UMIN-CTR Clinical Trial

Basic information
Official scientific title of the study	Induction of follicle development in poor responder patients based on suppression of Hippo signaling
Title of the study (Brief title)	Induction of follicle development in poor responder.
Region	Japan

Condition
Condition	Poor responder infertility patients
Classification by specialty	Obsterics and gynecology
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	The success of IVF treatment in poor responder patients is low due to decreases in the number of retrieved oocytes. Recent study demonstrated that suppression of Hippo signaling in somatic cells of ovarian follicles induced secondary follicle growth, resulting in increases in the number of antral follicles. To improve the outcome of IVF treatment in poor responder patients, we establish the method to increases the number of retrieved oocytes by induction of secondary follicle growth through ovarian tissue removal and fragmentation with in vitro culture followed by auto-transplantation.
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.

Base
Study type	Interventional

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

Intervention
No. of arms	1
Purpose of intervention	Treatment
Type of intervention	Maneuver
Interventions/Control_1	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 1x1cm with 1-2mm thickness of tissue stripes. Among the cortical tissue stripes, 2-3 stripes are further cut into 1-2mm cubes. Surplus cortical tissue stripes are cryopreserved using vitrification or slow freezing method. 3) Nine to ten of ovarian cubes are put onto cell culture insert and cultured for several hours to suppress Hippo signaling. Collect some ovarian cubes before and after culture to ensure suppression of Hippo signaling. 4) After culture, ovarian cubes are washed extensively by saline. These cubes are auto-transplanted beneath of the serosa of both Fallopian tubes, remaining ovaries and/or Douglus' pouch. In some patients who have relatively better ovarian reserve, we directly cut ovarian cortex inside of the body or scratch ovarian cortex to induce physical stimulation to the ovary. From the contra lateral side of ovary, we also remove a part of ovarian cortical tissues and cut into 1-2 mm cubes. Immediately after fragmentation of ovarian corticies, these ovarian cubes are grafted without cultures. 5) 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
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	45 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)Patients who can not obtain written informed consent. 4)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
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
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	Saint Mother Hospital
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	セントマザー産婦人科医院（福岡県）

Other administrative information
Date of disclosure of the study information	2015 Year 10 Month 02 Day

Progress
Recruitment status	Open public recruiting
Date of protocol fixation	2015 Year 08 Month 11 Day
Anticipated trial start date	2015 Year 10 Month 01 Day
Last follow-up date	2021 Year 12 Month 01 Day
Date of closure to data entry	2021 Year 12 Month 01 Day
Date trial data considered complete	2021 Year 12 Month 01 Day
Date analysis concluded	2021 Year 12 Month 01 Day

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

Management information
Registered date	2015 Year 10 Month 02 Day
Last modified on	2017 Year 04 Month 12 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021814