Clinical trial NCT04897269: Progesterone Supplementation on Women Having Low Progesterone Levels on Transfer Day
Official title: Effectiveness of Progesterone Supplementation for Women Having Low Progesterone Levels on the Day of Frozen Embryo Transfer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Assisted Reproductive Technology
Keywords: low progesterone levels
progesterone supplementation
clinical pregnancy
Lead sponsor: Tu Du Hospital
Sponsor class: OTHER_GOV
First posted: 2021-05-21
Enrollment: 824
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients who have progesterone levels below 10 ng/mL on the day of embryo transfer will be randomized into 2 groups:

1. Those who will be supplemented with intramuscular progesterone 50mg per day till day of beta-hcg testing
2. Those who will continue their regular medications
Primary purpose: TREATMENT

Brief summary: The main objective of this study is to compare clinical pregnancy rates between two groups of women who have progesterone levels below 10 ng/mL on the day of frozen embryo transfer: group 1 (vaginal micronized progesterone supplemented with progesterone intramuscular 50 mg per day) and group 2 (vaginal micronized progesterone with no supplementation)

Detailed description: Trial Design:

Single center, longitudinal, randomized, interventional, controlled, pharmacological study, enrolling women attending clinical Centers of medically assisted reproduction (ART).

The study protocol consists in the record of all the diagnostic and clinical outcome parameters, according to clinical practice, for the following patient cohorts:

* The patients who are undergoing frozen embryo transfers with blastocyst or cleavage stage embryos and have progesterone levels below 10 ng/mL on the day of embryo transfer
* Study groups

  * Group supplemented with progesterone intramuscular 50 mg per day until the day of beta-hcg testing (Intervention group);
  * Group with no supplementation (Control group).

    * Endometrial cycle is started with estradiol valerate dose of 4 mg to 8 mg per day, the patients then are appointed to have ultrasound scan of their endometrium every 3 to 7 days and the dose of estradiol may be increased to 16 mg per day maximum depends on the thickness of endometrium; when their endometrium reach 8 mm or higher and duration of endometrial preparation is ≥ 12 days, the embryo transfer will be planned and transvaginal progesterone are prescribed according to the day of transfer.
    * If this is the first cycle of embryo transfer and she is \< 35 years of age, 1 grade 1 embryo is transferred, otherwise 2 embryos are transferred.
    * In the morning of embryo-transferred day, all patients will have their blood tested for progesterone levels, if their levels below 10 ng/mL, they will be recruited into the study and randomized into two groups.
    * In the study group, the patients will be prescribed with intramuscular progesterone supplemetation 50 mg + 800mg vaginal micronized progesterone per day for 14 days, until the day of beta-hcg testing.
    * In the control group, the patients will continue their regular medications (800mg vaginal micronized progesterone per day) until the day of beta-hcg testing without any progesterone supplementation.
    * If the beta-hcg test is positive, the patients will be continued their prescriptions depending on study or control group as mentioned above till 7 weeks of pregnancy when the fetal heart can be confirmed, then the patients will be followed up till 11 - 12 weeks of pregnancy

Eligibility criteria: Inclusion Criteria:

* Patients undergone ART with frozen embryo transfer, blastocyst or cleavaged stage embryo transfer, from 18-45 years of age
* Normal BMI
* HRT for Endometrial preparation in FET cycles

Exclusion Criteria:

* Oocyte donor cycles
* Surrogacy
* IVM
* PGT
* Abnormal Uterine (firbroids 0 -\> 3 according to FIGO classification, polyp, adenomyosis, congenital malformation)
* Uterus fibroids type 4,5 (Figo classification) \> 4cm
* History of recurrent implantation failure
* Endometrial thickness \<7mm on the day of ET
* Cesarean scar defect (isthmocele)

Primary outcomes:
measure: Ongoing pregnancy rate
timeFrame: week 11 - 14 of pregnancy
Secondary outcomes:
measure: implantation rate
timeFrame: 3 weeks after embryo transfer
measure: Pregnancy rate
timeFrame: 2 weeks after embryo transfer
measure: clinical pregnancy rate
timeFrame: 3 weeks after embryo transfer
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: Department of Infertility of Tu Du hospital
Study officials:
affiliation: Department of Infertility, Tu Du Hospital
name: Chau TM Le
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cedrin-Durnerin I, Isnard T, Mahdjoub S, Sonigo C, Seroka A, Comtet M, Herbemont C, Sifer C, Grynberg M. Serum progesterone concentration and live birth rate in frozen-thawed embryo transfers with hormonally prepared endometrium. Reprod Biomed Online. 2019 Mar;38(3):472-480. doi: 10.1016/j.rbmo.2018.11.026. Epub 2019 Jan 5.
citation: Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Alvarez M, Parriego M, Barri PN, Polyzos N, Coroleu B. Low serum progesterone the day prior to frozen embryo transfer of euploid embryos is associated with significant reduction in live birth rates. Gynecol Endocrinol. 2019 May;35(5):439-442. doi: 10.1080/09513590.2018.1534952. Epub 2018 Dec 26.
citation: Labarta E, Mariani G, Holtmann N, Celada P, Remohi J, Bosch E. Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. Hum Reprod. 2017 Dec 1;32(12):2437-2442. doi: 10.1093/humrep/dex316.
citation: Volovsky M, Pakes C, Rozen G, Polyakov A. Do serum progesterone levels on day of embryo transfer influence pregnancy outcomes in artificial frozen-thaw cycles? J Assist Reprod Genet. 2020 May;37(5):1129-1135. doi: 10.1007/s10815-020-01713-w. Epub 2020 Feb 10.
citation: Le TMC, Duong KT, Nguyen QA, Ong PT, Nguyen THN, Thai TCT, Le QT, Roque M, Alviggi C. Effectiveness of progesterone supplementation in women presenting low progesterone levels on the day of frozen embryo transfer: a randomised controlled trial. BMJ Open. 2022 Feb 23;12(2):e057353. doi: 10.1136/bmjopen-2021-057353.