Infertility, FemalePhase 3NCT04537078
Progestin Primed Double Stimulation Protocol Versus Flexible GnRH Antagonist Protocol in Poor Responders
A Phase 3 study testing Duphaston, Gonadotropin and Cetrotide Injectable Product in people with Infertility, Female, run by El Shatby University Hospital for Obstetrics and Gynecology at 1 site in Egypt.
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). Read more about this study
- Who is it for?
- Ages 20 to 45 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Infertility, Female
- What is being tested?
- Duphaston, Gonadotropin and Cetrotide Injectable Product
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 1 siteEgypt
- Study dates
- 1 Sep 2020to 1 Sep 2021
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 45 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- poor ovarian responders patients defined by Bologna criteria
Who cannot join
- Male factor infertility due to azoospermia.
- Patients with uncorrected uterine pathology.
- Patients with the diagnosis of severe endometriosis.
- Patients with BMI over 35.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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.
Read the detailed 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:
- Complete history taking and full assessment of different infertility factors.
- Hormonal investigations
- FSH, LH, E2, Prolactin
- AMH, TSH
- Basal transvaginal ultrasound
Clinical and embryological procedures:
Group 1:
- The follicular phase of the double stimulation protocol
- 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).
- 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.
- Dydrogesterone (Duphaston, Abbott company, Illinois, United states) at 20 mg/day will be started from the first day of the ovulation induction.
- Patient response will be monitored by:
- Transvaginal follicular scanning and the dose of the gonadotropins will be modified according to the response.
- Serum estradiol.
- Serum progesterone and LH on the day of triggering.
- 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.
- Oocyte pickup will be done 36 hours after GnRh administration with precaution of leaving the follicles measuring 11 mm or less.
- 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.
- 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:
- 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).
- 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.
- GnRH antagonist ( Cetrotide , Merck Serono, Darmstadt, Germany) will be given daily as the biggest oocyte reaches size 14 mm.
- Patient response will be monitored by:
- Transvaginal follicular scanning and the dose of the gonadotropins will be modified according to the response.
- Serum estradiol.
- Serum progesterone on the day of triggering.
- 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.
- Oocyte pickup will be done 36 hours after GnRh administration.
- 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.
- Conditions
- Infertility, Female
- Being tested
- Duphaston, Gonadotropin, Cetrotide Injectable Product, Decapeptyl, Chorionic Gonadotropin
- Medical subject headings
- Infertility, Female
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DuphastonDrug
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.
GonadotropinDrug
Also called Fostimon, Menopure, Menogon, Gonapure
will be used for controlled ovarian hyperstimulation in both arms
Cetrotide Injectable ProductDrug
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
DecapeptylDrug
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 GonadotropinDrug
Also called choriomon
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 ContraceptiveDrug
Also called Gynera
luteal phase priming from day 21 of the cycle before controlled ovarian stimulation for one week .
Cyclo-ProgynovaDrug
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.
progesteroneDrug
Also called prontogest
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Gonadotropin; Drug: Cetrotide Injectable Product; Drug: Decapeptyl; Drug: Chorionic Gonadotropin; Drug: Combined Oral Contraceptive; Drug: Cyclo-Progynova; Drug: progesterone |
What is being measured
The primary outcome is the main question the study is designed to answer.
the Number of M2 Oocytes Retrieved
it is the number of M2 oocytes retrieved that were being assessed after denudation
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: at the 6 th weeks of pregnancy
Secondary outcomes (9)
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
Measured: 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
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
Measured: 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
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
Measured: 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
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
Measured: 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.
