Pre-IVF Treatment With a GnRH Antagonist in Women With Endometriosis

Pre-IVF Treatment With a GnRH Antagonist in Women With Endometriosis - A Prospective Clinical Trial

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04173169

Acronym

PREGnant

Enrollment

103

Registered

2019-11-21

Start date

2022-03-15

Completion date

2025-05-02

Last updated

2026-06-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Endometriosis, Infertility

Brief summary

A Phase 3 clinical trial of oral GnRH antagonist pre-treatment for women with endometriosis who are undergoing IVF, with a primary outcome of live birth rate. The investigators' central hypothesis is that in infertile woman with endometriosis undergoing in vitro fertilization-embryo transfer (IVF-ET), live birth rates will improve in those pretreated with GnRH antagonist compared to those not pretreated with GnRH antagonist.

Detailed description

Infertility is a common complication of endometriosis; while IVF successfully treats endometriosis-associated infertility, pregnancy rates are diminished compared to other etiologies of infertility. The study's long- term objectives are to better identify and treat endometriosis related infertility. The investigators' central hypothesis is that in infertile woman with endometriosis undergoing in vitro fertilization-embryo transfer (IVF-ET), live birth rates will improve in those pretreated with GnRH antagonist compared to those not pretreated with GnRH antagonist. The use of gonadotropin releasing hormone (GnRH) agonist prior to IVF has been suggested to improve success, however studies have been small and rarely reported live birth rates. Further, use of this approach is limited by the long treatment time required. Recent approval of an oral GnRH antagonist for endometriosis provides a novel option for women with endometriosis who are undergoing IVF. This agent avoids parenteral administration and the prolonged delay in initiation of action as was seen with GnRH agonists. There have been no studies on the efficacy of GnRH antagonists for the treatment of endometriosis-related infertility. The investigators propose a clinical trial of oral GnRH antagonist pre-treatment for women with endometriosis who are undergoing IVF, with a primary outcome of live birth rate. Participants will include those who agree to be randomized and those who do not want to be randomized. Those who agree to be randomized will be randomly assigned to either the elagolix group or placebo group. Those who do not want to be randomized can choose either the active treatment elagolix and follow the same procedures as those agreeing to be randomized or continue their ongoing or planned IVF and follow standard of care (SOC) (SOC IVF) if they do not want to delay the IVF procedure.

Interventions

DRUGElagolix 200 MG

Elagolix tablet

OTHERPlacebo or SOC IVF

Sugar pill manufactured to mimic Elagolix 200mg

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Masking description

For participants who agree to be randomized, a computer-generated randomization list will be created by the PREGnant Data Coordinating Center (DCC) and randomization will be performed prior to the first dose of elagolix. Randomization will have random sizes (2, 4, or 6) of blocks and be stratified by site, i.e. whole blocks are assigned to sites. The randomization list will not be available to any person involved in the conduct and evaluation of the trial until the trial is complete and database is declared clean and is released by the DCC. Likewise, treatment allocation information will not be accessible to investigators (except for serious safety concerns), trial staff at the site or central laboratory personnel during the trial.

Intervention model description

Half of the subjects (200, randomized or not randomized) will receive elagolix 200mg twice a day (BID) and the other half of subjects will receive placebo BID or SOC IVF (200, placebo or SOC IVF). Elagolix or placebo will be taken for a minimum of 60 days before IVF cycle start. For convenience of IVF cycle scheduling, participants may receive up to an additional 14 days of intervention (elagolix or placebo) beyond the minimum 60 days of pre-IVF treatment, such that the last dose of study intervention (elagolix or placebo) is received no more than 24 hours before start of IVF treatment protocol.

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 40 Years

Healthy volunteers

Inclusion criteria

1. Women who plan to undergo IVF for treatment of infertility. 2. Age ≥18 and \<40 years at time of egg retrieval or signing informed consent. 3. Documentation of diagnosis of endometriosis by surgical visualization of endometriosis (laparoscopy or laparotomy) or diagnosis by pathology within the last 10 years before the initial trial entry visit or documentation of ovarian endometrioma \>2 cm or two or more smaller endometriomas that total \>2 cm in diameter. If entry is based on the presence of an endometrioma, transvaginal ultrasound evaluation must document the same unambiguous endometrioma on two separate occasions in more than one menstrual cycle. Images will be printed or transmitted electronically and read centrally by investigators at Yale to assure uniform diagnostic criteria (classic ground glass appearance) are applied. 4. Body mass index (BMI) of 18-40 kg/m2 (both inclusive) at screening. 5. AMH \> 0.5ng/ml, within 12 months of a fresh IVF cycle start. For frozen embryo transfers (FET) , AMH level eligibility criteria may not be met as long as the patient has at least one good quality blastocyst stored for the FET. 6. No known uterine cavity abnormalities at time of screening. Uterine cavity assessment by sonohysterogram or hysteroscopy within 12 months of embryo transfer indicating absence of focal intracavitary pathology and hence establishing adequate cavity at the time of embryo transfer. Ultrasound or MRI features suggestive of adenomyosis will be acceptable for inclusion. Type 3 fibroids are allowed up to 4cm size. 7. Presence of at least one ovary with no clinically significant abnormalities other than endometrioma. For eligible women with evidence of a hemorrhagic ovarian cyst, a repeat US will be needed in a subsequent menstrual cycle to ensure persistent cyst for patient to be deemed eligible. 8. Negative urine or cervical swab for gonorrhea and chlamydia within 12 months of screening. 9. Willing and able to comply with trial procedures, including reporting of obstetrical outcomes after delivery.

