Pre-IVF Treatment With a GnRH Antagonist in Women With endometriosis_temp (PREGnant)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Infertility; Endometriosis
• Intervention / Treatment: Drug: Elagolix 200 MG; Other: Placebo or SOC IVF

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.

• Study Type: Interventional
• Enrollment (Estimated): 297
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Heping Zhang, PhD; Phone Number: 203-785-5185; Email: heping.zhang@yale.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Department of Obstetrics & Gynecology
      • Principal Investigator: Nanette Santoro
      • Contact: Asma Giornazi; Phone Number: 720-276-8941; Email: ASMA.GIORNAZI@UCDENVER.EDU
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale School of Medicine Dept.of Ob/Gyn & Reproductive Sciences
      • Contact: Michele Frank; Phone Number: 203-785-6949; Email: michele.frank@yale.edu
      • Principal Investigator: Hugn Taylor
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University Department of Obstetrics and Gynecology
      • Principal Investigator: Emily Jungheim
      • Contact: Riley Bonaccorsi; Phone Number: 312.926.6643; Email: riley.bonaccorsi@nm.org
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Recruiting
      • Johns Hopkins, Division of Reproductive Science and Women's Health Research
      • Principal Investigator: James Segars
      • Contact: Samya EI Sayed; Phone Number: 410-614-2000; Email: selsaye4@jh.edu
  • North Carolina
    • Morrisville, North Carolina, United States, 27560
      • Recruiting
      • Duke Fertility
      • Principal Investigator: Steven Young
      • Contact: Tifani Panek; Phone Number: 773-706-4202; Email: tifani.panek@duke.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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).

    • Exclusion criteria number 1,2, and 3 are not required to be met by individuals in the standard of care arm of the study. The study team will collect the information regarding whether the subject has used these drugs in the aforementioned time frame using the concomitant medication log and the individual will be allowed to participate in the study under the standard of care arm only.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pre-IVF Treatment with 60 day course of oral GnRH antagonist; For those who agree to be randomized, subjects will be randomized to elagolix 200mg BID. The medication will be taken orally and subjects will be counseled to take the medication at the same time each day. This arm will also include participants who do not want to be randomized while choose elagolix.	Drug: Elagolix 200 MG; Elagolix tablet; Other Names: Orlissa
Other: Pre-IVF Treatment with 60 day course of Placebo or SOC IVF; For those who agree to be randomized, subjects will be randomized to placebo, BID. The medication will be taken orally and subjects will be counseled to take the medication at the same time each day. This arm will also include participants who want to continue their ongoing or planned IVF and follow standard of care (SOC) (SOC IVF) if the participants do not want to delay the IVF procedure.	Other: Placebo or SOC IVF; Sugar pill manufactured to mimic Elagolix 200mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth rate	Live birth rate per participant is defined as live birth at ≥24 weeks of gestation.	Up to 15 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fertilization rate	Fertilization rate per participant is defined as the rate of [two pronuclei (2PN)]/[total number of oocytes injected or inseminated]	Up to 9 months
Number of embryos transferred	Number of embryos transferred per participant	Up to 9 months
Implantation rate	Implantation rate per participant is defined as the rate of (number of gestation sacs visible by Ultrasound) / (Number of Embryo Transfer),	Up to 9 months
Biochemical pregnancy rate	Biochemical pregnancy rate per participant is defined as positive pregnancy test following embryo transfer	Up to 9 months
Clinical pregnancy rate	Clinical pregnancy rate per participant is defined as ultrasound evidence of intrauterine gestational sac with fetal cardiac activity	Up to 10 months
Miscarriage rate	Miscarriage rate among those who achieved pregnancy. Miscarriage is defined as pregnancy loss prior to viability scan and including those confirmed on ultrasound scan up to ≤23+6 weeks of gestation gestation.	Up to 10 months
Overall pregnancy complication rate	Overall pregnancy complication rate among those who achieved pregnancy. Overall pregnancy complication including any of the following: preterm delivery, preeclampsia, incidence of abnormal placentation (placenta previa, accreta, increta, percreta, abruption), bleeding in pregnancy (antepartum or postpartum)	Up to 15 months
Gestation age at delivery	Gestation age (weeks) at delivery per infant delivered	Up to 15 months
Infant birth weight	Infant birth weight (gram) per infant delivered.	Up to 15 months

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Johns Hopkins University; University of Colorado, Denver; Northwestern University; Duke University; University of North Carolina
• Investigators: Principal Investigator: Hugh Taylor, MD, Yale University; Study Director: Nanette Santoro, MD, University of Colorado, Denver; Study Director: Emily Jungheim, MD, Northwestern University; Study Director: Heping Zhang, PhD, Yale University; Study Director: Steven Young, MD, PhD, Duke University; Study Director: Jim Segars, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2024
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: April 16, 2024
• First Submitted That Met QC Criteria: April 16, 2024
• First Posted (Actual): April 19, 2024

Study Record Updates

• Last Update Posted (Actual): July 24, 2025
• Last Update Submitted That Met QC Criteria: July 21, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Infertility; Endometriosis
• Other Study ID Numbers: 2000027121_a

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators have a plan to submit data and samples collected by the trial to NICHD DASH. The informed consent will include permission to bank these samples. The processes included initial data and documentation preparation (e.g., codebooks, protocols, informed consent for data sharing), data quality control, and submission.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No