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

NCT04537078 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: 0201350
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Infertility, Female

Outcome Measures

Primary Outcomes (5)

• 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

• 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

• 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

• 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

• 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 Outcomes (9)

• the Difference in the Ongoing Pregnancy Rate in Both Protocols.

  At the 20 th week of gestation

• 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

  From the first day of ovarian stimulation till the last day of ovarian stimulation in each phase ,the follicular and the luteal, of stimulation

• 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

  From the first day of ovarian stimulation till the last day of ovarian stimulation in each phase ,the follicular and the luteal, of stimulation

• the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Number of M2 Oocytes Retrieved

  1-2 hours after oocyte retrieval

• the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Fertilization Rate.

  16 to 20 hours after microinjection of the oocytes with the sperms

Study Arms (2)

the progestin primed double stimulation group

ACTIVE COMPARATOR

luteal phase priming using combined contraceptive pills from day 21 of the previous cycle for one week by Gynera tab. 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. Duphaston at 20 mg/day will be started from the first day of the ovulation induction.Decapeptyl in a dose of 2 ampules of 0.2 mg will be administered when leading follicle \>18 mm in diameter for triggering.Then, Controlled ovarian hyper-stimulation the next day after the previous oocyte pickup simultaneously with Duphaston. Starting from the next menstrual cycle Day 3, patients will receive oral estradiol valerate (Cyclo-Progynova (white tablets) daily.When endometrial thickness ≥ 7 mm.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.

Drug: Duphaston; Drug: Gonadotropin; Drug: Decapeptyl; Drug: Combined Oral Contraceptive; Drug: Cyclo-Progynova; Drug: progesterone

the flexible GnRh antagonist

ACTIVE COMPARATOR

This step will be done twice in two different cycles In each cycle: luteal phase priming using combined contraceptive pills from day 21 of the previous cycle for one week by Gynera tab. 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. Cetrotide ampule will be given daily as the biggest oocyte reaches size 14 mm. Decapeptyl ampules 0.2 mg will be administered when leading follicle \>18 mm in diameter. While in the second cycle HCG triggering (Choriomon)in a dose of 10,000 IU will be administered when the leading follicle \>18 mm in diameter. 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.

Drug: Gonadotropin; Drug: Cetrotide Injectable Product; Drug: Decapeptyl; Drug: Chorionic Gonadotropin; Drug: Combined Oral Contraceptive; Drug: Cyclo-Progynova; Drug: progesterone

Interventions

Duphaston DRUG

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.

the progestin primed double stimulation group

Gonadotropin DRUG

will be used for controlled ovarian hyperstimulation in both arms

Also known as: Fostimon, Menopure, Menogon, Gonapure

the flexible GnRh antagonist; the progestin primed double stimulation group

Cetrotide Injectable Product DRUG

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

the flexible GnRh antagonist

Decapeptyl DRUG

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.

the flexible GnRh antagonist; the progestin primed double stimulation group

Chorionic Gonadotropin DRUG

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.

Also known as: choriomon

the flexible GnRh antagonist

Combined Oral Contraceptive DRUG

luteal phase priming from day 21 of the cycle before controlled ovarian stimulation for one week .

Also known as: Gynera

the flexible GnRh antagonist; the progestin primed double stimulation group

Cyclo-Progynova DRUG

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.

the flexible GnRh antagonist; the progestin primed double stimulation group

progesterone DRUG

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.

Also known as: prontogest

the flexible GnRh antagonist; the progestin primed double stimulation group

Eligibility Criteria

• Age: 20 Years - 45 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• poor ovarian responders patients defined by Bologna criteria

You may not qualify if:

• Male factor infertility due to azoospermia.
• Patients with uncorrected uterine pathology.
• Patients with the diagnosis of severe endometriosis.
• Patients with BMI over 35.

Sponsors & Collaborators

• El Shatby University Hospital for Obstetrics and Gynecology: lead

Study Sites (1)

Elshatby University Maternity Hospital

Alexandria, Egypt

Location

Related Publications (15)

• 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.

  PMID: 23271957 BACKGROUND

• 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.

  PMID: 25362088 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

• 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.

  PMID: 22068695 BACKGROUND

• 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.

  PMID: 23571519 BACKGROUND

• 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.

  PMID: 25444501 BACKGROUND

• 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.

  PMID: 26209449 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

• 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.

  PMID: 27166216 BACKGROUND

• 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.

  PMID: 21558332 BACKGROUND

• 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.

  PMID: 26603821 BACKGROUND

• 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. doi: 10.1210/jcem-56-5-1022.

  PMID: 6403567 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

• 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.

  PMID: 25956370 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

MeSH Terms

Conditions

Infertility, Female

Interventions

Dydrogesterone; Gonadotropins; Menotropins; Triptorelin Pamoate; Chorionic Gonadotropin; Contraceptives, Oral, Combined; Progesterone

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Gonadotropins, Pituitary; Pituitary Hormones, Anterior; Pituitary Hormones; Peptides; Amino Acids, Peptides, and Proteins; Biological Products; Complex Mixtures; Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Neuropeptides; Oligopeptides; Nerve Tissue Proteins; Proteins; Placental Hormones; Pregnancy Proteins; Drug Combinations; Pharmaceutical Preparations; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptive Agents; Reproductive Control Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Pregnenediones; Pregnenes; Corpus Luteum Hormones; Gonadal Hormones; Progesterone Congeners; Gonadal Steroid Hormones

Results Point of Contact

• Title: Dr. Aly Hussein
• Organization: Elshatby University Maternity Hospital

emam_aly@me.com

002-0119448000

Study Officials

• Aly A Hussein, Ass.lecturer

  Elshatby University hospital

  PRINCIPAL INVESTIGATOR

• Sherif S Gaafar, Professor

  Elshatby University hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant lecturer, University of Alexandria

Study Record Dates

• First Submitted: August 28, 2020
• First Posted: September 3, 2020
• Study Start: September 1, 2020
• Primary Completion: March 1, 2021
• Study Completion: September 1, 2021
• Last Updated: February 17, 2022
• Results First Posted: February 17, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

EG (1)