Exclusion criteria

1. Use of depot GnRH agonists within 6 months of study start. Use of subcutaneous antagonists or nasal agonist within 2 months of study start unless part of regular IVF or previous IUI cycle°. 2. Use of depot medroxyprogesterone acetate (MPA) (injectable) or birth control implants (e.g., Implanon® or Nexplanon®) within 6 months of study start°. 3. Continuous use of oral progestins (MPA, NETA) within 1 month of study start°. 4. Use of aromatase inhibitors, danazol or hormonal contraceptives (Including combined oral contraceptive pill, progestin-only pill, transdermal patch or contraceptive ring, or double barrier contraception) within 1 month of study start. 5. Pregnancy greater than 8 weeks in length within the last 6 months. 6. Number of previous IVF/ICSI attempts ≥3 unsuccessful (negative pregnancy test). 7. Presence of hydrosalpinx measuring \>2cm on ultrasound, untreated endometrial polyps or intrauterine adhesions. 8. Abnormal cytology on a cervical screening based on the American College of Obstetricians and Gynecologists (ACOG) guidelines and patient age. (CIN1 or HPV allowed to participate in the study, CIN2 excluded unless treated and cleared, CIN3 excluded). 9. History of malignancy within 5 years of the start of screening, except for treated basal cell carcinoma and squamous cell carcinoma of the skin. 10. Any thoughts of suicide in the last 12 months per self-report, or documented in the electronic medical record (EMR). 11. Hypersensitivity to the study drugs. 12. Planned surgical treatment of endometriosis or planned surgery in the abdominal-pelvic area within the duration of the trial. 13. Untreated abnormal prolactin or TSH 14. Any conditions that preclude pregnancy. 15. Patients with a known history of a low-trauma fracture or other risk factors for osteoporosis or bone loss. 16. Patients with cirrhosis or abnormal LFTs per self report or documented in the electronic medical record (EMR). *

Design outcomes

Primary

Measure	Time frame	Description
Live Birth Rate	Up to 15 months	The percentage of the number of participants with a live birth at ≥24 weeks of gestation out of those who were enrolled in the study

Secondary

Measure	Time frame	Description
Fertilization Rate	Up to 9 months	The percentage of the total number of fertilized oocytes (two pronuclei) out of the total number of injected/inseminated oocytes across all participants in each Arm/Group who had the current or previous IVF data
Number of Embryos Transferred	Up to 9 months	Number of embryos transferred per participant
Implantation Rate	Up to 9 months	The percentage of the total number of gestation sacs visible by Ultrasound out of the total number of transferred embryos across all participants in each Arm/Group who completed embryo transfer
Biochemical Pregnancy Rate	Up to 9 months	The percentage of the number of participants with positive pregnancy tests following embryo transfer out of those who were enrolled in the study
Clinical Pregnancy Rate	Up to 10 months	The percentage of the number of participants with ultrasound evidence of intrauterine gestational sac with fetal cardiac activity out of those who were enrolled in the study
Miscarriage Rate	Up to 10 months	Percentage of the number of participants with a pregnancy loss out of those who have achieved pregnancy
Overall Pregnancy Complication Rate	Up to 15 months	Percentage of the number of participants who had the overall pregnancy complication out of those who have achieved pregnancy. Overall pregnancy complication including any of the following: preterm delivery, preeclampsia, gestational diabetes, intrauterine growth restriction, incompetent cervix, premature rupture of membrane, incidence of abnormal placentation (placenta previa, accreta, increta, percreta, abruption), bleeding in pregnancy (antepartum or postpartum)
Gestation Age at Delivery	Up to 15 months	Gestation age (weeks) at delivery per infant delivered
Infant Birth Weight	Up to 15 months	Infant birth weight (gram) per infant delivered.

Countries

United States

Contacts

STUDY_DIRECTORDavid Weinberg, PhD

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

PRINCIPAL_INVESTIGATORHugh Taylor, MD

Yale University

STUDY_DIRECTORHeping Zhang, PhD

Yale University

STUDY_DIRECTORNanette Santoro, MD

University of Colorado, Denver

STUDY_DIRECTOREmily Jungheim, MD

Northwestern University

STUDY_DIRECTORSteven Young, MD, PhD

Duke University

STUDY_DIRECTORAbisola Tepede, PharmD