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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04537078
Recruitment Status : Completed
First Posted : September 3, 2020
Results First Posted : February 17, 2022
Last Update Posted : February 17, 2022
Sponsor:
Information provided by (Responsible Party):
Aly Hussein, El Shatby University Hospital for Obstetrics and Gynecology

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.


Condition or disease Intervention/treatment Phase
Infertility, Female Drug: Duphaston Drug: Gonadotropin Drug: Cetrotide Injectable Product Drug: Decapeptyl Drug: Chorionic Gonadotropin Drug: Combined Oral Contraceptive Drug: Cyclo-Progynova Drug: progesterone Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Progestin Primed Double Stimulation Protocol Versus Flexible GnRH Antagonist Protocol in Poor Responders
Actual Study Start Date : September 1, 2020
Actual Primary Completion Date : March 1, 2021
Actual Study Completion Date : September 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: the progestin primed double stimulation group
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
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.

Drug: Gonadotropin
will be used for controlled ovarian hyperstimulation in both arms
Other Names:
  • Fostimon
  • Menopure
  • Menogon
  • Gonapure

Drug: 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.

Drug: Combined Oral Contraceptive
luteal phase priming from day 21 of the cycle before controlled ovarian stimulation for one week .
Other Name: Gynera

Drug: 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.

Drug: 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.
Other Name: prontogest

Active Comparator: the flexible GnRh antagonist
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
will be used for controlled ovarian hyperstimulation in both arms
Other Names:
  • Fostimon
  • Menopure
  • Menogon
  • Gonapure

Drug: 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

Drug: 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.

Drug: 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.
Other Name: choriomon

Drug: Combined Oral Contraceptive
luteal phase priming from day 21 of the cycle before controlled ovarian stimulation for one week .
Other Name: Gynera

Drug: 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.

Drug: 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.
Other Name: prontogest




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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


Secondary Outcome Measures :
  1. the Difference in the Ongoing Pregnancy Rate in Both Protocols. [ Time Frame: At the 20 th week of gestation ]
    Assessing the difference in the ongoing pregnancy rate when the pregnancy had completed ≥20 weeks of gestation

  2. 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 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

  3. 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 ]
    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

  4. 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 ]
    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

  5. 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 ]
    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

  6. 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 ]
    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

  7. 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 ]
    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

  8. 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 ]
    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

  9. 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 ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04537078


Locations
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Egypt
Elshatby University Maternity Hospital
Alexandria, Egypt
Sponsors and Collaborators
El Shatby University Hospital for Obstetrics and Gynecology
Investigators
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Principal Investigator: Aly A Hussein, Ass.lecturer Elshatby University hospital
Principal Investigator: Sherif S Gaafar, Professor Elshatby University hospital
  Study Documents (Full-Text)

Documents provided by Aly Hussein, El Shatby University Hospital for Obstetrics and Gynecology:
Publications:

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Responsible Party: Aly Hussein, Assistant lecturer, University of Alexandria, El Shatby University Hospital for Obstetrics and Gynecology
ClinicalTrials.gov Identifier: NCT04537078    
Other Study ID Numbers: 0201350
First Posted: September 3, 2020    Key Record Dates
Results First Posted: February 17, 2022
Last Update Posted: February 17, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Infertility
Infertility, Female
Triptorelin Pamoate
Contraceptive Agents
Contraceptives, Oral
Chorionic Gonadotropin
Cetrorelix
Contraceptives, Oral, Combined
Progesterone
Dydrogesterone
Estradiol
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Reproductive Control Agents
Contraceptive Agents, Female
Luteolytic Agents
Contraceptive Agents, Hormonal
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Fertility Agents, Female
Fertility Agents
Hormone Antagonists
Estrogens