Progestin Primed Double Stimulation Protocol Versus Flexible GnRH Antagonist Protocol in Poor Responders

Infertility, Female Clinical Trial

Official title:

Progestin Primed Double Stimulation Protocol Versus Flexible GnRH Antagonist Protocol in Poor Responders

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04537078
• Other study ID #: 0201350
• Status: Completed
• Phase: Phase 3
• Start date: September 1, 2020
• Est. completion date: September 1, 2021

Study information

• Verified date: January 2022
• Source: El Shatby University Hospital for Obstetrics and Gynecology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The worldwide prevalence of primary and secondary infertility is estimated at ~2% and 10.5%, respectively, among women aged 20-44 years and attempting to conceive. Poor ovarian responders (PORs) involve 9-24% of patients undergoing in-vitro fertilization (IVF). proper tailoring of the ovarian stimulation protocol in order to maximize the number of oocytes collected represents a crucial step for them to eventually conceive.

Recent evidence indicates that in the same menstrual cycle, there are multiple follicular recruitment waves. This coincides with the theory that folliculogenesis occurs in a wave-like fashion. Thus, within a single menstrual cycle, there can theoretically be multiple opportunities for a clinician to collect oocytes, as opposed to the conventional single cohort of antral follicles during the follicular phase.

Utilizing this concept, clinicians have been attempting to retrieve oocytes from poor responders using both the follicular-phase stimulation (FPS) and the luteal-phase stimulation (LPS) protocols to increase the number of oocytes collected shorter within shorter period of time. By increasing the number of the retrieved oocytes collected, a better clinical can be assured since there is a clear relationship between the number of oocytes collected and live birth rates across all female age groups.

which protocol is the most effective remains controversial and the efficacy of PPOS in POR compared with that of conventional protocols is unclear.

Description:

The study will be conducted on 90 infertile women indicated for ICSI with criteria of poor ovarian response defined by Bologna criteria All participants will be informed about the nature of the study and informed consent will be taken from all of them.

Group 1:45 patients will be given the progestin primed double stimulation protocol.

Group 2: 45 patients will be given the flexible GnRh antagonist follicular controlled ovarian stimulations will be done in 2 cycles.

Written informed consents will be obtained from all participants who accept to participate in the research protocol.

Work up:

1. Complete history taking and full assessment of different infertility factors.

2. Hormonal investigations

• FSH, LH, E2, Prolactin

• AMH, TSH

3. Basal transvaginal ultrasound

Clinical and embryological procedures:

Group 1:

I. The follicular phase of the double stimulation protocol

1. luteal phase priming using combined contraceptive pills from day 21 of the previous cycle for one week (0.03 mg ethinyl estradiol, gestodene 0.075 mg, Gynera tab, Bayer Pharma AG., Berlin, Germany).

2. Controlled ovarian hyper-stimulation with 225-375 IU of gonadotropins will be started day 2-3 of menses after vaginal ultrasound confirming the absence of ovarian cysts.

3. Dydrogesterone (Duphaston, Abbott company, Illinois, United states) at 20 mg/day will be started from the first day of the ovulation induction.

4. Patient response will be monitored by:

1. Transvaginal follicular scanning and the dose of the gonadotropins will be modified according to the response.

2. Serum estradiol.

3. Serum progesterone and LH on the day of triggering.

5. GnRh agonist triggering (Decapeptyl, Ferring, SAINT-PREX Switzerland) in a dose of 2 ampules of 0.2 mg will be administered when leading follicle >18 mm in diameter.

6. Oocyte pickup will be done 36 hours after GnRh administration with precaution of leaving the follicles measuring 11 mm or less.

7. After the pick-up, oocytes will be denuded. The denuded oocytes are then assessed for nuclear status. Mature oocytes will be used for ICSI.

II. The luteal phase of the double stimulation protocol

Controlled ovarian hyper-stimulation with 225-375 IU of gonadotropins will be started the next day after the previous oocyte pickup simultaneously with Dydrogesterone (Duphaston, Abbott company, Illinois, United states) at 20 mg/day.

The rest will be as the follicular phase.

III. Fertilization and embryo quality:

The fertilization check, which will be performed 16 to 20 hours after ICSI. The resultant embryos will be scored, and they will be vitrified for subsequent transfer.