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
Measured: 16 to 20 hours after microinjection of the oocytes with the sperms
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
Measured: the embryos number counted day 3 or 4or 5 after fertilization
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
Measured: 1-2 hours after oocyte retrieval
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
Measured: 16 to 20 hours after microinjection of the oocytes by the sperms
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
Measured: at day 3 or 4or 5 after fertilization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Sep 2020
- Study start1 Sep 2020
- Primary completion1 Mar 2021
- Study completion1 Sep 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Infertility, FemaleStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 90 participants (actual)
Sponsor and investigators
- Lead sponsor
- El Shatby University Hospital for Obstetrics and Gynecology
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Aly Hussein, El Shatby University Hospital for Obstetrics and Gynecology
- Investigators
- Aly A Hussein, Ass.lecturer, Principal investigator, Elshatby University hospitalSherif S Gaafar, Professor, Principal investigator, Elshatby University hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04537078
- Sponsor's protocol ID
- 0201350
- Status last verified
- Jan 2022
- First submitted
- 28 Aug 2020
- Last updated
- 17 Feb 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 23271957Briggs 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.
PubMed 25362088Drakopoulos 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.
PubMed 26724797Baerwald 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.
PubMed 22068695Vanden 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.
PubMed 23571519Kuang 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.
PubMed 25444501Zhang 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.
PubMed 26209449Liu 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.
PubMed 29030068Zhang 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.
PubMed 27166216Sunkara 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.
PubMed 21558332Wang 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.
PubMed 26603821McNatty 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.
PubMed 6403567Moffat 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.
PubMed 25311972Kuang 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.
PubMed 25956370Ferraretti 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.
PubMed 21505041
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Progestin Primed Double Stimulation Protocol Versus Flexible GnRH Antagonist Protocol in Poor Responders
- ClinicalTrials.gov ID
- NCT04537078
- Acronym / sponsor ID
- 0201350
- Conditions
- Infertility, Female
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 90 participants (actual)
- Lead sponsor
- El Shatby University Hospital for Obstetrics and GynecologyUniversity, hospital or other
- Study start
- 1 Sep 2020 (actual)
- Primary completion
- 1 Mar 2021 (actual)
- Study completion
- 1 Sep 2021 (actual)
- First posted
- 3 Sep 2020 (actual)
- Results
- Posted 17 Feb 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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:
- Complete history taking and full assessment of different infertility factors.
- Hormonal investigations
- FSH, LH, E2, Prolactin
- AMH, TSH
- Basal transvaginal ultrasound
Clinical and embryological procedures:
Group 1:
- The follicular phase of the double stimulation protocol
- 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).
- 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.
- Dydrogesterone (Duphaston, Abbott company, Illinois, United states) at 20 mg/day will be started from the first day of the ovulation induction.
- Patient response will be monitored by:
- Transvaginal follicular scanning and the dose of the gonadotropins will be modified according to the response.
- Serum estradiol.
- Serum progesterone and LH on the day of triggering.
- 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.
- Oocyte pickup will be done 36 hours after GnRh administration with precaution of leaving the follicles measuring 11 mm or less.
- 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.
- 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:
- 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).
- 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.
- GnRH antagonist ( Cetrotide , Merck Serono, Darmstadt, Germany) will be given daily as the biggest oocyte reaches size 14 mm.
- Patient response will be monitored by:
- Transvaginal follicular scanning and the dose of the gonadotropins will be modified according to the response.
- Serum estradiol.
- Serum progesterone on the day of triggering.
- 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.
- Oocyte pickup will be done 36 hours after GnRh administration.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| the progestin primed double stimulation group | Active comparator | Drug: Duphaston, Drug: Gonadotropin, Drug: Decapeptyl, Drug: Combined Oral Contraceptive, Drug: Cyclo-Progynova, Drug: progesteroneluteal 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. |
| the flexible GnRh antagonist | Active comparator | Drug: Gonadotropin, Drug: Cetrotide Injectable Product, Drug: Decapeptyl, Drug: Chorionic Gonadotropin, Drug: Combined Oral Contraceptive, Drug: Cyclo-Progynova, Drug: progesteroneThis 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. |
Who may qualify
- Ages
- 20 to 45 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- poor ovarian responders patients defined by Bologna criteria
Key exclusion criteria (4 listed)
- Male factor infertility due to azoospermia.
