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

NCT07613528 | Not Yet Recruiting Phase 3

• 2 other identifiers: RECHMPL_25_05812026-525452-28-00
• Study Type: interventional
• Target: 214
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pregnancy; Progesterone Supplementation; Low Serum Progesterone

Keywords

luteal phase support; Serum progesterone level; individualized treatment; fresh embryo transfer; live birth rate

Outcome Measures

Primary Outcomes (1)

• Live birth rate

  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.

  At postpartum follow-up (Visit 4: Month 9 ±1 month)

Secondary Outcomes (8)

• Clinical pregnancy rate

  At first trimester follow-up (Visit 3: Week 12-14 of gestation)

• Ongoing pregnancy rate

  At first trimester follow-up (Visit 3: Week 12-14 of gestation)

• Miscarriage rate

  From inclusion (Visit 1: positive pregnancy test or the following day) to 20 weeks of gestation

• Incidence of treatment-related adverse events

  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

  At postpartum follow-up (Visit 4: Month 9 ±1 month)

Other Outcomes (2)

• Serum 17-hydroxyprogesterone level

  At inclusion (Visit 1: positive pregnancy test or the following day)

• Serum estradiol level

  At inclusion (Visit 1: positive pregnancy test or the following day)

Study Arms (2)

Control group

PLACEBO COMPARATOR

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).

Drug: Placebo; Drug: Progesterone Vaginal Suppository

Experimental group

EXPERIMENTAL

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).

Drug: Progesterone Injectable; Drug: Progesterone Vaginal Suppository

Interventions

Placebo DRUG

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).

Also known as: PLACEBO, injectable solution

Control group

Progesterone Vaginal Suppository DRUG

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.

Also known as: PROGESTAN 200 mg, vaginal soft capsule

Control group; Experimental group

Progesterone Injectable DRUG

One injection of PROGIRON® (25 mg pre-filled syringe) per day will be administered until 8 weeks of gestation (Day 1 to Day 42).

Also known as: PROGIRON 25 mg, injectable solution

Experimental group

Eligibility Criteria

• Age: 18 Years - 37 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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;
• Subjects participating in another interventional research.

Sponsors & Collaborators

• IBSA Institut Biochimique SA: collaborator
• Hospices Civils de Lyon: collaborator
• Direction Générale de l'Offre de Soins: collaborator
• University Hospital, Montpellier: lead

Study Sites (1)

CHU de Montpellier

Montpellier, 34295, France

Location

Related Publications (15)

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• 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.

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• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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.

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• 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 BACKGROUND

• 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.

  PMID: 27666564 BACKGROUND

• 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.

  PMID: 11108871 BACKGROUND

• 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.

  PMID: 34384594 BACKGROUND

• 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.

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• 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.

  PMID: 23127204 BACKGROUND

• 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.

  PMID: 26371712 BACKGROUND

• 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.

  PMID: 26148507 BACKGROUND

Related Links

• 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.

Study Officials

• Noémie RANISAVLJEVIC, MD, PhD

  University Hospital, Montpellier

  PRINCIPAL INVESTIGATOR

• Tal ANAHORY, MD

  University Hospital, Montpellier

  STUDY CHAIR

Central Study Contacts

Noémie RANISAVLJEVIC, MD, PhD

CONTACT

+33467336481; n-ranisavljevic@chu-montpellier.fr

Tal ANAHORY, MD

CONTACT

+33467335955; t-anahory@chu-montpellier.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The placebo syringe will be identical in appearance to the treatment syringe. Its production will be managed according to standard good clinical research practices by a partner laboratory.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicentric, prospective, controlled, double-blinded, superiority, randomized trial in 2 parallel groups: injections of a placebo or injections of subcutaneous progesterone.

Study Record Dates

• First Submitted: May 21, 2026
• First Posted: May 29, 2026
• Study Start (Estimated): March 1, 2027
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): September 1, 2030
• Last Updated: June 2, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)