IV. Embryo transfer

• Starting from the next menstrual cycle Day 3, patients will receive oral estradiol valerate (Cyclo-Progynova (white tablets); Bayer, Germany) daily. From Day 10 onwards, endometrium growth will be monitored by transvaginal ultrasound. When endometrial thickness ≥ 7 mm. Progesterone administration (as 800 mg/day vaginal suppositories per day and 100 mg ampule IM every other day) will be initiated and Embryo transfer will be scheduled on Day 3, 4 or 5 with maximum number of 3 class A embryos whether of cleavage or blastocyst stage.

V. Luteal support - Progesterone administration (as 800 mg/day vaginal suppositories per day and 100 mg ampule IM every other day) will be continued until pregnancy testing 18 days after embryo transfer. The pregnant cases will continue the luteal support till the 12 weeks of gestation.

Group 2:

VI. The flexible GnRH antagonist protocol controlled ovarian stimulation This controlled ovarian stimulation will be done twice in two different cycles

In each cycle:

1. luteal phase priming using combined contraceptive pills from day 21 of the previous cycle for one week (0.03 mg ethinyl estradiol, gestodene 0.075 mg , Gynera tab, Bayer Pharma AG., Berlin, Germany).

2. Controlled ovarian hyper-stimulation using antagonist protocol will be used. Stimulation with 225-375 IU of gonadotropins will be started day 2-3 of menses after vaginal ultrasound confirming the absence of ovarian cysts.

3. GnRH antagonist ( Cetrotide , Merck Serono, Darmstadt, Germany) will be given daily as the biggest oocyte reaches size 14 mm.

4. Patient response will be monitored by:

1. Transvaginal follicular scanning and the dose of the gonadotropins will be modified according to the response.

2. Serum estradiol.

3. Serum progesterone on the day of triggering.

5. GnRh agonist triggering (Decapeptyl, Ferring, Saint-Prex Switzerland) in a dose of 2 ampules 0.2 mg will be administered when leading follicle >18 mm in diameter. While in the second cycle HCG triggering (Choriomon, IBSA, Lugano, Switzerland) in a dose of 10,000 IU will be administered when the leading follicle >18 mm in diameter.

6. Oocyte pickup will be done 36 hours after GnRh administration.

7. After the pick-up, oocytes will be denuded. The denuded oocytes are then assessed for nuclear status. Mature oocytes will be used for ICSI.

VII. Fertilization and embryo quality:

The fertilization check, which will be performed 16 to 20 hours after ICSI. The resultant embryos will be scored.

Embryos of the first cycle will be vitrified while embryos of the second cycle will be freshly transferred unless there is excess for vitrification for subsequent trials of transfer.

VIII. Embryo transfer

• Progesterone administration (as 800 mg/day vaginal suppositories per day and 100 mg ampule IM every other day) will be initiated on the day of the oocyte pick up of the second cycle. Embryo transfer will be scheduled on Day 3, 4 or 5 with maximum number of 3 class A embryos whether of cleavage or blastocyst stage that will be a mixture of the thawed embryos of the first cycle and fresh embryos of the second cycle.

IX. Luteal support Progesterone administration (as 800 mg/day vaginal suppositories per day and 100 mg ampule IM every other day) will be continued until pregnancy testing 18 days after embryo transfer. The pregnant cases will continue the luteal support till the 12 weeks of gestation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: September 1, 2021
• Est. primary completion date: March 1, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 20 Years to 45 Years

Eligibility

Inclusion Criteria:

poor ovarian responders patients defined by Bologna criteria

Exclusion Criteria:

