Individualized Prolonged Luteal Support After Fresh Embryo Transfer in Women With Low Progesterone (ProLIS)
Interest of Individualized Prolongation of Subcutaneous Luteal Phase Support up to 8 Weeks for Patients Pregnant After a Fresh Embryo Transfer and With Low Serum Progesterone Level at Pregnancy Test - a Multicentric Randomized Double Blinded Controlled Trial
The goal of this clinical trial is to compare live birth rate in a control group versus an interventional group in subjects aged 18 to 37, pregnant after a fresh embryo transfer and with a serum progesterone level below 17 ng/mL on the day of pregnancy test while using vaginal progesterone as a luteal support. .
This is the first randomized controlled trial to assess the benefit of prolonged subcutaneous progesterone administration in patients with a positive pregnancy test (Bêta chorionique gonadotropic hormone: β-hCG >100 IU/L) after fresh transfer and low progesterone level (<17 ng/mL).
Half the participants will be offered a an extension of luteal phase support , by subcutaneous progesterone supplementation for 6 weeks, the other half will have placebo injections. A double-blind, placebo-controlled, randomized design was chosen to prevent selection bias and ensure the comparability of both study arms.
Přehled studie
Postavení
Intervence / Léčba
Detailní popis
Introduction:
Progesterone is essential for implantation and early pregnancy maintenance. After ovarian stimulation for In vitro fertilization (IVF), luteal phase insufficiency may occur, requiring luteal phase support (LPS) with exogenous progesterone. Recent data suggest that patients with low serum progesterone levels (<17 ng/mL) at positive pregnancy test after fresh embryo transfer have lower live birth rates and higher miscarriage rates despite standard vaginal LPS.
Aim:
The primary objective of the study is to compare live birth rates between:
- a control group receiving standard luteal phase support with vaginal progesterone until pregnancy test and placebo subcutaneous injections until 8 weeks of gestation, and
- an intervention group receiving prolonged luteal phase support with subcutaneous progesterone until 8 weeks of gestation.
Secondary objectives include comparison of clinical pregnancy rate, ongoing pregnancy rate, miscarriage rate, treatment-related adverse events, obstetrical and neonatal outcomes, gestational age at delivery, birth weight, and cost-effectiveness of the individualized prolonged luteal support strategy.
An ancillary biological sub-study conducted at Montpellier University Hospital will assess serum 17-hydroxyprogesterone and estradiol levels at inclusion.
Methods:
This study is a phase III, multicenter, randomized, double-blind, placebo-controlled trial.
Women aged 18-37 years with positive pregnancy test (Bêta chorionique gonadotropic hormone: β-hCG >100 IU/L) and serum progesterone <17 ng/mL after fresh embryo transfer will be randomized (1:1) to receive either:
- subcutaneous progesterone (PROGIRON®) for 6 weeks, or
- matching placebo for 6 weeks. To ensure adequate progesterone exposure during treatment initiation, vaginal progesterone (PROGESTAN®) will be continued for the first 4 days after randomization in both groups.
Participants will be followed until delivery. A total of 214 participants will be enrolled across multiple In vitro fertilization (IVF) centers.
Typ studie
Zápis (Odhadovaný)
Fáze
- Fáze 3
Kontakty a umístění
Studijní kontakt
- Jméno: Noémie RANISAVLJEVIC, MD, PhD
- Telefonní číslo: +33467336481
- E-mail: n-ranisavljevic@chu-montpellier.fr
Studijní záloha kontaktů
- Jméno: Tal ANAHORY, MD
- Telefonní číslo: +33467335955
- E-mail: t-anahory@chu-montpellier.fr
Studijní místa
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Montpellier, Francie, 34295
- CHU de Montpellier
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Kontakt:
- Noémie RANISAVLJEVIC, MD, PhD
- Telefonní číslo: +33467336481
- E-mail: n-ranisavljevic@chu-montpellier.fr
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
- Dospělý
Přijímá zdravé dobrovolníky
Popis
Inclusion Criteria:
- Patient aged 18 to 37 year-old;
- Patients with a BMI below 34 kg/m2;
- After a fresh embryo transfer following an ovarian hyperstimulation for an IVF with a luteal phase support based on micronized vaginal progesterone;
- With a positive pregnancy test (β-hCG > 100 UI/L);
- With a serum progesterone level below 17 ng/mL on the day of pregnancy test;
- Patient able to self-administer subcutaneous progesterone injections, either alone or with the help of her partner.
