Oral GnRH Antagonist (Linzagolix) Versus Injectable GnRH Antagonist and Progestin-primed Ovarian Stimulation (PPOS) in Controlled Ovarian Stimulation for in Vitro Fertilization: a Prospective Comparative Observational Study
Preventing a premature rise in luteinizing hormone (LH) is essential during ovarian stimulation for in vitro fertilization (IVF), because such a rise can reduce the number of eggs collected. Current practice relies on either a daily injectable GnRH antagonist or an oral progestin (PPOS), which requires that all embryos be frozen.
Linzagolix is an oral GnRH antagonist already approved for uterine fibroids and endometriosis. It has not previously been used to control ovarian stimulation for IVF; this study represents its first use for this purpose.
This is an observational study: participants are not randomly assigned to a treatment. Each woman receives one of three approaches - oral linzagolix, an injectable GnRH antagonist (ganirelix or cetrorelix), or PPOS - chosen by the clinical team based on her individual situation. The three groups are then compared using statistical adjustment for baseline differences between them.
The study will enroll approximately 195 women undergoing IVF or ICSI, aged 18 to [42], who are not selected based on ovarian reserve. All participants receive individualized gonadotropin stimulation and standard monitoring; only the method used to prevent premature ovulation differs by group.
The main question is whether linzagolix leads to a similar number of mature eggs (MII) retrieved compared with the injectable antagonist. The study will also assess how well each approach suppresses LH, safety (including ovarian hyperstimulation), and the number of injections needed.
Study Overview
Status
Conditions
Detailed Description
Prevention of a premature luteinizing hormone (LH) surge is essential during controlled ovarian stimulation (COS) for IVF/ICSI, since an unopposed surge compromises oocyte retrieval. The established approaches are the injectable GnRH antagonist (ganirelix, cetrorelix), administered subcutaneously and considered standard of care, and progestin-primed ovarian stimulation (PPOS), which suppresses the LH surge with an oral progestin but mandates a freeze-all strategy. Non-peptide oral GnRH antagonists (relugolix, elagolix, linzagolix) are approved for uterine fibroids and endometriosis but have not previously been used in controlled ovarian stimulation; this study constitutes their first documented use in this indication.
Linzagolix is a non-peptide oral GnRH receptor antagonist producing dose-dependent suppression of the pituitary-ovarian axis; at 200 mg/day it fully suppresses endogenous estradiol secretion. In COS, however, follicular growth and estradiol production are driven by exogenous FSH acting directly on the follicle, independent of pituitary function, so linzagolix's role is limited to preventing the endogenous LH surge. Linzagolix has a shorter half-life (approximately 15-20 hours) than relugolix (approximately 37-42 hours), for which reduced oocyte yield has been reported when final maturation is triggered with a GnRH agonist. The faster elimination is expected to leave lower residual receptor occupancy at the time of trigger, allowing an agonist bolus to evoke an adequate maturation flare despite competitive antagonism - relevant to OHSS prevention in high responders. Preliminary center experience with linzagolix 200 mg is consistent with this expectation and informed the sample size assumptions.
This is a single-center, prospective, comparative observational study with three concurrent groups, conducted at CENTRO AMBRA. Patients receive one of three LH-surge suppression protocols - oral linzagolix, injectable GnRH antagonist, or PPOS - according to clinical judgment and center practice; treatment is not assigned by the study protocol and there is no randomization. Because assignment reflects clinical and organizational criteria (for example, an indication for a freeze-all strategy in the PPOS group), the three groups may differ systematically in baseline and prognostic characteristics - confounding by indication affecting all three groups, not PPOS alone. This is addressed through pre-specified multivariable adjustment rather than eliminated; results are interpreted as associations, not causal effects. For each patient, the clinical reason for treatment assignment is prospectively documented to support confounding assessment. As treatment is known to investigators and patients, there is no masking; oocyte and embryo assessment follows standardized, predefined laboratory procedures to limit subjectivity.
The primary objective is to estimate, with adjustment for confounders, the difference in mature (MII) oocytes retrieved between linzagolix and the injectable antagonist; this is an estimation study, not a hypothesis test. A clinically relevant reference value of 2.0 MII oocytes is pre-specified solely to aid interpretation of the confidence interval, not as a non-inferiority margin. Secondary objectives include an exploratory comparison with PPOS; efficacy of LH suppression; feasibility of GnRH agonist trigger under linzagolix; safety (OHSS and adverse events); stimulation duration and gonadotropin consumption; and embryological parameters including fertilization, blastulation, and euploidy in the PGT-A subgroup. Exploratory objectives include effect modification by responder category, the relationship between the last-dose-to-trigger interval and oocyte yield (linzagolix group), and the role of progestin type within the PPOS group.