- Patients with uncorrected uterine pathology.
- Patients with the diagnosis of severe endometriosis.
- Patients with BMI over 35.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Duphastonwill 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. | Drug | the progestin primed double stimulation group |
| GonadotropinAlso: Fostimon, Menopure, Menogon, Gonapurewill be used for controlled ovarian hyperstimulation in both arms | Drug | the flexible GnRh antagonist, the progestin primed double stimulation group |
| Cetrotide Injectable Productwill used in the second arm for pituitary suppression in the second group daily when the biggest oocyte reaches size 14 mm till ovulation triggering | Drug | the flexible GnRh antagonist |
| Decapeptylwill 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. | Drug | the flexible GnRh antagonist, the progestin primed double stimulation group |
| Chorionic GonadotropinAlso: choriomonwill 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. | Drug | the flexible GnRh antagonist |
| Combined Oral ContraceptiveAlso: Gyneraluteal phase priming from day 21 of the cycle before controlled ovarian stimulation for one week . | Drug | the flexible GnRh antagonist, the progestin primed double stimulation group |
| Cyclo-ProgynovaStarting 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. | Drug | the flexible GnRh antagonist, the progestin primed double stimulation group |
| progesteroneAlso: prontogestin 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. | Drug | the flexible GnRh antagonist, the progestin primed double stimulation group |
Primary outcome
the Number of M2 Oocytes Retrieved
Time frame: 1-2 hours after oocyte retrieval
it is the number of M2 oocytes retrieved that were being assessed after denudation
the Fertilization Rate
Time frame: 16 to 20 hours after microinjection of the oocytes with the sperms
percentage transformation of micro injected oocytes into two pronuclei. it is done 16 to 20 hours after microinjection of the oocytes by the sperms
the Resultant Embryos Number
Time frame: the embryos number counted day 3 or 4or 5 after fertilization
it is the resultant embryos number counted day 3 or 4 or 5 after fertilization
the Implantation Rate
Time frame: at the 6 th week of pregnancy
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
the Clinical Pregnancy Rate.
Time frame: at the 6 th weeks of pregnancy
percentage of cases in which observation of a gestational sac with fetal heart beat by transvaginal ultrasound at 6 weeks of pregnancy
9 secondary outcomes
the Difference in the Ongoing Pregnancy Rate in Both Protocols.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 16 to 20 hours after microinjection of the oocytes with the sperms
the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Resultant Embryos Number
Time frame: the embryos number counted day 3 or 4or 5 after fertilization
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 .
Time frame: 1-2 hours after oocyte retrieval
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.
Time frame: 16 to 20 hours after microinjection of the oocytes by the sperms
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.
Time frame: at day 3 or 4or 5 after fertilization
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 23271957Mascarenhas 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.
- Background: PubMed 25362088Briggs 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.
- Background: PubMed 26724797Drakopoulos 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.
- Background: PubMed 22068695Baerwald 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.
- Background: PubMed 23571519Vanden 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.
- Background: PubMed 25444501Kuang 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.
- Background: PubMed 26209449Zhang 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.
- Background: PubMed 29030068Liu 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.
- Background: PubMed 27166216Zhang 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.
- Background: PubMed 21558332Sunkara 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.
- Background: PubMed 26603821Wang 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.
- Background: PubMed 6403567McNatty 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Aly A Hussein, Ass.lecturer principal investigator
Elshatby University hospital
Sherif S Gaafar, Professor principal investigator
Elshatby University hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Duphaston, Gonadotropin and Cetrotide Injectable Product in people with Infertility, Female, run by El Shatby University Hospital for Obstetrics and Gynecology at 1 site in Egypt.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Egypt. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
the Number of M2 Oocytes Retrieved (time frame: 1-2 hours after oocyte retrieval). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04537078, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2022.