Modified Luteal Support for Frozen-Thawed Embryo Transfer - A Prospective Study

Embryo Transfer Clinical Trial

Official title:

Modified Luteal Support for Frozen-Thawed Embryo Transfer - A Prospective Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02825290
• Other study ID #: 2537-15-SMC
• Status: Recruiting
• Phase: Phase 4
• First received: July 3, 2016
• Last updated: December 11, 2016
• Start date: July 2016
• Est. completion date: June 2017

Study information

• Verified date: December 2016
• Source: Sheba Medical Center
• Contact: Eran Zilberberg, MD
• Phone: +97235302882
• Email: eran.zilberberg[@]gmail.com
• Is FDA regulated: No
• Health authority: Israel: Ethics Commission
• Study type: Interventional

Clinical Trial Summary

This study evaluates the outcomes of frozen-thawed embryo transfer (FET) success rate with modified luteal support - addition of a single injection of HCG and GnRH-agonist, on day of ET and 4 days later, respectively vs. traditional luteal support with vaginal progesterone only in ovulating women.

Description:

Background With the recent trend toward single embryo transfer (ET) adopted in an attempt to reduce the risk of multiple pregnancy, the remaining extra embryos are cryopreserved, providing further possibilities for conception after the initial fresh transfer. Moreover, several studies that compared fresh and frozen-thawed embryo transfer (FET) cycles in normal responders have demonstrated a significantly higher clinical pregnancy rate per transfer in the FET versus the fresh cycles.

There are several currently employed replacement protocols for FET. The choice of protocol depends on the individual woman's ovarian function and convenience of the method, as well as on the experience gained with the method by the physicians. Whatever protocol is used, the success requires optimal synchronization between the embryonic stage at thawing and date of the endometrium within the endometrial preparation cycle. While there is a consensus regarding the duration, route of delivery and dosage of estrogen supplementation, and the optimal ultrasonographic endometrial appearance and thickness, the effect of the different modes of luteal support remains unclear.

Prompted by the study demonstrating higher ongoing pregnancy rate following the transfer of frozen-thawed embryos in natural cycles with spontaneous LH rise compared with natural cycles controlled by hCG for final oocyte maturation and the reports showing improved pregnancy rate in patients who received a mid-luteal injection of a GnRH-agonist (0.1 mg triptorelin), the investigators started beginning at June 2014 to offer ovulatory patients with regular menstrual cycles a natural FET with modified luteal support. Starting on the day of spontaneous ovulation, patients received daily vaginal progesterone, supplemented by a single injection of HCG and GnRH-agonist, on day of ET and 4 days later, respectively.

The results for this study were very promising - the investigators were able to show a significant increase in implantation rate (30% vs. 17%; p<0.03), clinical pregnancy (48% vs. 26%; p<0.01) and ongoing pregnancy (39% vs. 20%; p<0.01) for the patients receiving the aforementioned modified luteal support protocol.

After the completion of this retrospective study the investigators are heading to prove the superiority of the modified luteal support protocol for ovulatory patients by conducting a prospective study.

Materials & Methods Study design - A prospective, randomized, blinded study. Primary endpoint - Ongoing pregnancy. Secondary endpoints - Implantation rate, clinical pregnancy. Study sample - According to the previous, retrospective study the investigators will need 31 patients in each study arm in order to show an increase from 20% clinical pregnancy to 39% (confidence level 5%, beta error level 50%).

The patients - The investigators will offer each patient treated in the unit for frozen-thawed embryo transfer to participate in the study. The randomization of the participants will be on the day of embryo transfer with a computer program on a 1:1 enrollment ratio.

All transfers will be performed by an experienced physician who will be blinded to the luteal support protocol.

Both groups will be treated with the accepted progesterone luteal support - starting on ovulation day - vaginal progesterone 90 mg (Crinone; Merck Serono, Hellerup, Denmark) once a day.

Study group - Patients in the study group will receive additional two injections - the first

• recombinant hCG 250 mcg (Ovitrelle; Merck Serono) on the transfer day and the second - GnRH-agonist 0.1 mg (Decapeptyl; Ferring Pharmaceuticals Israel) 4 days after the embryo transfer day. Patients in the control group will receive no injection.

B-hCG levels will be examined 12 days after embryo transfer and if positive ultrasound examinations will be performed as usual to document pregnancy outcome.

