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The Effectiveness and Safety of the Prolonged Down-regulation Protocol for Controlled Ovarian Hyperstimulation

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ClinicalTrials.gov Identifier: NCT03809221
Recruitment Status : Not yet recruiting
First Posted : January 18, 2019
Last Update Posted : January 18, 2019
Sponsor:
Collaborators:
West China Hospital
Peking University First Hospital
The First Affiliated Hospital of Zhengzhou University
Henan Provincial Hospital
The Second Hospital of Hebei Medical University
First Affiliated Hospital of Wenzhou Medical University
Jiangxi Maternal and Child Health Hospital
Second Affiliated Hospital of Wenzhou Medical University
Second Affiliated Hospital of Zhengzhou University
Shanxi Provincial Maternity and Children's Hospital
First Affiliated Hospital of Guangxi Medical University
Guangxi Maternal and Child Health Hospital
Yinchuan Municipal Maternal and Child Health Hospital
Xinjiang Jiayin Hospital
Information provided by (Responsible Party):
Jiang Li, Peking University People's Hospital

Brief Summary:

Since the first "tube baby", Louise Brown, was born in the United Kingdom in 1978, many infertile couples have been benefitted from in vitro fertilization and embryo transfer (IVF-ET) and intracytoplasmic sperm injection (ICSI). Although a late starter, China is developing rapidly in ART and playing a more and more important role in the area of reproductive medicine.

In spite of the continuous development in ART, so far, the overall success rate of IVF/ICSI is still hovering around 25-40%. There are many factors influencing the success rate of IVF/ICSI. Among them, an appropriate controlled ovarian hyperstimulation (COH) protocol is directly associated with the number of oocyte retrieved, as well as the number and quality of embryos, which exert an important influence on the success rate of IVF/ICSI. The luteal phase pituitary down-regulation protocol is one of the most widely used COH protocols in clinical practice, particularly in China. Though effective, it may lead to an increased incidence of ovarian hyperstimulation syndrome (OHSS), as well as a negative impact on endometrial receptivity. The coping strategy is to freeze all the embryos and transfer in the next cycle. Though avoiding the above mentioned adverse effects, such strategy increases the time to pregnancy (TTP) and therefore results in certain psychological and economic burdens for infertile couples.

In recent years, some Chinese researches applied the early follicular full-dose down-regulation protocol that is always performed to women with endometriosis to a more general IVF/ICSI population and found a clinical pregnancy rate of 64% in the fresh embryo transfer cycle, much higher than that of the luteal phase down-regulation protocol. Furthermore, since this protocol decrease the risk of progesterone elevation on hCG day, it increases the fresh embryo transfer rate and shortens TTP.

Given most studies regarding the effectiveness and safety of the early follicular phase full-dose down-regulation protocol are retrospective studies, the results may be biased by several confounding factors. Therefore, we would like to conduct a multicenter, randomized controlled trial to compare the pregnancy outcome and safety indicators between the early follicular phase full-dose down-regulation protocol and the luteal phase down-regulation protocol.


Condition or disease Intervention/treatment Phase
Infertility, Female Drug: Triptorelin acetate Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1892 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: After the evaluation, patients met the eligible criteria will be informed, sign the consent form and be included in this study. We will randomly assign women (1:1) to early follicular phase prolonged down-regulation group (intervention group) or luteal phase long down-regulation group (control group), using a central randomization system with block sizes of 4 to 6 (changing constantly) and setting hospital as a stratification factor.
Masking: Single (Outcomes Assessor)
Masking Description: The researchers (physicians, nurses and embryologists) and patients are not blinded due to the nature of both interventions while the data analysts are blinded.
Primary Purpose: Treatment
Official Title: The Effectiveness and Safety of the Early Follicular Phase Prolonged Down-regulation Protocol for Controlled Ovarian Hyperstimulation: a Randomized, Paralleled, Controlled, Multicenter Trial
Estimated Study Start Date : February 1, 2019
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: early follicular phase down-regulation
Patients have a injection of 3.75mg long-acting Triptorelin acetate (Dipherelin®, IPSEN, France) on the 1st-4th day of menstrual cycle. If complete pituitary down-regulation is achieved after 28-42 days, exogenous gonadotropins will be given according to the participants' BMI. The physician will monitor the follicular growth and adjust the dose of exogenous gonadotropins accordingly. When the desired follicle size is reached, human chorionic gonadotropin will be administered. Oocyte retrieval will be performed 36-38 hours after pre-ovulatory hCG injection transvaginally under ultrasound monitoring. Oocyte retrieved will be cultured in vitro for 3-6h before being fertilized via IVF or ICSI. Two top-quality Day 3 cleavage embryos will be transferred 72h after retrieval.
Drug: Triptorelin acetate
Achieve pituitary down regulation with triptorelin acetate and start controlled ovarian stimulation after complete pituitary down regulation
Other Names:
  • recombinant follicular stimulating hormone (rFSH)
  • recombinant luteinizing hormone (rLH)
  • urinanry human postmenopausal gonadotropin (HMG)

