Double Stimulation Followed by a Fresh Embryo Transfer

NCT04446845 | Completed Phase 4

• 1 other identifier: FSD-DUO-2020-02
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

The major goal of controlled ovarian stimulation (COS) is to increase the number of oocytes harvested in order to result in the generation of a higher number of available embryos, extended embryo culture, embryo selection and finally providing higher cumulative live birth rates in infertile patients. Moreover, with the idea of the multiple waves of follicular production, we could start to take full advantage of the whole follicular cohort, and not only of the follicular wave. In the context of low prognosis women such as women with poor ovarian response where, the success rates are very low due to the low number of oocytes retrieved and consequently of viable embryos), Dual stimulation may be of great value as a tool to improve outcomes. The reported advantage of DuoStim is retrieved of more oocytes within a shorter time span, resulting in an increase in the probability of having transferable embryos increases, and theoretically reducing time to live birth as well as cycle cancellation.

Conditions

Infertility

Outcome Measures

Primary Outcomes (1)

• Number of good-quality blastocysts

  Embryo quality will be assessed according to the Istanbul consensus workshop criteria (Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Human Reproduction 2011) and good quality embryo (GQE) at this developmental will be an expanded through to hatched blastocyst with an inner cell mass (ICM) that is prominent, easily discernible and consisting of many cells, with the cells compacted and tightly adhered together, and with a trophectoderm (TE) that comprises many cells forming a cohesive epithelium

  Day of embryo transfer (9 -20 days from initiation of the last ovarian stimulation)

Secondary Outcomes (10)

• Number oocytes retrieved

  9 -20 days from initiation of the last ovarian stimulation

• Number of cycles reaching the stage of embryo transfer

  9 -20 days from initiation of the last ovarian stimulation

• Clinical pregnancy

  6-7 weeks of gestation

• Ongoing pregnancy

  8-10 weeks of gestation

• Time to pregnancy

  4-6 weeks of gestation

Other Outcomes (1)

• Adverse events

  Up to 30 days from treatment start date

Study Arms (2)

Double Stimulation (Elonva+rFSH) in luteal /follicular phase

EXPERIMENTAL

A first stimulation Stimulation will initiate in the luteal phase of the menstrual cycle On day 21 of the previous cycle150mcg of corifollitropin alfa (Elonva, Merck Sharp \& Dohme (MSD), Spain) will be administrated and from day 8 of the stimulation when necessary, r-FSH of 250 IU per day will start until the day of ovulation trigger in a flexible gonadotropin-releasing hormone (GnRH) antagonist protocol. The first ovulation triggering will be induced with GnRH-agonist (triptorelin 0.2 ml). The embryos obtained from the first stimulation will be cryopreserved in a freeze-all approach. A second stimulation will start on day 2 of bleeding after the first oocyte retrieval. This time will correspond to a conventional COS where corifollitropin alfa will be administered on the beginning of the follicular phase, in a flexible antagonist protocol, and the second ovulation will be triggered with 250μg of Recombinant Human Chorionic Gonadotropin (rhCG)

Drug: Double Stimulation (Elonva+rFSH) in luteal /follicular phase

Conventional Stimulation (Elonva+rFSH) in follicular phase

ACTIVE COMPARATOR

A conventional COS where Corifollitropin alfa will be administered on the beginning of the follicular phase, in a flexible antagonist protocol, and the second ovulation will be triggered with 250μg of rhCG

Drug: Conventional Stimulation (Elonva+rFSH) in follicular phase

Interventions

Double Stimulation (Elonva+rFSH) in luteal /follicular phase DRUG

Following the 2nd oocyte retrieval, the patient will start luteal phase support (LPS) with vaginal micronized progesterone 200mg x 3 times a day until the day of the pregnancy test. All embryos will be cultured until day 5 in time-lapse incubators. In case of no blastocyst in the second cycle, or in case of poor embryo quality and in case of availability of frozen embryos from the first stimulation cycle, 1 frozen blastocyst from the first cycle will be thawed and will be transferred 5 days following the 2nd oocyte retrieval. Embryo transfer will be performed in all patients with available blastocysts, except in cases of high risk of ovarian hyperstimulation syndrome (OHSS) or progesterone elevation which is considered clinically relevant on the day of human chorionic gonadotropin (hCG) trigger, in which freeze-all strategy and deferred frozen embryo transferred will be considered.

Double Stimulation (Elonva+rFSH) in luteal /follicular phase

Conventional Stimulation (Elonva+rFSH) in follicular phase DRUG

From the day of oocyte retrieval, the patients will be asked to start the LPS with vaginal micronized progesterone 3 times a day until the day of the pregnancy test. Embryo transfer will be performed in all patients with available blastocysts, except in cases of high risk of OHSS or progesterone elevation which is considered clinically relevant on the day of hCG trigger, in which freeze-all strategy and deferred frozen embryo transferred will be considered.

Conventional Stimulation (Elonva+rFSH) in follicular phase

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Poor prognosis patients according to the POSEIDON group 3 \& 4 (based on AMH)
• AMH \<1.2
• age \<40 years old
• BMI \>18 and \<35 kg/m2
• Body weight \>50kg (in women \<36 years old body weight \>60kg)

You may not qualify if:

• Maternal age \> 40 years
• History of untreated autoimmune, endocrine or metabolic disorders
• Previous ovarian cystectomy or oophorectomy
• Body weight \<50kg (and body weight \<60kg in women \<36 years old)

Sponsors & Collaborators

• Fundación Santiago Dexeus Font: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Hospital Universitario Quiron Dexeus

Barcelona, 08028, Spain

Location

Related Publications (17)

• Alsbjerg B, Haahr T, Elbaek HO, Laursen R, Povlsen BB, Humaidan P. Dual stimulation using corifollitropin alfa in 54 Bologna criteria poor ovarian responders - a case series. Reprod Biomed Online. 2019 May;38(5):677-682. doi: 10.1016/j.rbmo.2019.01.007. Epub 2019 Jan 22.

