Low Serum Progesterone, Pregnancy, Progesterone Supplementation
Conditions
Keywords
luteal phase support, Serum progesterone level, individualized treatment, fresh embryo transfer, live birth rate
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.
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.
Interventions
DRUGProgesterone 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).
DRUGPlacebo
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).
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.
Sponsors
University Hospital, Montpellier
IBSA Institut Biochimique SA
Hospices Civils de Lyon
Direction Générale de l'Offre de Soins
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
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.
Intervention model description
Multicentric, prospective, controlled, double-blinded, superiority, randomized trial in 2 parallel groups: injections of a placebo or injections of subcutaneous progesterone.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 37 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Live birth rate | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical pregnancy rate | 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 |
| Ongoing pregnancy rate | At first trimester follow-up (Visit 3: Week 12-14 of gestation) | Defined as a viable intrauterine pregnancy at ≥12 weeks of gestation. |
| Miscarriage rate | 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). |
| 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 adverse events reported during the intervention period. |
| Incidence of obstetrical and neonatal complications | 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. |
| Birth weight | At postpartum follow-up (Visit 4: Month 9 ±1 month) | Weight of the newborn at delivery. |
| Gestational age at delivery | At postpartum follow-up (Visit 4: Month 9 ±1 month) | Gestational age in weeks at the time of delivery. |
| Incremental cost-effectiveness ratio (ICER) | 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. |
Countries
France
Contacts
CONTACTNoémie RANISAVLJEVIC, MD, PhD
CONTACTTal ANAHORY, MD
PRINCIPAL_INVESTIGATORNoémie RANISAVLJEVIC, MD, PhD
University Hospital, Montpellier
STUDY_CHAIRTal ANAHORY, MD
University Hospital, Montpellier
Outcome results
None listed