Active Comparator: luteal phase down-regulation
Patients have a injection 0.1mg short-acting Triptorelin acetate (Decapeptyl®, Ferring, Germany) every day, 10-12 days before the next menstrual cycle. If complete pituitary down-regulation is achieved after 14-21 days, exogenous gonadotropins will be given according to the participants' BMI. The physician will monitor the follicular growth and the serum hormone level and adjust the dose of exogenous gonadotropins accordingly. When the desired follicle size is reached, human chorionic gonadotropin will be administered. Oocyte retrieval will be performed 36-38 hours later under ultrasound monitoring. Oocyte retrieved will be cultured in vitro for 3-6h before being fertilized via IVF or ICSI. Two top-quality Day 3 cleavage embryos will be transferred 72h after retrieval.
Drug: Triptorelin acetate
Achieve pituitary down regulation with triptorelin acetate and start controlled ovarian stimulation after complete pituitary down regulation
Other Names:
  • recombinant follicular stimulating hormone (rFSH)
  • recombinant luteinizing hormone (rLH)
  • urinanry human postmenopausal gonadotropin (HMG)




Primary Outcome Measures :
  1. live birth rate per transferred cycle [ Time Frame: 28 weeks of gestation ]
    the number of live births (after 28 gestational week) divided by the number of transferred fresh cycles ×100%;


Secondary Outcome Measures :
  1. live birth rate per stimulated cycle [ Time Frame: 28 gestational week ]
    the number of live births (after 28 gestational week) divided by the number of all patients who started COH×100%

  2. biochemical pregnancy rate per stimulated cycle [ Time Frame: 12-15 days after embryo transfer ]
    the number of patients with a serum beta hCG of at least 10mIU/ml divided by the number of all patients who started COH ×100%

  3. clinical pregnancy rate per stimulated cycle [ Time Frame: 28-30 days after embryo transfer ]
    the number of patients with a intrauterine gestational sac divided by the number of all patients who started COH×100%

  4. ongoing pregnancy rate per stimulated cycle [ Time Frame: 10-12 weeks of gestation ]
    the number of patients with a viable intrauterine pregnancy divided by the number of all patients who started COH×100%

  5. biochemical pregnancy rate per transferred cycle [ Time Frame: 12-15 days after embryo transfer ]
    the number of patients with a serum beta hCG of at least 10mIU/ml divided by the number of transferred fresh cycles ×100%

  6. clinical pregnancy rate per transferred cycle [ Time Frame: 28-30 days after embryo transfer ]
    the number of patients with a intrauterine gestational sac divided by the number of transferred cycles×100%

  7. ongoing pregnancy rate per transferred cycle [ Time Frame: 10-12 weeks of gestation ]
    the number of patients with a viable intrauterine pregnancy divided by the number of transferred fresh cycles×100%

  8. pregnancy loss rate [ Time Frame: till 28 weeks of gestation ]
    the number of miscarriage and intrauterine fetal death cases divided by the number of participants with clinical pregnancy


Other Outcome Measures:
  1. the incidence of moderate to severe OHSS [ Time Frame: since oocyte retrieval to 13 weeks gestation ]
    the number of severe OHSS cases divided by the number of participants receiving oocyte retrieval

  2. pregnancy complications [ Time Frame: since embryo transfer to delivery (during pregnancy) ]
    all the complications occurred during pregnancy, e.g. preeclampsia, gestational diabetes, etc.

  3. adverse fetal outcomes [ Time Frame: 1 month after delivery ]
    all the recorded adverse fetal outcomes, e.g. fetal malformation etc

  4. neonatal birth weight [ Time Frame: at delivery ]
    birth weigh of the neonate at delivery



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Women aged between 20 to 35 years old and with a history of infertility (fail to get pregnant after over one year's regular, unprotected sex), who receive IVF/ICSI for one of the following reasons:

    ① Tubal factor: e.g. peritubal adhesions, tubal obstruction, etc.. Patients with hydrosalpinx can be enrolled after salpingectomy or tubal ligation;

    ② Male factor: e.g. oligospermia, asthenozoospermia, teratozoospermia, etc.;

    ③ Unexplained infertility: patients with a history of infertility more than 1 year but with no specific cause for infertility (ovulation, tubal, endometrial and male factor), or still not get pregnant after the above-mentioned causes being removed.

  2. Women with a normal ovarian reserve according to: ①basal steroid hormone on day 2-4 of menstrual cycle: basal FSH≤10mIU/ml, estradiol (E2) <50pg/ml;②1.5<anti-Müllerian hormone (AMH)<4.0;③8≤antral follicle count (AFC) ≤15;
  3. First IVF/ICSI cycle;
  4. BMI≥18 and ≤25kg/m2;
  5. Informed consent

Exclusion Criteria:

  1. Women with a negative reproductive history, including a history of:

    ① recurrent miscarriage: women with twice and more than twice spontaneous miscarriage, missed abortion, biochemical pregnancies, etc.;

    ② fetal malformation or chromosomal abnormalities;

    ③ intrauterine death.