The primary analysis uses a multivariable model (ANCOVA or negative binomial regression, as dictated by dispersion) with linzagolix as the reference category, adjusting for ovarian reserve, age, BMI, gonadotropin type and dose, and trigger type. Sensitivity analyses include restriction to comparable patients and, where sample size permits, propensity-score methods. As linzagolix is used off-label in this indication, eligibility for the observational-study regulatory pathway (per AIFA Determination 425/2024) is being confirmed with the Ethics Committee prior to final submission; should off-label use require interventional classification, the corresponding regulatory pathway will apply. Reporting will follow STROBE recommendations for observational studies.
Study Type
Enrollment (Estimated)
Phase
- Early Phase 1
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
Inclusion Criteria:
- Female, aged 18 to 42 years
- Indication for IVF/ICSI with controlled ovarian stimulation at CENTRO AMBRA
- Population unselected for ovarian reserve (normal, poor, and high responders are eligible)
- Written informed consent, including consent for off-label use of linzagolix and for data processing
- For the two antagonist arms (Linzagolix and Injectable GnRH Antagonist): acceptance of randomization
Exclusion Criteria:
- Known contraindications or hypersensitivity to the study drugs
- Uterine pathology relevant to the study outcome (e.g., uterine malformations, significant submucosal fibroids)
- Contraindications to pregnancy or to ovarian stimulation
- Concurrent participation in another interfering interventional study
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
|---|---|
|
B - Injectable GnRH Antagonist (Ganirelix/Cetrorelix)
|
Ganirelix Type: Drug Group: B Description: Ganirelix acetate 0.25 mg administered by daily subcutaneous injection, per fixed or flexible protocol according to center practice, to suppress the premature LH surge during controlled ovarian stimulation. Cetrorelix Type: Drug Arm: B Description: Cetrorelix acetate 0.25 mg administered by daily subcutaneous injection, per fixed or flexible protocol according to center practice, to suppress the premature LH surge during controlled ovarian stimulation. |
|
C - PPOS (Progestin-Primed Ovarian Stimulation) Cohort
|
Medroxyprogesterone Acetate Type: Drug Group: C Description: Medroxyprogesterone acetate 10 mg/day administered orally from stimulation day 1-2 through the day of trigger, as part of a progestin-primed ovarian stimulation (PPOS) protocol with mandatory freeze-all strategy. Dienogest Type: Drug Arm: C Description: Dienogest 2 mg/day administered orally from stimulation day 1-2 through the day of trigger, as part of a progestin-primed ovarian stimulation (PPOS) protocol with mandatory freeze-all strategy. Micronized Progesterone Type: Drug Arm: C Description: Micronized progesterone 100-200 mg/day administered orally from stimulation day 1-2 through the day of trigger, as part of a progestin-primed ovarian stimulation (PPOS) protocol with mandatory freeze-all strategy. |
|
A - Linzagolix
|
Description: Linzagolix Type: Drug Group: A Description: Linzagolix 200 mg administered orally once daily, started per center protocol (fixed stimulation day or upon appearance of the dominant follicle) and continued through the day of trigger.
Investigational off-label use for suppression of the premature LH surge during controlled ovarian stimulation.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Number of Mature (MII) Oocytes Retrieved
Time Frame: At oocyte retrieval, approximately 36 hours after trigger (first study cycle)
|
Number of metaphase II (mature) oocytes collected at oocyte retrieval.
This measure is used to estimate, with multivariable adjustment for baseline confounders (ovarian reserve, age, BMI, gonadotropin type and dose, trigger type), the difference in oocyte yield between the linzagolix group and the injectable GnRH antagonist group (primary comparison); an exploratory comparison with the PPOS group is also performed.
As this is an observational estimation study, results are reported as an adjusted difference with 95% confidence interval rather than a formal hypothesis test.
|
At oocyte retrieval, approximately 36 hours after trigger (first study cycle)
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Incidence of Premature LH Rise
Time Frame: From initiation of LH-suppressive treatment to the day of trigger (up to approximately 12 days)
|
From initiation of LH-suppressive treatment to the day of trigger (up to approximately 12 days)
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Urogenital Diseases
- Genital Diseases
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Genital Diseases, Female
- Infertility
- Infertility, Female
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Polycyclic Compounds
- Pregnanes
- Steroids
- Fused-Ring Compounds
- Gonadal Steroid Hormones
- Gonadal Hormones
- Pregnenediones
- Pregnenes
- Medroxyprogesterone
- Hydroxyprogesterones
- Corpus Luteum Hormones
- Progesterone Congeners
- Medroxyprogesterone Acetate
- Progesterone
- dienogest
- ganirelix
- cetrorelix
- linzagolix
Other Study ID Numbers
- LINZA-COS
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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.