Individualized Prolonged Luteal Support After Fresh Embryo Transfer in Women With Low Progesterone

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Progesterone Injectable
  One injection of PROGIRON® (25 mg pre-filled syringe) per day will be administered until 8 weeks of gestation (Day 1 to Day 42).
• Препарат Placebo
  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).
• Препарат Progesterone Vaginal Suppository
  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.

Первичные конечные точки

• Live birth rate [Срок оценки: At postpartum follow-up (Visit 4: Month 9 ±1 month)]

Вторичные конечные точки (8)

• Clinical pregnancy rate [Срок оценки: At first trimester follow-up (Visit 3: Week 12-14 of gestation)]
• Ongoing pregnancy rate [Срок оценки: At first trimester follow-up (Visit 3: Week 12-14 of gestation)]
• Miscarriage rate [Срок оценки: From inclusion (Visit 1: positive pregnancy test or the following day) to 20 weeks of gestation]
• Incidence of treatment-related adverse events [Срок оценки: From inclusion (Visit 1: positive pregnancy test or the following day) to follow-up (Visit 2: Week 6-7 after test +)]
• Incidence of obstetrical and neonatal complications [Срок оценки: At postpartum follow-up (Visit 4: Month 9 ±1 month)]
• Birth weight [Срок оценки: At postpartum follow-up (Visit 4: Month 9 ±1 month)]
• Gestational age at delivery [Срок оценки: At postpartum follow-up (Visit 4: Month 9 ±1 month)]
• Incremental cost-effectiveness ratio (ICER) [Срок оценки: From inclusion (Visit 1: Positive pregnancy test or the following day) to postpartum follow-up (Visit 4: Month 9 ±1 month)]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

• CHU de Montpellier — Montpellier

Публикации

• 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. PMID 28204519
• 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. PMID 28277886
• 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. PMID 10785239
• 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. PMID 39395245
• 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. PMID 37455896
• 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. PMID 21296804
• 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. PMID 15591085
• 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. PMID 30655726

Идентификаторы

NCT: NCT07613528 · RECHMPL_25_0581 · 2026-525452-28-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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