Double Ovarian Stimulation as Accumulation Strategy for Older Infertile Patients With Suboptimal Ovarian Response

Sponsor

Nova Clinic, Russia (Other)

Overall Status

Unknown status

CT.gov ID

NCT03400722

Collaborator

(none)

120

Enrollment

Location

Arms

Anticipated Duration (Months)

7.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Patients with infertility of the older age group of 37-42 years - a large cohort of patients of reproductive medicine. Two possible causes reduce their probability of pregnancy - an increasing age and a decrease of the ovarian reserve. In these conditions, the early receipt of embryos for future transfer can serve as a correct strategy for treating infertility in this category of patients. According to statistical data, patients of the 37-42-year-old age group need 3-5 blastocysts, out of them 1-2 euploid to achieve pregnancy.

The POSEIDON group of researchers identified a group of 2b patients with a suboptimal response to the induction of superovulation in IVF programs - patients older than 35 years with a normal ovarian reserve (the number of antral follicles greater than 5 and Anti-Müllerian hormone (AMH) greater than 1.2 ng / ml), resulting in 4-9 oocytes after a standard ovarian stimulation.

In this situation standard stimulation protocols can stretch the process of obtaining embryos indefinitely, during which the patient will move to another age category with a decrease in the likelihood of pregnancy.

Thus, these patients are shown the fastest reception of oocytes and the accumulation of embryos, which can be done using double ovarian stimulation in the same menstrual cycle.

The aim of the study is to compare the different schemes of double stimulation in patients with infertility of the older age group of 37-42 years with the preceding suboptimal response.

Group 1 - patients of the DUOSTIM group. Group 2 - Patients of the Shanghai Protocol.

The investigated parameters - primary outcome measures: total number of retrieved oocytes per cycle, secondary outcome measures: total number of blastocyst per cycle, number of cycles with double ovarian stimulation required to obtain 3-5 blastocyst, time until embryo transfer, pregnancy rate and birth rate This is a prospective randomized non-blinded clinical study.

Condition or Disease	Intervention/Treatment	Phase
Infertility, Female Ovarian Stimulation In Vitro Fertilisation	Drug: Pergoveris Drug: Clomiphene	Phase 4

Detailed Description

The aim of the study is to compare the different schemes of double stimulation in patients with infertility of the older age group of 37-42 years with the preceding suboptimal response.

Materials and methods. Patients with preserved ovarian reserve of 37-42 years old, who had the history of standard stimulation in IVF programs, which produce less 4-7 oocytes. Patients will be randomised in two groups. Group 1 - patients of the double ovarian stimulation in the same cycle with recombinant gonadotropin (DUOSTIM group). Group 2 - patients of the double ovarian stimulation in the same cycle with clomifen and recombinant gonadotropin (modified Shanghai Protocol).

The stimulation protocol in the Group 1 - Follitropin and Lutropin Alfa (Pergoveris) 150 -300 IU start from day 2 of the cycle up to the day of trigger, gonadotropin-releasing hormone (GnRH) antagonist 0,25 mg start from day 7-8 of the cycle up to the day of trigger, final trigger of ovarian stimulation - gonadotropin-releasing hormone agonist (GnRH-a) 0,2 mg, oocyte retrieval 35 hours after trigger, stop period for 5 days, after stop period start Pergoveris 150 - 300 IU start up to the day of trigger, GnRH antagonist 0,25 mg start from day 6 of ovarian stimulation up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger.

After oocyte retrieval fertilization will be carried out by invitro insemination (IVI) or intracytoplasmic sperm injection (ICSI), the development of embryos will be carried out up to blastocyst stage, then blastocyst vitrification will be performed. The cycles of double ovarian stimulation will be performed until the patient will have not less than 3-5 blastocysts. Then the embryo accumulation process will be completed and the unfrozen embryos transferred in the hormonal replacement cycle or natural ovulatory cycle.

The stimulation protocol in the Group 2 - Clomiphene 50 mg start from day 2-3 of the cycle up to the day of trigger, Pergoveris 150 IU - 6,8, 10 days of the cycle, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger, after stop period for 2-3 days start Pergoveris 150 - 300 IU up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger. After oocyte retrieval fertilization will be carried out by IVI or ICSI, the development of embryos will be carried out up to blastocyst stage, then blastocyst vitrification will be performed. The cycles of double ovarian stimulation will be performed until the patient will have not less than 3-5 blastocysts. Then the embryo accumulation process will be completed and the unfrozen embryos transferred in the hormonal replacement cycle or natural ovulatory cycle.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Double Ovarian Stimulation as Accumulation Strategy for Older Infertile Patients With Suboptimal Ovarian Response in Assisted Reproductive Treatment