Exclusion Criteria:
- Patient undertaking an additional source of progesterone (oral or injected) or a treatment stimulating endogenous progesterone secretion (such as Gonadotropin-Releasing Hormone: GnRH agonist, or chorionique gonadotropic hormone: hCG injections);
- Patients with intolerance or contraindication to subcutaneous progesterone administration;
- Patients with a known 21-hydroxylase deficiency;
- Patients with uterine pathology or untreated hydrosalpinx;
- Patients with a history of recurrent miscarriages (3 or more);
- Patient undergoing pre-implantation genetic testing;
- Patient unavailable or unwilling to participate in future visits or is unable to comply with trial protocol;
- Subjects unable to read or/and write French;
- Failure to obtain the consent;
- Subjects non-beneficiary of the French social security (Government medical aid (AME) excluded);
- Subjects placed under legal protection, under guardianship or under curatorship;
- Patient in an exclusion period determined by a previous study;
- Subjects participating in another interventional research.
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: Randomizované
- Intervenční model: Paralelní přiřazení
- Maskování: Dvojnásobek
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
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Komparátor placeba: Control group
Discontinuation of luteal phase support with a subcutaneous placebo daily until 8 weeks of gestation (for 6 weeks). Vaginal progesterone will be continued for 4 days after placebo initiation. Apart from these 4 days of transition treatment, the patient will not receive any additional treatment for luteal phase support (discontinuation of progesterone soft capsule administration according to the center's standard practice). |
One injection of PLACEBO (identical in appearance to the PROGIRON® pre-filled syringe) per day will be administered until 8 weeks of gestation (Day 1 to Day 42).
Ostatní jména:
Vaginal progesterone treatment with PROGESTAN® (200 mg 3 times daily) will be continued for 4 days after initiation of the investigational medicinal product (Day 1 to Day 4), pending achievement of stable progesterone serum concentrations with injectable progesterone.
Ostatní jména:
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Experimentální: Experimental group
Prolonged luteal phase support, switched to subcutaneous progesterone 25 mg daily until 8 weeks of gestation (for 6 weeks). Vaginal progesterone will be continued for 4 days after subcutaneous progesterone initiation to ensure adequate serum levels while awaiting steady-state concentration of subcutaneous progesterone. Apart from these 4 days of transition treatment, the patient will not receive any additional treatment for luteal phase support (discontinuation of progesterone soft capsule administration according to the center's standard practice). |
Vaginal progesterone treatment with PROGESTAN® (200 mg 3 times daily) will be continued for 4 days after initiation of the investigational medicinal product (Day 1 to Day 4), pending achievement of stable progesterone serum concentrations with injectable progesterone.
Ostatní jména:
One injection of PROGIRON® (25 mg pre-filled syringe) per day will be administered until 8 weeks of gestation (Day 1 to Day 42).
Ostatní jména:
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Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Live birth rate
Časové okno: At postpartum follow-up (Visit 4: Month 9 ±1 month)
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Defined as a birth of at least one live born baby, weighing 500 g or more or 20 weeks or more of gestation, with the birth of twins counted as one live birth.
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At postpartum follow-up (Visit 4: Month 9 ±1 month)
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Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Clinical pregnancy rate
Časové okno: At first trimester follow-up (Visit 3: Week 12-14 of gestation)
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Defined as ultrasound visualization of a gestational sac, excluding ectopic pregnancy. Multiple gestational sacs in one participant will be counted as one clinical pregnancy |
At first trimester follow-up (Visit 3: Week 12-14 of gestation)
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Ongoing pregnancy rate
Časové okno: At first trimester follow-up (Visit 3: Week 12-14 of gestation)
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Defined as a viable intrauterine pregnancy at ≥12 weeks of gestation.
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At first trimester follow-up (Visit 3: Week 12-14 of gestation)
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Miscarriage rate
Časové okno: From inclusion (Visit 1: positive pregnancy test or the following day) to 20 weeks of gestation
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Defined as spontaneous pregnancy loss before 20 weeks of gestation, including early pregnancy loss (<12 weeks) and late pregnancy loss (12-20 weeks).
