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: March 17, 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 randomized 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 placebo.

Condition or disease	Intervention/treatment	Phase
Infertility; Endometriosis	Drug: Elagolix 200 MG; Drug: Placebo	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 placebo. 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 randomized 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 have also recently demonstrated aberrant microRNAs in the circulation of women with endometriosis, a panel of which investigators have subsequently validated as a biomarker with high sensitivity and specificity for the detection of active disease. It is secondarily proposed that disease biomarkers will identify women who will benefit from GnRH antagonist pre-treatment, allowing a precision medicine approach to endometriosis-related infertility. The proposed study is significant due to the common occurrence of both infertility and endometrioses as well as the lack of precision in both diagnosis and therapy. The investigators use an innovative approach to identify endometriosis as well as a novel intervention designed to improve the prognosis of women with endometriosis undergoing IVF.

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) will receive elagolix 200mg twice a day (BID) and the other half of subjects (407) will receive placebo BID, both 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: 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 Double-blind Placebo-controlled Trial
• Actual Study Start Date: March 15, 2022
• Estimated Primary Completion Date: October 2023
• Estimated Study Completion Date: October 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pre-IVF Treatment with 60 day course of oral GnRH antagonist; 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.	Drug: Elagolix 200 MG; Elagolix tablet; Other Name: Orlissa
Placebo Comparator: Pre-IVF Treatment with 60 day course of Placebo; 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.	Drug: Placebo; 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. Live birth rate per transfer [ Time Frame: Up to 15 months ]
   Live birth rate per participant per ET cycle is defined as live birth at ≥24 weeks of gestation. (parity per transfer)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 38 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 <38 years at time of 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 > 0.8 ng/ml, resulted within 6 months of planned IVF cycle start.
6. Uterine cavity assessment by sonohysterogram or hysteroscopy within 6 months indicating absence of focal intracavitary pathology and hence adequacy for embryo transfer. Ultrasound 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 subjects 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 GnRH agonists or antagonists within 6 months of study start, unless the antagonist was a part of a regular IVF cycle.
2. Use of depot medroxyprogesterone acetate (MPA) or birth control implants (e.g. Implanon® or Nexplanon®) within 10 months of study start.
3. Continuous use of oral progestins (MPA, NETA) within 3 months 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) 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
7. Presence of hydrosalpinx measuring >2cm on ultrasound, untreated endometrial polyps or intrauterine adhesions.
8. Abnormal cytology on a pap smear within last year. (CIN1 or HPV okay, 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 suicide attempts in last 1 year.
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. -

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: Luisa Coraluzzi 203-785-2164 luisa.coraluzzi@yale.edu

Principal Investigator: Hugn Taylor

United States, Illinois

Northwestern University Department of Obstetrics and Gynecology; Not yet 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: Jana Phillips 919-908-0000 ext 812 jlphilli@med.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: Jared Robbins, 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):

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: March 17, 2022
• Last Verified: March 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