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

Comparison of Two Types of Dual Ovarian Stimulation: Duostim Versus Shanghai Protocols in Patients With Poor Ovarian Reserve: A Randomized Controlled Trial

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.

Study Overview

• Status: Completed
• Conditions: Assisted Reproductive Techniques
• Intervention / Treatment: Other: Doustim protocol

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.

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 3

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of
    • Royan Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Other: 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..; Other Names: Double GnRH-antagonist stimulation
No Intervention: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of MII oocytes	Oocytes that were mature at the time of oocyte collection (Metaphase II)	Immediately after oocyte puncture

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical pregnancy rate	The observation of gestational sac on ultrasound examination two-three weeks after positive serum βhCG	4-6 weeks after embryo transfer
Number of cleaved embryos	2-3 days embryo from fertilization	2-3 days after oocyte puncture
Number of blastocyst embryos	The stage the embryo reaches after 5 days in culture from the oocyte retrieval	5 days after oocyte puncture and sperm insemination
Fertilization rate	Percentage of transformation of micro injected oocytes into two pronuclei	2-5 days after sperm insemination
Quality of oocytes	Oocyte quality were assessed by embryologist based on The Istanbul consensus workshop (Hum Reprod.2011). Quality of MII oocytes (based on intracytoplasmic and extracytoplasmic abnormalities) was divided into 3 groups; morph, slightly dysmorph, and dysmorph.	Immediately after oocyte puncture

Collaborators and Investigators

• Sponsor: Royan Institute
• Investigators: Principal Investigator: Mehri Mashayekhi, M.D, Department of Endocrinology and Female Infertility

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2019
• Primary Completion (Actual): May 10, 2022
• Study Completion (Actual): November 20, 2023

Study Registration Dates

• First Submitted: February 9, 2021
• First Submitted That Met QC Criteria: January 8, 2024
• First Posted (Actual): January 10, 2024

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Other Study ID Numbers: 97000185

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No