What is the Optimal Cycle Regimen for Frozen- Thawed Embryo Transfer Cycles

NCT ID: NCT03954587

Last Updated: 2021-03-08

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

TERMINATED

Total Enrollment

4 participants

Study Classification

OBSERVATIONAL

Study Start Date

2019-06-10

Study Completion Date

2020-07-30

Brief Summary

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Investigators will be comparing artificial (HRT) frozen-thawed embryo transfer cycles to correctly conducted spontaneous natural cycles after the transfer of a chromosomally normal embryo.

Detailed Description

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The most common treatment protocols for frozen embryo transfers include natural cycles with or without human chorionic gonadotrophin (HCG) trigger or endometrial preparation with hormonal treatment (artificial cycles), with or without Gonadotrophin - releasing hormone agonist suppression. Recent studies comparing artificial and natural cycles concluded that the optimal means of endometrial preparation for frozen- thawed cycle remains unclear and both options may be offered to women with regular ovulatory cycles.

Correctly identified spontaneous natural cycles are the preferred option for frozen-thawed embryo transfer in women with regular menstrual cycles.

Investigators will be comparing artificial (HRT) frozen-thawed embryo transfer cycles to correctly conducted spontaneous natural cycles after the transfer of a chromosomally normal embryo.

Conditions

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Infertility Female Infertility Pregnancy Early

Study Design

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Observational Model Type

OTHER

Study Time Perspective

PROSPECTIVE

Study Groups

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Artificial (HRT) Cycles

1. Commence estradiol valerate (E2) 4mg from day 2 or 3 of period for 3 days
2. Increase E2 to 6mg on day 4 of E2 treatment, according to clinician discretion based on endometrial thickness.
3. Transvaginal scan throughout the HRT cycle to not only monitor endometrial development but to also exclude the presence of a dominant follicle on the ovaries.
4. Serial measurements of serum LH (luteinizing hormone), estradiol and progesterone levels.
5. Initial progesterone dose of 100mg at 22hrs (vaginal suppository) after ≥ 7 days and ≤ 16 days of estradiol administration when the minimal endometrial thickness achieved is 6mm with a trilaminar appearance.
6. Subsequently increase progesterone administration to 100mg vaginally three times daily. Continue E2 administration 6mg (3 tablets daily).
7. Embryo transfer is scheduled on the 5th full day of progesterone administration.

No interventions assigned to this group

Spontaneous natural cycles:

1. Day 2 of menses and throughout patients' natural cycle scans to monitor follicular growth.
2. Measurements of serum LH, estradiol and progesterone levels to determine ovulation.
3. The LH surge will be considered to have begun when the concentration rises by 180% above the most recent serum value and continues to rise thereafter (Irani et al. 2017, Fatemi et al., 2010).
4. Day 1 after the LH rise, a decrease in estradiol concentration is identified. Twenty four hours later progesterone concentrations rise with a level of greater than or equal to 1.5ng/mL confirming ovulation (day 0) (Irani et al., 2017; Speroff et al.). This is considered as day 0 with initiation of vaginal progesterone 100mg at 22hrs that night. The following day (day 1) the patient increases progesterone administration to 100mg vaginally 8 hourly and continues until 7 weeks gestation as per clinic protocol. Embryo transfer is scheduled 5 days (day 5) following confirmation of ovulation (day 0).

No interventions assigned to this group

Eligibility Criteria

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Inclusion Criteria

1. Women aged 18 years to 42 years with regular menses (26-34 days)
2. Having 1 or 2 chromosomally normal cryopreserved blastocysts available for transfer.
3. First frozen-thawed transfer cycle
4. Progesterone level \< 1.5 ng/mL day of trigger injection in stimulation cycle from which embryos to be transferred were created.

