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

• ClinicalTrials.gov Identifier: NCT04173169
• Recruitment Status: Recruiting
• First Posted: November 21, 2019
• Last Update Posted: August 16, 2022
• Sponsor: Yale University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Colorado, Denver; Northwestern University; University of North Carolina
• Information provided by (Responsible Party): Yale University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Infertility; Endometriosis	Drug: Elagolix 200 MG; Other: Placebo or SOC IVF	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 814 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Half of the subjects (407, 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 (407, 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.
• Masking: Triple (Participant, Care Provider, 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.
• Primary Purpose: Treatment
• Official Title: Pre-IVF Treatment With a GnRH Antagonist in Women With Endometriosis - A Prospective Clinical Trial
• Actual Study Start Date: March 15, 2022
• Estimated Primary Completion Date: September 30, 2024
• Estimated Study Completion Date: September 30, 2024

Arms and Interventions

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 Name: Orlissa
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 they do not want to delay the IVF procedure.	Other: Placebo or SOC IVF; Sugar pill manufactured to mimic Elagolix 200mg

Outcome Measures

Primary Outcome Measures :

1. Live birth rate [ Time Frame: Up to 15 months ]
   Live birth rate per participant is defined as live birth at ≥24 weeks of gestation.

Secondary Outcome Measures :

1. Fertilization rate [ Time Frame: Up to 9 months ]
   Fertilization rate per participant is defined as the rate of [two pronuclei (2PN)]/[total number of oocytes injected or inseminated]
2. Number of embryos transferred [ Time Frame: Up to 9 months ]
   Number of embryos transferred per participant
3. Implantation rate [ Time Frame: Up to 9 months ]
   Implantation rate per participant is defined as the rate of (number of gestation sacs visible by Ultrasound) / (Number of Embryo Transfer),
4. Biochemical pregnancy rate [ Time Frame: Up to 9 months ]
   Biochemical pregnancy rate per participant is defined as positive pregnancy test following embryo transfer
5. Clinical pregnancy rate [ Time Frame: Up to 10 months ]
   Clinical pregnancy rate per participant is defined as ultrasound evidence of intrauterine gestational sac with fetal cardiac activity
6. Miscarriage rate [ Time Frame: Up to 10 months ]
   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.
7. Overall pregnancy complication rate [ Time Frame: Up to 15 months ]
   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)
8. Gestation age at delivery [ Time Frame: Up to 15 months ]
   Gestation age (weeks) at delivery per infant delivered
9. Infant birth weight [ Time Frame: Up to 15 months ]
   Infant birth weight (gram) per infant delivered.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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 egg collection for a FET or within 12 months of a fresh IVF cycle start.
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).

Contacts and Locations

Contacts

Contact: Heping Zhang, PhD; 203-785-5185; heping.zhang@yale.edu

Locations

United States, Colorado

University of Colorado Department of Obstetrics & Gynecology; Recruiting

Aurora, Colorado, United States, 80045

Contact: Shannon Pretzel 303-724-5276 SHANNON.PRETZEL@CUANSCHUTZ.EDU

Principal Investigator: Nanette Santoro

United States, Connecticut

Yale School of Medicine Dept.of Ob/Gyn & Reproductive Sciences; Recruiting

New Haven, Connecticut, United States, 06520

Contact: Michele Frank 203-785-6949 michele.frank@yale.edu

Principal Investigator: Hugn Taylor

United States, Illinois

Northwestern University Department of Obstetrics and Gynecology; Recruiting

Chicago, Illinois, United States, 60611

Contact: Shriya Shah 312-503-3488 shriya.shah@northwestern.edu

Principal Investigator: Emily Jungheim

United States, Maryland

Johns Hopkins, Division of Reproductive Science and Women's Health Research; Recruiting

Baltimore, Maryland, United States, 21205

Contact: Bhuchitra Singh 410-955-6771 bsingh10@jhmi.edu

Principal Investigator: James Segars

United States, North Carolina

UNC Fertility; Recruiting

Raleigh, North Carolina, United States, 27617

Contact: Tifani Panek 773-706-4202 tipanek@email.unc.edu

Principal Investigator: Steven Young

Sponsors and Collaborators

Yale University

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

University of Colorado, Denver

Northwestern University

University of North Carolina

Investigators

• Study Director: Esther Eisenberg, MD; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Principal Investigator: Hugh Taylor, MD; Yale University
• Study Director: Heping Zhang, PhD; Yale University
• Study Director: Nanette Santoro, MD; University of Colorado, Denver
• Study Director: Emily Jungheim, MD; Northwestern University
• Study Director: Steven Young, MD, PhD; University of North Carolina

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Taylor H, Li HJ, Carson S, Flores V, Pal L, Robbins J, Santoro NF, Segars JH, Seifer D, Huang H, Young S, Zhang H. Pre-IVF treatment with a GnRH antagonist in women with endometriosis (PREGNANT): study protocol for a prospective, double-blind, placebo-controlled trial. BMJ Open. 2022 Jun 17;12(6):e052043. doi: 10.1136/bmjopen-2021-052043.

Pretzel S, Kuhn K, Pal L, Polotsky A, Taylor HS, Zhang H, Robins J, Young SL, Santoro N. Willingness of Women with Endometriosis Planning to Undergo IVF to Participate in a Randomized Clinical Trial and the Effects of the COVID-19 Pandemic on Potential Participation. Reprod Sci. 2022 Feb;29(2):620-626. doi: 10.1007/s43032-021-00705-0. Epub 2021 Aug 6.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT04173169
• Other Study ID Numbers: 2000027121; 1R01HD100336-01 ( U.S. NIH Grant/Contract )
• First Posted: November 21, 2019
• Last Update Posted: August 16, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: We 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Infertility; Endometriosis