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From inclusion (Visit 1: positive pregnancy test or the following day) to 20 weeks of gestation
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Incidence of treatment-related adverse events
Časové okno: From inclusion (Visit 1: positive pregnancy test or the following day) to follow-up (Visit 2: Week 6-7 after test +)
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Incidence of adverse events reported during the intervention period.
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From inclusion (Visit 1: positive pregnancy test or the following day) to follow-up (Visit 2: Week 6-7 after test +)
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Incidence of obstetrical and neonatal complications
Časové okno: At postpartum follow-up (Visit 4: Month 9 ±1 month)
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Including premature rupture of membranes, preterm labor or delivery, fetal growth restriction, hypertensive disorders, pre-eclampsia, gestational diabetes, macrosomia, placental abnormalities, birth defects, stillbirth, perinatal death, and neonatal hospitalization.
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At postpartum follow-up (Visit 4: Month 9 ±1 month)
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Birth weight
Časové okno: At postpartum follow-up (Visit 4: Month 9 ±1 month)
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Weight of the newborn at delivery.
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At postpartum follow-up (Visit 4: Month 9 ±1 month)
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Gestational age at delivery
Časové okno: At postpartum follow-up (Visit 4: Month 9 ±1 month)
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Gestational age in weeks at the time of delivery.
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At postpartum follow-up (Visit 4: Month 9 ±1 month)
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Incremental cost-effectiveness ratio (ICER)
Časové okno: From inclusion (Visit 1: Positive pregnancy test or the following day) to postpartum follow-up (Visit 4: Month 9 ±1 month)
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Cost-effectiveness analysis comparing prolonged subcutaneous progesterone versus placebo, with effectiveness defined by live birth rate.
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From inclusion (Visit 1: Positive pregnancy test or the following day) to postpartum follow-up (Visit 4: Month 9 ±1 month)
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Další výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Serum 17-hydroxyprogesterone level
Časové okno: At inclusion (Visit 1: positive pregnancy test or the following day)
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Sub-study objectives, only for participants from Montpellier University Hospital the serum levels of 17-hydroxy-progesterone (ng/mL) will be investigated on the day of inclusion.
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At inclusion (Visit 1: positive pregnancy test or the following day)
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Serum estradiol level
Časové okno: At inclusion (Visit 1: positive pregnancy test or the following day)
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Sub-study objectives, only for participants from Montpellier University Hospital the serum levels of estradiol (pg/mL) will be investigated on the day of inclusion.
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At inclusion (Visit 1: positive pregnancy test or the following day)
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Spolupracovníci a vyšetřovatelé
Sponzor
Spolupracovníci
Vyšetřovatelé
- Vrchní vyšetřovatel: Noémie RANISAVLJEVIC, MD, PhD, University Hospital, Montpellier
- Studijní židle: Tal ANAHORY, MD, University Hospital, Montpellier
Publikace a užitečné odkazy
Obecné publikace
- van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2015 Jul 7;2015(7):CD009154. doi: 10.1002/14651858.CD009154.pub3.
- Melo P, Chung Y, Pickering O, Price MJ, Fishel S, Khairy M, Kingsland C, Lowe P, Petsas G, Rajkhowa M, Sephton V, Tozer A, Wood S, Labarta E, Wilcox M, Devall A, Gallos I, Coomarasamy A. Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis. Fertil Steril. 2021 Dec;116(6):1534-1556. doi: 10.1016/j.fertnstert.2021.07.002. Epub 2021 Aug 10.
- Sator M, Radicioni M, Cometti B, Loprete L, Leuratti C, Schmidl D, Garhofer G. Pharmacokinetics and safety profile of a novel progesterone aqueous formulation administered by the s.c. route. Gynecol Endocrinol. 2013 Mar;29(3):205-8. doi: 10.3109/09513590.2012.736560. Epub 2012 Nov 6.
- Eijkemans MJC, Kersten FAM, Lintsen AME, Hunault CC, Bouwmans CAM, Roijen LH, Habbema JDF, Braat DDM. Cost-effectiveness of 'immediate IVF' versus 'delayed IVF': a prospective study. Hum Reprod. 2017 May 1;32(5):999-1008. doi: 10.1093/humrep/dex018.