Exclusion Criteria

1. Polycystic ovarian syndrome
2. Poor ovarian responder in accordance with Bologna criteria
3. Uterine abnormality US / saline infusion sonohysterogram
4. Previous dilatation \& curettage (D\&C)
5. Hydrosalpinx
6. Asherman syndrome
7. History of endometriosis
8. ICSI due to severe male factor with testicular sperm
9. Any known contraindications or allergy to oral estradiol or progesterone.
10. Discontinuation of HRT medication ( medication error in research HRT cycle )
11. Failure to detect ovulation in the research natural cycle
12. Duration of estradiol exposure ≥ 17 days and endometrium \< 6mm
13. Spontaneous ovulation in HRT artificial cycle
Minimum Eligible Age

18 Years

Maximum Eligible Age

42 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes

Sponsors

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ART Fertility Clinics LLC

OTHER

Sponsor Role lead

Responsible Party

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Prof Dr. Human Fatemi

Medical Director

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Carol Coughlan, PhD

Role: PRINCIPAL_INVESTIGATOR

IVI Middle East Fertility Clinic LLC

Locations

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IVI Middle East Fertility Clinic

Abu Dhabi, , United Arab Emirates

Site Status

Countries

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United Arab Emirates

References

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Roque M, Lattes K, Serra S, Sola I, Geber S, Carreras R, Checa MA. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril. 2013 Jan;99(1):156-162. doi: 10.1016/j.fertnstert.2012.09.003. Epub 2012 Oct 3.

Reference Type BACKGROUND
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Roque M, Valle M, Guimaraes F, Sampaio M, Geber S. Freeze-all policy: fresh vs. frozen-thawed embryo transfer. Fertil Steril. 2015 May;103(5):1190-3. doi: 10.1016/j.fertnstert.2015.01.045. Epub 2015 Mar 4.

Reference Type BACKGROUND
PMID: 25747130 (View on PubMed)

Bourgain C, Devroey P. The endometrium in stimulated cycles for IVF. Hum Reprod Update. 2003 Nov-Dec;9(6):515-22. doi: 10.1093/humupd/dmg045.

Reference Type BACKGROUND
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Devroey P, Bourgain C, Macklon NS, Fauser BC. Reproductive biology and IVF: ovarian stimulation and endometrial receptivity. Trends Endocrinol Metab. 2004 Mar;15(2):84-90. doi: 10.1016/j.tem.2004.01.009.

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Kolibianakis E, Bourgain C, Albano C, Osmanagaoglu K, Smitz J, Van Steirteghem A, Devroey P. Effect of ovarian stimulation with recombinant follicle-stimulating hormone, gonadotropin releasing hormone antagonists, and human chorionic gonadotropin on endometrial maturation on the day of oocyte pick-up. Fertil Steril. 2002 Nov;78(5):1025-9. doi: 10.1016/s0015-0282(02)03323-x.

Reference Type BACKGROUND
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Nikas G, Develioglu OH, Toner JP, Jones HW Jr. Endometrial pinopodes indicate a shift in the window of receptivity in IVF cycles. Hum Reprod. 1999 Mar;14(3):787-92. doi: 10.1093/humrep/14.3.787.

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Simon C, Garcia Velasco JJ, Valbuena D, Peinado JA, Moreno C, Remohi J, Pellicer A. Increasing uterine receptivity by decreasing estradiol levels during the preimplantation period in high responders with the use of a follicle-stimulating hormone step-down regimen. Fertil Steril. 1998 Aug;70(2):234-9. doi: 10.1016/s0015-0282(98)00140-x.

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Weinerman R, Mainigi M. Why we should transfer frozen instead of fresh embryos: the translational rationale. Fertil Steril. 2014 Jul;102(1):10-8. doi: 10.1016/j.fertnstert.2014.05.019. Epub 2014 Jun 2.

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Liu Y, Lee KF, Ng EH, Yeung WS, Ho PC. Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles. Fertil Steril. 2008 Dec;90(6):2152-64. doi: 10.1016/j.fertnstert.2007.10.020. Epub 2008 Jan 14.

