Dual Ovarian Stimulation (Duostim) and Shanghai Protocols in Poor Ovarian Responders

NCT ID: NCT06199960

Last Updated: 2024-01-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 116 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-02
• Study Completion Date: 2023-11-20

Brief Summary

A combination of follicular phase stimulation and luteal phase stimulation in the same cycle, can be a valuable choice in poor responder patients with reduced ovarian reserve, in order to achieve extreme the number of oocytes in a single menstrual cycle. In the present study, the results of two different Double stimulation cycles including shanghai protocol and Duostim protocol in patients with reduced ovarian reserve, compared with each other to help select a more appropriate treatment for this group of patients. The number of retrieved oocytes and the number of obtained embryos and clinical pregnancy from each protocol will be compared as the primary and secondary outcome.

Detailed Description

The proposal of this randomized clinical trial study is a comparison of two different type of double stimulation protocols in patients who meet the POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) stratification (group 4) criteria.

In mild double stimualtion (Shanghai protocol), patients will be received Clomiphene citrate 25 mg/day (Ovumid®; Iran Hormone pharmaceutical Co., Iran) co-treatment and letrozole 2.5 mg/day (Femati®, Atipharmed Co., Iran) will be given from cycle day 3. Letrozole is given for 4 days and clomiphene citrate is used daily before the trigger day. Patients take 150 IU of Human menopausal gonadotropin (HMG) (Humegnan®, Darou Pakhsh Co., Iran) every other day beginning on cycle day 6. When one dominant follicle will reach 18 mm, the final triggering will induce 34-36 h after 0.5 cc of Buserelin acetate (CinnaFact®; CinnaGen pharmaceutical Co., Iran) administration. In luteal phase stimulation a total of 225 IU HMG and letrozole 2.5 mg will administered daily from3 to 5 days after oocyte retrieval. Letrozole administration will be stopped when the dominant follicles reached 12 mm. When one dominant follicle will reach 18 mm, the final triggering will be induced with 0.5 cc of Buserelin acetate (CinnaFact®; CinnaGen pharmaceutical Co., Iran).

In the double GnRH- antagonist (Duostim protocol), both follicular and luteal phases stimulation will perform with 150-225 IU of recombinant FSH (Gonal-F®, Merck-sereno, Germany) and HMG (Humegnan, Darou Pakhsh Co., Iran) in GnRH antagonist treatment. The follicular stimulation will be started on day 2-3 of the menstrual. Daily administration of 0.25 mg of GnRH antagonist (Cetrotide®, Merck-Serono; Germany) will be started when the leading follicle are 13-14mm and continue until the day of the oocyte trigger. When one follicle reached 17-18 mm ovulation will be triggered with 0.5 cc of Buserelin acetate (CinnaFact®; CinnaGen pharmaceutical Co., Iran) and oocyte retrieval will be performed after 34-36 hours. Five days after the first oocyte retrieval, a GnRH antagonist protocol identical to the first one will start. When at least two follicles reached 17-18 mm, the ovulation will be triggered with a subcutaneous bolus GnRH-agonist and the second oocyte retrieval will be performed.

In all of groups all of embryos will be freeze and will be used in subsequent frozen embryo transfer (FET) cycles. Endometrial preparation for FET cycle will perform with hormonal replacement therapy (HRT) cycle protocol.

Conditions

Assisted Reproductive Techniques

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Double GnRH-antagonist protocol (Duostim protocol)

In Duostim group, both follicular and luteal phases stimulation will perform with 150-225 IU of recombinant FSH (Gonal-F®, Merck-sereno, Germany) and HMG (Humegnan, Darou Pakhsh Co., Iran) in GnRH antagonist treatment. The follicular stimulation will be started on day 2-3 of the menstrual. Daily administration of 0.25 mg of GnRH antagonist (Cetrotide®, Merck-Serono; Germany) will be started when the leading follicle are 13-14mm and continue until the day of the oocyte trigger. When one follicle reached 17-18 mm ovulation will be triggered with 0.5 cc of Buserelin acetate (CinnaFact®; CinnaGen pharmaceutical Co., Iran) and oocyte retrieval will be performed after 34-36 hours. Five days after the first oocyte retrieval, a GnRH antagonist protocol identical to the first one will start. When at least two follicles reached 17-18 mm, the ovulation will be triggered with a subcutaneous bolus GnRH-agonist and the second oocyte retrieval will be performed.

Group Type: EXPERIMENTAL

Doustim protocol

Intervention Type: OTHER

In Duostim group, the follicular stimulation will be started with a fixed dose of 150 IU of rFSH and HMG 75 IU for 4 days. Daily administration of a GnRH antagonist will be started when the leading follicle are 13-14mm in diameter and continue until the day of the trigger of the ovulation. Five days after the first oocyte retrieval second gonadotropin stimulation will be started identical to the first one..

Double mild stimulation protocol

In double mild stimulation protocol, Clomiphene citrate 25 mg/day (Ovumid®; Iran Hormone pharmaceutical Co., Iran) and co-treatment with letrozole 2.5 mg/day (Femati®, Atipharmed Co., Iran) will be given from cycle day 3. Letrozole is given for 4 days and clomiphene citrate is used daily before the trigger day. Patients take 150 IU of Human menopausal gonadotropin (HMG) (Humegnan®, Darou Pakhsh Co., Iran) every other day beginning on cycle day 6. When one dominant follicle will reach 18 mm, the final triggering will induce 34-36 h after 0.5 cc of Buserelin acetate (CinnaFact®; CinnaGen pharmaceutical Co., Iran) administration. In luteal phase stimulation a total of 225 IU HMG and letrozole 2.5 mg will administered daily from3 to 5 days after oocyte retrieval. Letrozole administration will be stopped when the dominant follicles reached 12 mm. When one dominant follicle will reach 18 mm, the final triggering will be induced with 0.5 cc of Buserelin acetate.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Doustim protocol

In Duostim group, the follicular stimulation will be started with a fixed dose of 150 IU of rFSH and HMG 75 IU for 4 days. Daily administration of a GnRH antagonist will be started when the leading follicle are 13-14mm in diameter and continue until the day of the trigger of the ovulation. Five days after the first oocyte retrieval second gonadotropin stimulation will be started identical to the first one..

Intervention Type: OTHER

Other Intervention Names

Double GnRH-antagonist stimulation

Eligibility Criteria

Inclusion Criteria

1. Age ≥35 years

2. Antimullerian hormone (AMH) <1.2 ng/ml and/or Antral follicular count≤5 follicles

3. ≤4 oocyte retrieved from previous ART cycle 4-18.5<BMI<30

Exclusion Criteria

1. Endometriosis (stage III and IV)

2. Myoma with a compression effect

3. Uterine anomalies (Unicorn, Didelphis,etc,….)

4. Male factor infertility with azoospermia, severe oligospermia and oligoasthenospermia, TESE/PESA

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Royan Institute

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mehri Mashayekhi, M.D

Role: PRINCIPAL_INVESTIGATOR

Department of Endocrinology and Female Infertility

Locations

Royan Institute

Tehran, , Iran

Countries

Iran

Other Identifiers

97000185

Identifier Type: -

Identifier Source: org_study_id