of ovarian cortex tissue, we perform hematoxylin eosin stain and immunohistochemistry to evaluate the presence of residual follicles. 2. Prophylactic hormone therapy by low dose estrogen progestin or dienogest is performed until the time desiring pregnancy. At the time desiring to conceive, infertility treatment including timing therapy, artificial insemination and assisted reproductive technology are performed. In failed cases by conventional treatments, autografting of ovarian tissue is performed. After thawing, ovarian tissue are fragmented into 1-2mm cubes and transplanted to the ovary or beneath serosa of fallopian tubes. In cases of extremely low ovarian reserves, fragmented ovarian tissues are cultured with IVA medium containing a PTEN inhibitor and PI3K activators for 48h to induce not only physical but also chemical stimulation. Using part of the ovarian tissue, we measure a variety of molecular markers to evaluate the efficacy of Hippo signaling suppression and perform ultrasound/ Far infrared ray scanning and histological examination (follicle count, fibrotic evaluation, and inflammatory change) to evaluate the effect of IVA and the presence of residual follicles. We measure the serum angiogenesis factors to evaluate the angiogenic response of autografting ovarian tissue. 3. After grafting, patients reinstitute infertility treatment by IVF-ET. The treatment continues for 1-2 years. If ovarian stimulation is not effective, patients can receive another autografting.
Interventions/Control_2	Laparoscopic cystectomy. 1. Laparoscopic cystectomy for ovarian endometrioma is performed. 2. Prophylactic hormone therapy by low dose estrogen progestin or dienogest is performed until the time desiring pregnancy. At the time desiring to conceive, infertility treatment including timing therapy, artificial insemination and assisted reproductive technology are performed.
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	20 years-old <=
Age-upper limit	50 years-old >=
Gender	Female
Key inclusion criteria	1. Reproductive age women who is 20 years old or older at the acquision of agreement. 2. Ovarian endometrioma larger than 4cm diameter. 3. Women having desire for future pregnancy. 4. Women who give their voluntary informed consent after receiving the enough explanation and understanding about the participation for this study.
Key exclusion criteria	1. Women under 20 years old or over reproductive age. 2. Women who does not have desire for future pregnancy. 3. Women with ovarian cancer. 4. Women who have some risk to undergo laparoscopic surgery by their fundamental disorders. 5. Women who are considered as inadequate for participating this study by lead principal investigator.
Target sample size	200

Research contact person
Name of lead principal investigator	1st name Mari Middle name Last name Kitade
Organization	Juntendo University Faculty of Medicine
Division name	Obstetrics and Gynecology
Zip code	113-8431
Address	3-1-3 Hongo, Bunkyo-ku, Tokyo
TEL	03-3813-3111
Email	kitade@juntendo.ac.jp

Public contact
Name of contact person	1st name Keisuke Middle name Last name Murakami
Organization	Juntendo University Faculty of Medicine
Division name	Obstetrics and Gynecology
Zip code	113-8431
Address	3-1-3 Hongo, Bunkyo-ku, Tokyo
TEL	03-3813-3111
Homepage URL
Email	kmuraka@juntendo.ac.jp

Sponsor
Institute	Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine
Institute
Department

Funding Source
Organization	Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine
Organization
Division
Category of Funding Organization	Self funding
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Hospital Ethics Committee Office, Juntendo University Faculty of Medicine
Address	3-1-3 Hongo, Bunkyo-ku, Tokyo
Tel	03-5802-1584
Email	kenkyu5858@juntendo.ac.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	順天堂大学医学部附属順天堂医院(東京都）

Other administrative information
Date of disclosure of the study information	2019 Year 10 Month 01 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
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	Preinitiation
Date of protocol fixation	2019 Year 09 Month 21 Day
Date of IRB
Anticipated trial start date	2019 Year 10 Month 01 Day
Last follow-up date	2034 Year 03 Month 31 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other
Other related information

Management information
Registered date	2019 Year 09 Month 21 Day
Last modified on	2019 Year 09 Month 21 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000042387