Actual Study Start Date :

Dec 1, 2017

Anticipated Primary Completion Date :

Aug 1, 2018

Anticipated Study Completion Date :

May 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DUOSTIM group Pergoveris 150 -300 IU start from day 2 of the cycle up to the day of trigger, GnRH antagonist 0,25 mg start from day 7-8 of the cycle up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger, stop period for 5 days, after stop period start Pergoveris 150 - 300 IU start up to the day of trigger, GnRH antagonist 0,25 mg start from day 6 of ovarian stimulation up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger. After oocyte retrieval fertilization will be carried out by IVI or ICSI, the development of embryos will be carried out up to blastocyst stage, then blastocyst vitrification will be performed.	Drug: Pergoveris Two controlled ovarian stimulation within the same menstrual cycle. It will be followed by ovarian puncture, fertilisation of oocyte by IVI or ICSI, blastocyst vitrification. If there are 3-5 blastocysts, the embryo accumulation process will be completed and the unfrozen embryos transferred. Other Names: antagonist of gonadotropin releasing hormone agonist of gonadotropin releasing hormone
Experimental: Modified Shanghai Protocol group Clomiphene 50 mg start from day 2-3 of the cycle up to the day of trigger, Pergoveris 150 - 300 IU - 6,8, 10 days of the cycle, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger, after stop period for 2-3 days start Pergoveris 150 - 300 IU up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger. After oocyte retrieval fertilization will be carried out by IVI or ICSI, the development of embryos will be carried out up to blastocyst stage, then blastocyst vitrification will be performed.	Drug: Clomiphene Two controlled ovarian stimulation within the same menstrual cycle. It will be followed by ovarian puncture, fertilisation of oocyte by IVI or ICSI, blastocyst vitrification. If there are 3-5 blastocysts, the embryo accumulation process will be completed and the unfrozen embryos transferred. Other Names: Pergoveris agonist of gonadotropin releasing hormone

Arm

Intervention/Treatment

Experimental: DUOSTIM group

Pergoveris 150 -300 IU start from day 2 of the cycle up to the day of trigger, GnRH antagonist 0,25 mg start from day 7-8 of the cycle up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger, stop period for 5 days, after stop period start Pergoveris 150 - 300 IU start up to the day of trigger, GnRH antagonist 0,25 mg start from day 6 of ovarian stimulation up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger. After oocyte retrieval fertilization will be carried out by IVI or ICSI, the development of embryos will be carried out up to blastocyst stage, then blastocyst vitrification will be performed.

Drug: Pergoveris

Two controlled ovarian stimulation within the same menstrual cycle. It will be followed by ovarian puncture, fertilisation of oocyte by IVI or ICSI, blastocyst vitrification. If there are 3-5 blastocysts, the embryo accumulation process will be completed and the unfrozen embryos transferred.

Other Names:

antagonist of gonadotropin releasing hormone

agonist of gonadotropin releasing hormone

Experimental: Modified Shanghai Protocol group

Clomiphene 50 mg start from day 2-3 of the cycle up to the day of trigger, Pergoveris 150 - 300 IU - 6,8, 10 days of the cycle, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger, after stop period for 2-3 days start Pergoveris 150 - 300 IU up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger. After oocyte retrieval fertilization will be carried out by IVI or ICSI, the development of embryos will be carried out up to blastocyst stage, then blastocyst vitrification will be performed.

Drug: Clomiphene

Other Names:

Pergoveris

agonist of gonadotropin releasing hormone

Outcome Measures

Primary Outcome Measures

Total number of retrieved oocytes per cycle [up to 9 months]
evaluation the total number of retrieved oocytes after double ovarian stimulation in one cycle

Secondary Outcome Measures

total number of blastocyst per cycle [up to 9 months]
evaluation the total number of blastocyst after double ovarian stimulation in one cycle
Time until embryo transfer [up to 9 months]
period from start double ovarian stimulation until embryo transfer
number of cycles need to treat [up to 9 months]
number of cycles with double ovarian stimulation required to obtain 3-5 blastocyst
pregnancy rate [up to 9 months]
pregnancy rate after embryo transfer of thawed blastocyst
the birth rate [up to 18 months]
the birth rate after embryo transfer

Eligibility Criteria

Criteria

Ages Eligible for Study:

37 Years to 42 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

37 - 42 years of age
BMI 18-30 kg\m2
Suboptimal ovarian responders with normal ovarian reserve: the number of antral follicles greater than 5 and AMH greater than 1.2 ng / ml, resulting in 4-9 oocytes after a standard ovarian stimulation, according Poseidon classification - group 2b
Informed consent