UMIN-CTR Clinical Trial

Basic information
Official scientific title of the study	Induction of secondary follicle growth by physical stimulation to ovary
Title of the study (Brief title)	Induction of secondary follicle growth by physical stimulation to ovary
Region	Japan

Condition
Condition	Infertility patients with poor response to gonadotropins
Classification by specialty	Obsterics and gynecology
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	In poor responders for ovarian stimulation, the numbers of oocytes retrieved from ovaries are low due to decreases in the number of developing antral follicles, resulting in poor clinical outcome of in vitro fertilization and embryo transfer. Recently, disruption of Hippo signaling pathway in ovarian somatic cells by fragmentation of ovarian cortex is shown to increase the number of antral follicles by induction of secondary follicle growth. In this study, we sought to establish the method for increase in the number of retrieved oocytes by induction of secondary follicle growth followed by physical stimulation to the ovarian tissues. As the methods for physical stimulation, we perform laparoscopic surgery for (1) partial removal of cortex from ovary and subsequent auto-transplantation immediately after fragmentation, and/or (2) in situ incision of ovarian cortex, and the compare the effectiveness of these methods to induce secondary follicle growth.
Basic objectives2	Safety,Efficacy
Basic objectives -Others
Trial characteristics_1	Confirmatory
Trial characteristics_2	Pragmatic
Developmental phase	Phase III

Assessment
Primary outcomes	Comparison of the number of oocytes retrieved after ovarian stimulation with those of base line numbers.
Key secondary outcomes	Comparison of proportions of fertilization, pregnancy and abortion with those of base line levels. Comparison of the levels of molecular markers reflecting the results of Hippo signal suppression in ovarian tissues and serum before and after culture and grafting operation, respectively. Also, we count the number of secondary follicles in grafting tissues by histological analysis. To evaluate the effect of in situ incision of ovarian cortex for secondary follicle growth, we measure the levels of serum AMH and inhibin B derived from granulosa cells of secondary follicles. Based on these data, we attempt to identify a suitable time point for initiation of ovarian stimulation.

Base
Study type	Interventional

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

Intervention
No. of arms	3
Purpose of intervention	Treatment
Type of intervention	Maneuver
Interventions/Control_1	In situ incision of ovarian cortex 1) Correct serum from the patients before surgery to measure molecular markers to ensure suppression of Hippo signaling. 2) 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. 3) 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_2	Auto-transplantation of ovarian cortical fragments + in situ incision of ovarian cortex 1) Correct serum from the patients before surgery to measure molecular markers to ensure suppression of Hippo signaling. 2) 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 1-2 mm 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. 3) 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 side of ovary inside of the body to induce physical stimulation to the ovary. 4) 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_3	To determine the effectiveness of these two different methods for physical stimulation to induce secondary follicle growth, we perform (1) bilateral In situ incision of ovarian cortex, (2) auto-transplantation of ovarian cortical fragments in one side of ovary + in situ incision of ovarian cortex on the contra lateral side of ovary, and (3) auto-transplantation of ovarian cortical fragments in both side of ovaries. In patients with poor response to gonadotropins, a considerable number of patients show follicle growth from one side of ovary only. Therefore, we enroll the patients who experienced follicle growth at both side of ovaries to the method (2). Because the physical stimulation to one ovary could affect the contra lateral side of ovary via endocrine manner, we perform method (1) and (3) as controls.
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	51 years-old >
Gender	Female
Key inclusion criteria	All following four features must be present: 1) Advanced maternal age (=>40 years) or any other risk factor for POR 2) A previous POR (<=3 oocytes with a conventional stimulation protocol) 3) An abnormal ovarian reserve test (i.e. AFC, 5-7 follicles or AMH, 0.5-1.1 ng/ml). 4) Married women
Key exclusion criteria	1)Patients with severe ovarian dysfunction who can not retrieve oocytes after ovarian stimulation. 2)Patients with high risk for laparoscopy. 3)anovulatory amenorrhea patient 4)Male infertility patients with Y chromosome microdeletion and chromosome abnormalities. 5)Patients who can not obtain written informed consent. 6)Patients judged to be inappropriate for the study by the physicians.
Target sample size	200

Research contact person
Name of lead principal investigator	Atsushi Tanaka
Organization	Saint Mother Hospital
Division name	Medical office
Address	4-9-12 Orio Yahatanishiku Kitakyusyu, Fukuoka, Japan
TEL	093-601-2000
Email	incho@stmother.com

Public contact
Name of contact person	Atsushi Tanaka
Organization	Saint Mother Hospital
Division name	Medical office
Address	4-9-12 Orio Yahatanishiku Kitakyusyu, Fukuoka, Japan
TEL	093-601-2000
Homepage URL
Email	incho@stmother.com

Sponsor
Institute	Saint Mother Hospital
Institute
Department

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

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

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

Other administrative information
Date of disclosure of the study information	2017 Year 07 Month 01 Day

Progress
Recruitment status	Open public recruiting
Date of protocol fixation	2017 Year 04 Month 27 Day
Anticipated trial start date	2017 Year 07 Month 01 Day
Last follow-up date
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Related information
URL releasing protocol
Publication of results	Unpublished
URL releasing results
Results
Other related information

Management information
Registered date	2017 Year 07 Month 01 Day
Last modified on	2017 Year 07 Month 01 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000032031