  2. Women with a history of one side adnexectomy;
  3. Women with a poor ovarian response or diminished ovarian reserve (based on Bologna' criteria);
  4. Women with ovulation dysfunction;
  5. Women with PCOS (based on Rotterdam's criteria);
  6. Women with endometriosis;
  7. Women with the following uterine abnormalities: uterine malformation (unicornuate uterus, uterus bicornis, uterus duplex, mediastinum uterus), adenomyosis, submucosa myoma, intrauterine adhesion;
  8. Chromosomal abnormality for either or both of the couple;
  9. Women with contraindications for ART or pregnancy: uncontrolled diabetes mellitus, cardiac disease, undiagnosed liver and/or renal function, vaginal bleeding, suspected or a past history of cervical cancer, endometrial cancer, breast cancer, and a history of deep venous thrombosis, pulmonary embolism, stroke, etc.;
  10. Women who are enrolled in other clinical trials.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03809221


Contacts
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Contact: Li Jiang, MD, MPH 86-0-13661212539 narnia_vota@hotmail.com
Contact: Fumei Gao, MD 86-10-88324436

Sponsors and Collaborators
Peking University People's Hospital
West China Hospital
Peking University First Hospital
The First Affiliated Hospital of Zhengzhou University
Henan Provincial Hospital
The Second Hospital of Hebei Medical University
First Affiliated Hospital of Wenzhou Medical University
Jiangxi Maternal and Child Health Hospital
Second Affiliated Hospital of Wenzhou Medical University
Second Affiliated Hospital of Zhengzhou University
Shanxi Provincial Maternity and Children's Hospital
First Affiliated Hospital of Guangxi Medical University
Guangxi Maternal and Child Health Hospital
Yinchuan Municipal Maternal and Child Health Hospital
Xinjiang Jiayin Hospital
Investigators
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Principal Investigator: Huan Shen, MD,phD Peking University
Principal Investigator: Li Jiang, MD,MPH Peking University
  Study Documents (Full-Text)

Documents provided by Jiang Li, Peking University People's Hospital:

Publications:
The United Kingdom national data. Human Fertility and Embryology Authority. 2015
The United States national assisted reproductive technology(ART) data. Centers for Disease Control and Prevention.2015
Chinese Reproductive Medicine Society national assisted reproductive technology (ART) data. 2015
L Hu, Y Sun. The impact of various controlled ovarian hyperstimulation (COS) protocols on the outcome of in vitro fertilization and embryo transfer (IVF-ET). Journal of Practical Obstetrics and Gynecology. 2014;30(10);723-725.
Y Hu, T Ding, Y Zhao, Q Wu. The comparison of the birth outcome of in vitro fertilization and embryo transfer (IVF-ET) after two different down-regulation protocols. Maternal and Child Health Care of China.2017;32(4):808-810.
D Xu, Q Wu. The comparison of the application of ultra-long down-regulation protocol and antagonist protocol in in vitro fertilization and embryo transfer (IVF-ET). Jiangxi Medical Journal. 2015;50(1):13-15.
Q Su, Q Wu, L Tian, Y Li. The clinical analysis of different controlled ovarian hyperstimulation (COS) protocols in in vitro fertilization and embryo transfer (IVF-ET). Jiangxi Medical Journal. 2014;49(8):723-725.
Y Li, Q Wu, Y Yi. The impact of the follicular phase ultra-long long down-regulation protocol on PCOS patients' outcome after in vitro fertilization and embryo transfer (IVF-ET). Jiangxi Medical Journal. 2014;49(2):117-120.
L Nie, Q Wu, Y Zhang, J Chen. The analysis of the application of the follicular phase ultra-long down-regulation protocol in patients with fine ovarian reserve but a failed previous in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI) and embryo transfer. Progress in Obstetrics and Gynecology. 2011;20(6):470-472.
F Gong, K Luo, G Lu. The effectiveness of the modified ultra-long down-regulation protocol in PCOS patients receiving in vitro fertilization and embryo transfer (IVF-ET). Basic and Clinical Medicine. 2010,30(9):984-987.

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Responsible Party: Jiang Li, attending doctor, Peking University People's Hospital
ClinicalTrials.gov Identifier: NCT03809221     History of Changes
Other Study ID Numbers: prolonged down regulation
First Posted: January 18, 2019    Key Record Dates
Last Update Posted: January 18, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jiang Li, Peking University People's Hospital:
down-regulation
controlled ovarian hyperstimulation
IVF/ICSI

Additional relevant MeSH terms:
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Infertility
Ovarian Hyperstimulation Syndrome
Infertility, Female
Genital Diseases, Male
Genital Diseases, Female
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases
Hormones
Follicle Stimulating Hormone
Triptorelin Pamoate
Chorionic Gonadotropin
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Luteolytic Agents
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents