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

NCT03809221 | Unknown Phase 4 DMC

• 1 other identifier: prolonged down regulation
• Study Type: interventional
• Target: 1,892
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Infertility, Female

Keywords

down-regulation; controlled ovarian hyperstimulation; IVF/ICSI

Outcome Measures

Primary Outcomes (1)

• live birth rate per transferred cycle

  the number of live births (after 28 gestational week) divided by the number of transferred fresh cycles ×100%;

  28 weeks of gestation

Secondary Outcomes (8)

• live birth rate per stimulated cycle

  28 gestational week

• biochemical pregnancy rate per stimulated cycle

  12-15 days after embryo transfer

• clinical pregnancy rate per stimulated cycle

  28-30 days after embryo transfer

• ongoing pregnancy rate per stimulated cycle

  10-12 weeks of gestation

• biochemical pregnancy rate per transferred cycle

  12-15 days after embryo transfer

Other Outcomes (4)

• the incidence of moderate to severe OHSS

  since oocyte retrieval to 13 weeks gestation

• pregnancy complications

  since embryo transfer to delivery (during pregnancy)

• adverse fetal outcomes

  1 month after delivery

Study Arms (2)

early follicular phase down-regulation

EXPERIMENTAL

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

luteal phase down-regulation

ACTIVE COMPARATOR

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

Interventions

Triptorelin acetate DRUG

Achieve pituitary down regulation with triptorelin acetate and start controlled ovarian stimulation after complete pituitary down regulation

Also known as: recombinant follicular stimulating hormone (rFSH), recombinant luteinizing hormone (rLH), urinanry human postmenopausal gonadotropin (HMG)

early follicular phase down-regulation; luteal phase down-regulation

Eligibility Criteria

• Age: 20 Years - 35 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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;
• First IVF/ICSI cycle;
• BMI≥18 and ≤25kg/m2;
• Informed consent

You may not qualify if:

• 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.
• Women with a history of one side adnexectomy;
• Women with a poor ovarian response or diminished ovarian reserve (based on Bologna' criteria);
• Women with ovulation dysfunction;
• Women with PCOS (based on Rotterdam's criteria);
• Women with endometriosis;
• Women with the following uterine abnormalities: uterine malformation (unicornuate uterus, uterus bicornis, uterus duplex, mediastinum uterus), adenomyosis, submucosa myoma, intrauterine adhesion;
• Chromosomal abnormality for either or both of the couple;
• 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.;
• Women who are enrolled in other clinical trials.

Sponsors & Collaborators

• Peking University People's Hospital: lead
• West China Hospital: collaborator
• Peking University First Hospital: collaborator
• The First Affiliated Hospital of Zhengzhou University: collaborator
• Henan Provincial People's Hospital: collaborator
• The Second Hospital of Hebei Medical University: collaborator
• First Affiliated Hospital of Wenzhou Medical University: collaborator
• Jiangxi Maternal and Child Health Hospital: collaborator
• Second Affiliated Hospital of Wenzhou Medical University: collaborator
• Second Affiliated Hospital of Zhengzhou University: collaborator
• Shanxi Provincial Maternity and Children's Hospital: collaborator
• First Affiliated Hospital of Guangxi Medical University: collaborator
• Guangxi Maternal and Child Health Hospital: collaborator
• Yinchuan Municipal Maternal and Child Health Hospital: collaborator
• Xinjiang Jiayin Hospital: collaborator

Related Publications (11)

• The United Kingdom national data. Human Fertility and Embryology Authority. 2015

  BACKGROUND

• The United States national assisted reproductive technology(ART) data. Centers for Disease Control and Prevention.2015

  BACKGROUND

• Chinese Reproductive Medicine Society national assisted reproductive technology (ART) data. 2015

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG; Consolidated Standards of Reporting Trials Group. CONSORT 2010 Explanation and Elaboration: Updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010 Aug;63(8):e1-37. doi: 10.1016/j.jclinepi.2010.03.004. Epub 2010 Mar 25.

  PMID: 20346624 BACKGROUND

MeSH Terms

Conditions

Infertility, Female

Interventions

Triptorelin Pamoate; Luteinizing Hormone

Condition Hierarchy (Ancestors)

Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Infertility

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Gonadotropins, Pituitary; Gonadotropins; Pituitary Hormones, Anterior; Pituitary Hormones

Study Officials

• Huan Shen, MD,phD

  Peking University

  PRINCIPAL INVESTIGATOR

• Li Jiang, MD,MPH

  Peking University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Li Jiang, MD, MPH

CONTACT

86-0-13661212539; narnia_vota@hotmail.com

Fumei Gao, MD

CONTACT

86-10-88324436

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The researchers (physicians, nurses and embryologists) and patients are not blinded due to the nature of both interventions while the data analysts are blinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: attending doctor

Model Details: 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.

Study Record Dates

• First Submitted: January 15, 2019
• First Posted: January 18, 2019
• Study Start: February 1, 2019
• Primary Completion: September 1, 2020
• Study Completion: December 31, 2020
• Last Updated: January 18, 2019

Record last verified: 2019-01