  PMID: 30795977 BACKGROUND

• Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011 Jun;26(6):1270-83. doi: 10.1093/humrep/der037. Epub 2011 Apr 18.

  PMID: 21502182 BACKGROUND

• Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril. 2003 Jul;80(1):116-22. doi: 10.1016/s0015-0282(03)00544-2.

  PMID: 12849812 BACKGROUND

• Cardoso MCA, Evangelista A, Sartorio C, Vaz G, Werneck CLV, Guimaraes FM, Sa PG, Erthal MC. Can ovarian double-stimulation in the same menstrual cycle improve IVF outcomes? JBRA Assist Reprod. 2017 Sep 1;21(3):217-221. doi: 10.5935/1518-0557.20170042.

  PMID: 28837031 BACKGROUND

• Coutifaris C. Freeze-only in vitro fertilization cycles for all? Fertil Steril. 2017 Aug;108(2):233-234. doi: 10.1016/j.fertnstert.2017.06.028. No abstract available.

  PMID: 28778278 BACKGROUND

• Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, Polyzos NP. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod. 2016 Feb;31(2):370-6. doi: 10.1093/humrep/dev316. Epub 2016 Jan 2.

  PMID: 26724797 BACKGROUND

• Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011 Jul;26(7):1616-24. doi: 10.1093/humrep/der092. Epub 2011 Apr 19.

  PMID: 21505041 BACKGROUND

• Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, Shoham Z. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril. 2014 Jan;101(1):105-11. doi: 10.1016/j.fertnstert.2013.09.007. Epub 2013 Oct 23.

  PMID: 24161646 BACKGROUND

• Liu C, Jiang H, Zhang W, Yin H. Double ovarian stimulation during the follicular and luteal phase in women >/=38 years: a retrospective case-control study. Reprod Biomed Online. 2017 Dec;35(6):678-684. doi: 10.1016/j.rbmo.2017.08.019. Epub 2017 Aug 24.

  PMID: 29030068 BACKGROUND

• Moffat R, Pirtea P, Gayet V, Wolf JP, Chapron C, de Ziegler D. Dual ovarian stimulation is a new viable option for enhancing the oocyte yield when the time for assisted reproductive technnology is limited. Reprod Biomed Online. 2014 Dec;29(6):659-61. doi: 10.1016/j.rbmo.2014.08.010. Epub 2014 Sep 4.

  PMID: 25311972 BACKGROUND

• Morin SJ, Patounakis G, Juneau CR, Neal SA, Scott RT, Seli E. Diminished ovarian reserve and poor response to stimulation in patients <38 years old: a quantitative but not qualitative reduction in performance. Hum Reprod. 2018 Aug 1;33(8):1489-1498. doi: 10.1093/humrep/dey238.

  PMID: 30010882 BACKGROUND

• Polyzos NP, Nwoye M, Corona R, Blockeel C, Stoop D, Haentjens P, Camus M, Tournaye H. Live birth rates in Bologna poor responders treated with ovarian stimulation for IVF/ICSI. Reprod Biomed Online. 2014 Apr;28(4):469-74. doi: 10.1016/j.rbmo.2013.11.010. Epub 2013 Dec 4.

  PMID: 24581984 BACKGROUND

• Poseidon Group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number); Alviggi C, Andersen CY, Buehler K, Conforti A, De Placido G, Esteves SC, Fischer R, Galliano D, Polyzos NP, Sunkara SK, Ubaldi FM, Humaidan P. A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril. 2016 Jun;105(6):1452-3. doi: 10.1016/j.fertnstert.2016.02.005. Epub 2016 Feb 26. No abstract available.

  PMID: 26921622 BACKGROUND

• Sighinolfi G, Sunkara SK, La Marca A. New strategies of ovarian stimulation based on the concept of ovarian follicular waves: From conventional to random and double stimulation. Reprod Biomed Online. 2018 Oct;37(4):489-497. doi: 10.1016/j.rbmo.2018.07.006. Epub 2018 Aug 11.

  PMID: 30170909 BACKGROUND

• Tsampras N, Gould D, Fitzgerald CT. Double ovarian stimulation (DuoStim) protocol for fertility preservation in female oncology patients. Hum Fertil (Camb). 2017 Dec;20(4):248-253. doi: 10.1080/14647273.2017.1287433. Epub 2017 Feb 9.

  PMID: 28423955 BACKGROUND

• Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, Trabucco E, Venturella R, Vajta G, Rienzi L. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil Steril. 2016 Jun;105(6):1488-1495.e1. doi: 10.1016/j.fertnstert.2016.03.002. Epub 2016 Mar 25.

  PMID: 27020168 BACKGROUND

• Racca A, Rodriguez I, Garcia S, Arroyo G, Polyzos NP. Double versus single stimulation in young low prognosis patients followed by a fresh embryo transfer: a randomized controlled trial (DUOSTIM-fresh). Hum Reprod. 2024 Jun 6:deae104. doi: 10.1093/humrep/deae104. Online ahead of print.

  PMID: 38845190 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Infertility

Interventions

Follicular Phase

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Menstrual Cycle; Reproductive Physiological Phenomena; Reproductive and Urinary Physiological Phenomena

Study Officials

• Nikolaos P Polyzos, MD PhD

  Hopital Universitari Dexeus

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 19, 2020
• First Posted: June 25, 2020
• Study Start: October 30, 2020
• Primary Completion: January 15, 2023
• Study Completion: May 2, 2023
• Last Updated: May 15, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)