Reference Type BACKGROUND
PMID: 18191855 (View on PubMed)

Haouzi D, Assou S, Mahmoud K, Tondeur S, Reme T, Hedon B, De Vos J, Hamamah S. Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients. Hum Reprod. 2009 Jun;24(6):1436-45. doi: 10.1093/humrep/dep039. Epub 2009 Feb 26.

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PMID: 19246470 (View on PubMed)

Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2017 Jul 5;7(7):CD003414. doi: 10.1002/14651858.CD003414.pub3.

Reference Type BACKGROUND
PMID: 28675921 (View on PubMed)

Groenewoud ER, Cantineau AE, Kollen BJ, Macklon NS, Cohlen BJ. What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis. Hum Reprod Update. 2013 Sep-Oct;19(5):458-70. doi: 10.1093/humupd/dmt030. Epub 2013 Jul 2.

Reference Type BACKGROUND
PMID: 23820515 (View on PubMed)

Groenewoud ER, Cohlen BJ, Macklon NS. Programming the endometrium for deferred transfer of cryopreserved embryos: hormone replacement versus modified natural cycles. Fertil Steril. 2018 May;109(5):768-774. doi: 10.1016/j.fertnstert.2018.02.135.

Reference Type BACKGROUND
PMID: 29778369 (View on PubMed)

Agha-Hosseini M, Hashemi L, Aleyasin A, Ghasemi M, Sarvi F, Shabani Nashtaei M, Khodarahmian M. Natural cycle versus artificial cycle in frozen-thawed embryo transfer: A randomized prospective trial. Turk J Obstet Gynecol. 2018 Mar;15(1):12-17. doi: 10.4274/tjod.47855. Epub 2018 Mar 29.

Reference Type BACKGROUND
PMID: 29662710 (View on PubMed)

Fatemi HM, Kyrou D, Bourgain C, Van den Abbeel E, Griesinger G, Devroey P. Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle. Fertil Steril. 2010 Nov;94(6):2054-8. doi: 10.1016/j.fertnstert.2009.11.036. Epub 2010 Jan 25.

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PMID: 20097333 (View on PubMed)

Zimmermann G, Ackermann W, Alexander H. Epithelial human chorionic gonadotropin is expressed and produced in human secretory endometrium during the normal menstrual cycle. Biol Reprod. 2009 May;80(5):1053-65. doi: 10.1095/biolreprod.108.069575. Epub 2009 Jan 21.

Reference Type BACKGROUND
PMID: 19164178 (View on PubMed)

Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, Zhu Y, Deng X, Qi X, Li H, Ma X, Ren H, Wang Y, Zhang D, Wang B, Liu F, Wu Q, Wang Z, Bai H, Li Y, Zhou Y, Sun M, Liu H, Li J, Zhang L, Chen X, Zhang S, Sun X, Legro RS, Chen ZJ. Transfer of Fresh versus Frozen Embryos in Ovulatory Women. N Engl J Med. 2018 Jan 11;378(2):126-136. doi: 10.1056/NEJMoa1705334.

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O'Connor KA, Brindle E, Miller RC, Shofer JB, Ferrell RJ, Klein NA, Soules MR, Holman DJ, Mansfield PK, Wood JW. Ovulation detection methods for urinary hormones: precision, daily and intermittent sampling and a combined hierarchical method. Hum Reprod. 2006 Jun;21(6):1442-52. doi: 10.1093/humrep/dei497. Epub 2006 Jan 26.

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Irani M, Robles A, Gunnala V, Reichman D, Rosenwaks Z. Optimal parameters for determining the LH surge in natural cycle frozen-thawed embryo transfers. J Ovarian Res. 2017 Oct 16;10(1):70. doi: 10.1186/s13048-017-0367-7.

Reference Type BACKGROUND
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Other Identifiers

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1901-ABU-015-CC

Identifier Type: -

Identifier Source: org_study_id

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