The data - The investigators will use demographic data such as age, BMI, gynecological data as gravida, para, etiology of infertility and data about previous & current IVF treatments such as number of treatments, stimulation protocol, hormone levels, number of oocytes, embryos' characteristics, etc.

Statistics - Statistical analysis will be performed with Student's t-test and Chi square, as appropriate. Results will be presented as means ± standard deviations; p<0.05 will be considered significant.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 62
• Est. completion date: June 2017
• Est. primary completion date: June 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 20 Years to 40 Years

Eligibility

Inclusion Criteria:

• 20-40 years old women

• Spontaneously ovulating women

• Treated in our IVF unit for frozen-thawed embryo transfer

• At least one top quality embryo

Exclusion Criteria:

• PGD patients

• More than 4 previous embryo transfers

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Embryo Transfer
• Luteal Support

Intervention

Drug:
• Choriogonadotropin alfa

• Triptorelin acetate

Locations

Country	Name	City	State
Israel	Sheba medical center	Ramat Gan

Sponsors (1)

Lead Sponsor	Collaborator
Sheba Medical Center

Country where clinical trial is conducted

Israel, 

References & Publications (13)

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. — View Citation

Haas J, Lantsberg D, Feldman N, Manela D, Machtinger R, Dar S, Rabinovici J, Orvieto R. Modifying the luteal phase support in natural cycle frozen-thawed embryo transfer improves cycle outcome. Gynecol Endocrinol. 2015;31(11):891-3. doi: 10.3109/09513590.2015.1075502. — View Citation

Le Lannou D, Griveau JF, Laurent MC, Gueho A, Veron E, Morcel K. Contribution of embryo cryopreservation to elective single embryo transfer in IVF-ICSI. Reprod Biomed Online. 2006 Sep;13(3):368-75. — View Citation

Meldrum DR. Female reproductive aging--ovarian and uterine factors. Fertil Steril. 1993 Jan;59(1):1-5. Review. — View Citation

Navot D, Laufer N, Kopolovic J, Rabinowitz R, Birkenfeld A, Lewin A, Granat M, Margalioth EJ, Schenker JG. Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N Engl J Med. 1986 Mar 27;314(13):806-11. — View Citation

Orvieto R, Brengauz M, Feldman B. A novel approach to normal responder patient with repeated implantation failures--a case report. Gynecol Endocrinol. 2015 Jun;31(6):435-7. doi: 10.3109/09513590.2015.1005595. — View Citation

Orvieto R, Fisch B, Feldberg D. Endometrial Preparation for Patients undergoing Frozen- Thawed Embryo Transfer Cycles. In: The Art & Science of Assisted Reproductive Techniques. G. Allahbadia, R. asuray, R. Merchant, Eds. Jaypee Brothers Medical Publishers (P) Ltd. New Delhi, India, 2003, pp. 396-9.

Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. Hum Reprod. 2002 Sep;17(9):2287-99. Review. — View Citation

Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders. Fertil Steril. 2011 Aug;96(2):344-8. doi: 10.1016/j.fertnstert.2011.05.050. — View Citation

Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C. Clinical rationale for cryopreservation of entire embryo cohorts in lieu of fresh transfer. Fertil Steril. 2014 Jul;102(1):3-9. doi: 10.1016/j.fertnstert.2014.04.018. Review. — View Citation

Tesarik J, Hazout A, Mendoza C. Enhancement of embryo developmental potential by a single administration of GnRH agonist at the time of implantation. Hum Reprod. 2004 May;19(5):1176-80. — View Citation

Tesarik J, Hazout A, Mendoza-Tesarik R, Mendoza N, Mendoza C. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Hum Reprod. 2006 Oct;21(10):2572-9. — View Citation

Thurin A, Hausken J, Hillensjö T, Jablonowska B, Pinborg A, Strandell A, Bergh C. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med. 2004 Dec 2;351(23):2392-402. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ongoing pregnancy	Number of viable pregnancies at about 10-12 weeks of gestation.	About 10-12 weeks after embryo transfer	No
Secondary	Implantation rate	Positive BhCG blood test	2 weeks after embryo transfer	No
Secondary	Clinical pregnancy	Visible intrauterine gestational sacs on ultrasound exam	About 3-4 weeks after embryo transfer	No