UMIN-CTR Clinical Trial

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

Ovarian endometrioma

Classification by specialty

Obstetrics and Gynecology

Classification by malignancy

Others

Genomic information

YES

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

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.

Study type

Interventional

Basic design

Parallel

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Active

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

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

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

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

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

Institute

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine

Institute

Department

Personal name

Organization

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

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

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

順天堂大学医学部附属順天堂医院(東京都）

Date of disclosure of the study information

2019

Year

10

Month

01

Day

URL releasing protocol

Publication of results

Unpublished

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

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 related information

Registered date

2019

Year

09

Month

21

Day

Last modified on

2019

Year

09

Month

21

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000042387