1. Male factor infertility due to azoospermia.

2. Patients with uncorrected uterine pathology.

3. Patients with the diagnosis of severe endometriosis.

4. Patients with BMI over 35.

Related Conditions & MeSH terms

• Infertility
• Infertility, Female

Intervention

Drug:
• Duphaston
will be used for pituitary suppression in the first arm:20 mg/day will be started from the first day of the ovulation induction in the follicular phase and in the luteal phase will be started the next day after oocyte pickup at 20 mg/day.
• Gonadotropin
will be used for controlled ovarian hyperstimulation in both arms
• Cetrotide Injectable Product
will used in the second arm for pituitary suppression in the second group daily when the biggest oocyte reaches size 14 mm till ovulation triggering
• Decapeptyl
will be used for ovulation triggering.in the first arm:in a dose of 2 ampules of 0.2 mg will be administered when leading follicle >18 mm in diameter. in the second arm:in a dose of 2 ampules 0.2 mg will be administered when leading follicle >18 mm in diameter in the first cycle only.
• Chorionic Gonadotropin
will be used in the second cycle of the second arm for ovulation triggering in a dose of 10,000 IU when the leading follicle >18 mm in diameter.
• Combined Oral Contraceptive
luteal phase priming from day 21 of the cycle before controlled ovarian stimulation for one week .
• Cyclo-Progynova
Starting from cycle Day 3 of the intented cycle for thawed embryo transfer, patients will receive the white tablets of Cyclo-Progynova daily. From Day 10 onwards, endometrium growth will be monitored by transvaginal ultrasound.
• progesterone
in the intended cycle of embryo transfer when endometrial thickness = 7 mm. Progesterone administration (as 800 mg/day vaginal suppositories per day and 100 mg ampule IM every other day) will be continued until pregnancy testing 18 days after embryo transfer and in pregnant cases will continued till the 12 weeks of gestation.

Locations

Country	Name	City	State
Egypt	Elshatby University Maternity Hospital	Alexandria

Sponsors (1)

Lead Sponsor	Collaborator
El Shatby University Hospital for Obstetrics and Gynecology

Country where clinical trial is conducted

Egypt, 

References & Publications (15)

Baerwald AR, Adams GP, Pierson RA. Ovarian antral folliculogenesis during the human menstrual cycle: a review. Hum Reprod Update. 2012 Jan-Feb;18(1):73-91. doi: 10.1093/humupd/dmr039. Epub 2011 Nov 8. Review. — View Citation

Briggs R, Kovacs G, MacLachlan V, Motteram C, Baker HW. Can you ever collect too many oocytes? Hum Reprod. 2015 Jan;30(1):81-7. doi: 10.1093/humrep/deu272. Epub 2014 Oct 31. — View Citation

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. — View Citation

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. — View Citation

Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, Ai A, Shoham Z. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril. 2015 Jul;104(1):62-70.e3. doi: 10.1016/j.fertnstert.2015.03.022. Epub 2015 May 5. — View Citation

Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014 Dec;29(6):684-91. doi: 10.1016/j.rbmo.2014.08.009. Epub 2014 Sep 6. — View Citation

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. — View Citation

Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med. 2012;9(12):e1001356. doi: 10.1371/journal.pmed.1001356. Epub 2012 Dec 18. — View Citation

McNatty KP, Hillier SG, van den Boogaard AM, Trimbos-Kemper TC, Reichert LE Jr, van Hall EV. Follicular development during the luteal phase of the human menstrual cycle. J Clin Endocrinol Metab. 1983 May;56(5):1022-31. — View Citation

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. — View Citation

Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011 Jul;26(7):1768-74. doi: 10.1093/humrep/der106. Epub 2011 May 10. — View Citation

Vanden Brink H, Chizen D, Hale G, Baerwald A. Age-related changes in major ovarian follicular wave dynamics during the human menstrual cycle. Menopause. 2013 Dec;20(12):1243-54. doi: 10.1097/GME.0b013e31828cfb62. — View Citation

Wang N, Wang Y, Chen Q, Dong J, Tian H, Fu Y, Ai A, Lyu Q, Kuang Y. Luteal-phase ovarian stimulation vs conventional ovarian stimulation in patients with normal ovarian reserve treated for IVF: a large retrospective cohort study. Clin Endocrinol (Oxf). 2016 May;84(5):720-8. doi: 10.1111/cen.12983. Epub 2015 Dec 21. — View Citation

Zhang J. Luteal phase ovarian stimulation following oocyte retrieval: is it helpful for poor responders? Reprod Biol Endocrinol. 2015 Jul 25;13:76. doi: 10.1186/s12958-015-0076-2. — View Citation