- Aslih N, Ellenbogen A, Shavit T, Michaeli M, Yakobi D, Shalom-Paz E. Can we alter pregnancy outcome by adjusting progesterone treatment at mid-luteal phase: a randomized controlled trial. Gynecol Endocrinol. 2017 Aug;33(8):602-606. doi: 10.1080/09513590.2017.1298742. Epub 2017 Mar 9.
- Cedrin-Durnerin I, Bstandig B, Herve F, Wolf J, Uzan M, Hugues J. A comparative study of high fixed-dose and decremental-dose regimens of gonadotropins in a minidose gonadotropin-releasing hormone agonist flare protocol for poor responders. Fertil Steril. 2000 May;73(5):1055-6. doi: 10.1016/s0015-0282(00)00471-4. No abstract available.
- Cozzolino M, Hervas I, Ergun Y, Massaro MG, Pellicer N, de Angelis F, Labarta E, Galliano D. Higher serum progesterone level has no negative impact on live birth rate in frozen embryo transfer. Eur J Obstet Gynecol Reprod Biol. 2024 Dec;303:15-21. doi: 10.1016/j.ejogrb.2024.10.011. Epub 2024 Oct 9.
- Duport Percier M, Brouillet S, Mollevi C, Duraes M, Anahory T, Ranisavljevic N. Serum progesterone concentration on pregnancy test day might predict ongoing pregnancy after controlled ovarian stimulation and fresh embryo transfer. Front Endocrinol (Lausanne). 2023 Jun 26;14:1191648. doi: 10.3389/fendo.2023.1191648. eCollection 2023.
- Griesinger G. Editorial commentary: is it time to abandon progesterone supplementation of early pregnancy after IVF? Hum Reprod. 2011 May;26(5):1017-9. doi: 10.1093/humrep/der013. Epub 2011 Feb 4. No abstract available.
- Ioannidis G, Sacks G, Reddy N, Seyani L, Margara R, Lavery S, Trew G. Day 14 maternal serum progesterone levels predict pregnancy outcome in IVF/ICSI treatment cycles: a prospective study. Hum Reprod. 2005 Mar;20(3):741-6. doi: 10.1093/humrep/deh644. Epub 2004 Dec 9.
- Kawachiya S, Bodri D, Hirosawa T, Yao Serna J, Kuwahara A, Irahara M. Endogenous progesterone levels could predict reproductive outcome in frozen embryo replacement cycles supplemented with synthetic progestogens: A retrospective cohort study. Reprod Med Biol. 2018 Nov 1;18(1):91-96. doi: 10.1002/rmb2.12254. eCollection 2019 Jan.
- Kawwass JF, Kulkarni AD, Hipp HS, Crawford S, Kissin DM, Jamieson DJ. Extremities of body mass index and their association with pregnancy outcomes in women undergoing in vitro fertilization in the United States. Fertil Steril. 2016 Dec;106(7):1742-1750. doi: 10.1016/j.fertnstert.2016.08.028. Epub 2016 Sep 22.
- Levy T, Yairi Y, Bar-Hava I, Shalev J, Orvieto R, Ben-Rafael Z. Pharmacokinetics of the progesterone-containing vaginal tablet and its use in assisted reproduction. Steroids. 2000 Oct-Nov;65(10-11):645-9. doi: 10.1016/s0039-128x(00)00121-5.
- Petersen JF, Andersen AN, Klein BM, Helmgaard L, Arce JC. Luteal phase progesterone and oestradiol after ovarian stimulation: relation to response and prediction of pregnancy. Reprod Biomed Online. 2018 Apr;36(4):427-434. doi: 10.1016/j.rbmo.2017.12.019. Epub 2018 Jan 17.
- Segal L, Breyzman T, Kol S. Luteal phase support post IVF: individualized early stop. Reprod Biomed Online. 2015 Nov;31(5):633-7. doi: 10.1016/j.rbmo.2015.07.011. Epub 2015 Aug 10.
Užitečné odkazy
- Haute Autorité de Santé. Choix méthodologiques pour l'évaluation économique à l'HAS. Saint-Denis La Plaine: HAS; 2020
- Drummond, M. (2015). Methods for the economic evaluation of health care programmes. Oxford, United Kingdom; 4th Edition (November 24, 2015). New York, NY, USA, Oxford University Press.
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Odhadovaný)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
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