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

May 29, 2026 updated by: University Hospital, Montpellier

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

214

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: 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).
Drug: 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).
Other Names:
  • PLACEBO, injectable solution
Drug: 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.
Other Names:
  • PROGESTAN 200 mg, vaginal soft capsule
Experimental: 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).
Drug: 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.
Other Names:
  • PROGESTAN 200 mg, vaginal soft capsule
Drug: 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).
Other Names:
  • PROGIRON 25 mg, injectable solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Live birth rate
Time Frame: At postpartum follow-up (Visit 4: Month 9 ±1 month)
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical pregnancy rate
Time Frame: At first trimester follow-up (Visit 3: Week 12-14 of gestation)

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)
Ongoing pregnancy rate
Time Frame: At first trimester follow-up (Visit 3: Week 12-14 of gestation)
Defined as a viable intrauterine pregnancy at ≥12 weeks of gestation.
At first trimester follow-up (Visit 3: Week 12-14 of gestation)
Miscarriage rate
Time Frame: From inclusion (Visit 1: positive pregnancy test or the following day) to 20 weeks of gestation
Defined as spontaneous pregnancy loss before 20 weeks of gestation, including early pregnancy loss (<12 weeks) and late pregnancy loss (12-20 weeks).
From inclusion (Visit 1: positive pregnancy test or the following day) to 20 weeks of gestation
Incidence of treatment-related adverse events
Time Frame: From inclusion (Visit 1: positive pregnancy test or the following day) to follow-up (Visit 2: Week 6-7 after test +)
Incidence of adverse events reported during the intervention period.
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
Time Frame: At postpartum follow-up (Visit 4: Month 9 ±1 month)
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.
At postpartum follow-up (Visit 4: Month 9 ±1 month)
Birth weight
Time Frame: At postpartum follow-up (Visit 4: Month 9 ±1 month)
Weight of the newborn at delivery.
At postpartum follow-up (Visit 4: Month 9 ±1 month)
Gestational age at delivery
Time Frame: At postpartum follow-up (Visit 4: Month 9 ±1 month)
Gestational age in weeks at the time of delivery.
At postpartum follow-up (Visit 4: Month 9 ±1 month)
Incremental cost-effectiveness ratio (ICER)
Time Frame: From inclusion (Visit 1: Positive pregnancy test or the following day) to postpartum follow-up (Visit 4: Month 9 ±1 month)
Cost-effectiveness analysis comparing prolonged subcutaneous progesterone versus placebo, with effectiveness defined by live birth rate.
From inclusion (Visit 1: Positive pregnancy test or the following day) to postpartum follow-up (Visit 4: Month 9 ±1 month)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum 17-hydroxyprogesterone level
Time Frame: At inclusion (Visit 1: positive pregnancy test or the following day)
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.
At inclusion (Visit 1: positive pregnancy test or the following day)
Serum estradiol level
Time Frame: At inclusion (Visit 1: positive pregnancy test or the following day)
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.
At inclusion (Visit 1: positive pregnancy test or the following day)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Montpellier

Collaborators

Hospices Civils de Lyon
Direction Générale de l'Offre de Soins
IBSA Institut Biochimique SA

Investigators

  • Principal Investigator: Noémie RANISAVLJEVIC, MD, PhD, University Hospital, Montpellier
  • Study Chair: Tal ANAHORY, MD, University Hospital, Montpellier

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

March 1, 2027

Primary Completion (Estimated)

September 1, 2029

Study Completion (Estimated)

September 1, 2030

Study Registration Dates

First Submitted

May 21, 2026

First Submitted That Met QC Criteria

May 21, 2026

First Posted (Actual)

May 29, 2026

Study Record Updates

Last Update Posted (Actual)

June 2, 2026

Last Update Submitted That Met QC Criteria

May 29, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • RECHMPL_25_0581
  • 2026-525452-28-00 (Ctis)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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