Zhang Q, Guo XM, Li Y. Implantation rates subsequent to the transfer of embryos produced at different phases during double stimulation of poor ovarian responders. Reprod Fertil Dev. 2017 Jun;29(6):1178-1183. doi: 10.1071/RD16020. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the Number of M2 Oocytes Retrieved	it is the number of M2 oocytes retrieved that were being assessed after denudation	1-2 hours after oocyte retrieval
Primary	the Fertilization Rate	percentage transformation of micro injected oocytes into two pronuclei. it is done 16 to 20 hours after microinjection of the oocytes by the sperms	16 to 20 hours after microinjection of the oocytes with the sperms
Primary	the Resultant Embryos Number	it is the resultant embryos number counted day 3 or 4 or 5 after fertilization	the embryos number counted day 3 or 4or 5 after fertilization
Primary	the Implantation Rate	it is calculated as the number of intrauterine gestational sacs observed by transvaginal ultrasonography divided by the number of transferred embryos at the 6 th week of pregnancy and then multiplied by 100	at the 6 th week of pregnancy
Primary	the Clinical Pregnancy Rate.	percentage of cases in which observation of a gestational sac with fetal heart beat by transvaginal ultrasound at 6 weeks of pregnancy	at the 6 th weeks of pregnancy
Secondary	the Difference in the Ongoing Pregnancy Rate in Both Protocols.	Assessing the difference in the ongoing pregnancy rate when the pregnancy had completed =20 weeks of gestation	At the 20 th week of gestation
Secondary	the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Total Days of Controlled Ovarian Hyperstimulation	the total number of days of the controlled ovarian hyperstimulation in both follicular and luteal phase of the progestin primed double stimulation protocol are studied so as to asses the difference between the two phases, the follicular phase and the luteal phase of the progestin primed double stimulation protocol	From the first day of ovarian stimulation till the last day of ovarian stimulation in each phase ,the follicular and the luteal, of stimulation
Secondary	the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Total Dosage of Gonadotropins Used in the Controlled Ovarian Hyperstimulation	Assessing the difference between the follicular phase and the luteal phase of the progestin primed double stimulation protocol regarding the total dosage of gonadotropins used in the controlled ovarian hyperstimulation so as to the difference between the two phases	From the first day of ovarian stimulation till the last day of ovarian stimulation in each phase ,the follicular and the luteal, of stimulation
Secondary	the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Number of M2 Oocytes Retrieved	it is the number of M2 oocytes retrieved that were being assessed after denudation so as to the difference between the results between the two phases, the follicular phase and the luteal phase of the progestin primed double stimulation protocol	1-2 hours after oocyte retrieval
Secondary	the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Fertilization Rate.	percentage of transformation of micro injected oocytes into two pronuclei at 16 -20 hours after microinjection of the oocytes by the sperms so as to the difference between the results between the two phases, the follicular phase and the luteal phase of the progestin primed double stimulation protocol	16 to 20 hours after microinjection of the oocytes with the sperms
Secondary	the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Resultant Embryos Number	the resultant embryos number are counted day 3 or 4 or 5 after fertilization so as to the difference between the results between the two phases, the follicular phase and the luteal phase of the progestin primed double stimulation protocol	the embryos number counted day 3 or 4or 5 after fertilization
Secondary	Assessing the Difference Between the Follicular Phase of the Progestin Primed Double Stimulation Protocol and the First Round of the Conventional GnRH Antagonist Protocol Regarding the Number of M2 Oocytes Retrieved .	it is the number of M2 oocytes retrieved that were being assessed after denudation.so as to study the effect of the progestin used on the ovarian response in poor ovarian responders, we have compared the follicular phase of the dual stimulation group and first follicular wave of the flexible antagonist group	1-2 hours after oocyte retrieval
Secondary	Assessing the Difference Between the Follicular Phase of the Progestin Primed Double Stimulation Protocol and the First Round of the Conventional GnRH Antagonist Protocol Regarding the Fertilization Rate.	it is percentage transformation of micro injected oocytes into two pronuclei.so as to study the effect of the progestin used on the ovarian response and its results in poor ovarian responders, we have compared the follicular phase of the dual stimulation group and first follicular wave of the flexible antagonist group	16 to 20 hours after microinjection of the oocytes by the sperms
Secondary	Assessing the Difference Between the Follicular Phase of the Progestin Primed Double Stimulation Protocol and the First Round of the Conventional GnRH Antagonist Protocol Regarding the Resultant Embryos Number.	it is the number of the resultant embryos counted at day 3 or 4 or 5 after fertilization.so as to study the effect of the progestin used on the ovarian response and the resultant embryos number in poor ovarian responders, we have compared the follicular phase of the dual stimulation group and first follicular wave of the flexible antagonist group	at day 3 or 4or 5 after fertilization