Clinical trial NCT04537078: Progestin Primed Double Stimulation Protocol Versus Flexible GnRH Antagonist Protocol in Poor Responders
Official title: Progestin Primed Double Stimulation Protocol Versus Flexible GnRH Antagonist Protocol in Poor Responders
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infertility, Female
Lead sponsor: El Shatby University Hospital for Obstetrics and Gynecology
Sponsor class: OTHER
First posted: 2020-09-03
Enrollment: 90
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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:

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.

Eligibility criteria: 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.

Primary outcomes:
measure: the Number of M2 Oocytes Retrieved
timeFrame: 1-2 hours after oocyte retrieval
measure: the Fertilization Rate
timeFrame: 16 to 20 hours after microinjection of the oocytes with the sperms
measure: the Resultant Embryos Number
timeFrame: the embryos number counted day 3 or 4or 5 after fertilization
measure: the Implantation Rate
timeFrame: at the 6 th week of pregnancy
measure: the Clinical Pregnancy Rate.
timeFrame: at the 6 th weeks of pregnancy
Secondary outcomes:
measure: the Difference in the Ongoing Pregnancy Rate in Both Protocols.
timeFrame: At the 20 th week of gestation
measure: 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
timeFrame: From the first day of ovarian stimulation till the last day of ovarian stimulation in each phase ,the follicular and the luteal, of stimulation
measure: 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
timeFrame: From the first day of ovarian stimulation till the last day of ovarian stimulation in each phase ,the follicular and the luteal, of stimulation
measure: the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Number of M2 Oocytes Retrieved
timeFrame: 1-2 hours after oocyte retrieval
measure: the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Fertilization Rate.
timeFrame: 16 to 20 hours after microinjection of the oocytes with the sperms
measure: the Difference Between the Follicular Phase and the Luteal Phase of the Progestin Primed Double Stimulation Protocol Regarding the Resultant Embryos Number
timeFrame: the embryos number counted day 3 or 4or 5 after fertilization
measure: 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 .
timeFrame: 1-2 hours after oocyte retrieval
measure: 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.
timeFrame: 16 to 20 hours after microinjection of the oocytes by the sperms
measure: 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.
timeFrame: at day 3 or 4or 5 after fertilization
Other outcomes:
Locations:
city: Alexandria
country: Egypt
facility: Elshatby University Maternity Hospital
Study officials:
affiliation: Elshatby University hospital
name: Aly A Hussein, Ass.lecturer
role: PRINCIPAL_INVESTIGATOR
affiliation: Elshatby University hospital
name: Sherif S Gaafar, Professor
role: PRINCIPAL_INVESTIGATOR
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