search
Back to results

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

Primary Purpose

Infertility, Endometriosis

Status
Recruiting
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Elagolix 200 MG
Placebo or SOC IVF
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infertility

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept 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 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).

Sites / Locations

  • University of Colorado Department of Obstetrics & GynecologyRecruiting
  • Yale School of Medicine Dept.of Ob/Gyn & Reproductive SciencesRecruiting
  • Northwestern University Department of Obstetrics and GynecologyRecruiting
  • Johns Hopkins, Division of Reproductive Science and Women's Health ResearchRecruiting
  • Duke FertilityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Other

Arm Label

Pre-IVF Treatment with 60 day course of oral GnRH antagonist

Pre-IVF Treatment with 60 day course of Placebo or SOC IVF

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Live birth rate
Live birth rate per participant is defined as live birth at ≥24 weeks of gestation.

Secondary Outcome Measures

Fertilization rate
Fertilization rate per participant is defined as the rate of [two pronuclei (2PN)]/[total number of oocytes injected or inseminated]
Number of embryos transferred
Number of embryos transferred per participant
Implantation rate
Implantation rate per participant is defined as the rate of (number of gestation sacs visible by Ultrasound) / (Number of Embryo Transfer),
Biochemical pregnancy rate
Biochemical pregnancy rate per participant is defined as positive pregnancy test following embryo transfer
Clinical pregnancy rate
Clinical pregnancy rate per participant is defined as ultrasound evidence of intrauterine gestational sac with fetal cardiac activity
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.
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)
Gestation age at delivery
Gestation age (weeks) at delivery per infant delivered
Infant birth weight
Infant birth weight (gram) per infant delivered.

Full Information

First Posted
November 20, 2019
Last Updated
June 13, 2023
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
search

1. Study Identification

Unique Protocol Identification Number
NCT04173169
Brief Title
Pre-IVF Treatment With a GnRH Antagonist in Women With Endometriosis
Acronym
PREGnant
Official Title
Pre-IVF Treatment With a GnRH Antagonist in Women With Endometriosis - A Prospective Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 15, 2022 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
September 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the 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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infertility, Endometriosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigator
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.
Allocation
Randomized
Enrollment
814 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Pre-IVF Treatment with 60 day course of oral GnRH antagonist
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Pre-IVF Treatment with 60 day course of Placebo or SOC IVF
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Elagolix 200 MG
Other Intervention Name(s)
Orlissa
Intervention Description
Elagolix tablet
Intervention Type
Other
Intervention Name(s)
Placebo or SOC IVF
Intervention Description
Sugar pill manufactured to mimic Elagolix 200mg
Primary Outcome Measure Information:
Title
Live birth rate
Description
Live birth rate per participant is defined as live birth at ≥24 weeks of gestation.
Time Frame
Up to 15 months
Secondary Outcome Measure Information:
Title
Fertilization rate
Description
Fertilization rate per participant is defined as the rate of [two pronuclei (2PN)]/[total number of oocytes injected or inseminated]
Time Frame
Up to 9 months
Title
Number of embryos transferred
Description
Number of embryos transferred per participant
Time Frame
Up to 9 months
Title
Implantation rate
Description
Implantation rate per participant is defined as the rate of (number of gestation sacs visible by Ultrasound) / (Number of Embryo Transfer),
Time Frame
Up to 9 months
Title
Biochemical pregnancy rate
Description
Biochemical pregnancy rate per participant is defined as positive pregnancy test following embryo transfer
Time Frame
Up to 9 months
Title
Clinical pregnancy rate
Description
Clinical pregnancy rate per participant is defined as ultrasound evidence of intrauterine gestational sac with fetal cardiac activity
Time Frame
Up to 10 months
Title
Miscarriage rate
Description
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.
Time Frame
Up to 10 months
Title
Overall pregnancy complication rate
Description
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)
Time Frame
Up to 15 months
Title
Gestation age at delivery
Description
Gestation age (weeks) at delivery per infant delivered
Time Frame
Up to 15 months
Title
Infant birth weight
Description
Infant birth weight (gram) per infant delivered.
Time Frame
Up to 15 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Women who plan to undergo IVF for treatment of infertility. Age ≥18 and <40 years at time of egg retrieval or signing informed consent. 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. Body mass index (BMI) of 18-40 kg/m2 (both inclusive) at screening. 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. 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. 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. Negative urine or cervical swab for gonorrhea and chlamydia within 12 months of screening. Willing and able to comply with trial procedures, including reporting of obstetrical outcomes after delivery. Exclusion Criteria: 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°. Use of depot medroxyprogesterone acetate (MPA) (injectable) or birth control implants (e.g., Implanon® or Nexplanon®) within 6 months of study start°. Continuous use of oral progestins (MPA, NETA) within 1 month of study start°. 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. Pregnancy greater than 8 weeks in length within the last 6 months. Number of previous IVF/ICSI attempts ≥3 unsuccessful (negative pregnancy test). Presence of hydrosalpinx measuring >2cm on ultrasound, untreated endometrial polyps or intrauterine adhesions. 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). History of malignancy within 5 years of the start of screening, except for treated basal cell carcinoma and squamous cell carcinoma of the skin. Any thoughts of suicide in the last 12 months per self-report, or documented in the electronic medical record (EMR). Hypersensitivity to the study drugs. Planned surgical treatment of endometriosis or planned surgery in the abdominal-pelvic area within the duration of the trial. Untreated abnormal prolactin or TSH Any conditions that preclude pregnancy. Patients with a known history of a low-trauma fracture or other risk factors for osteoporosis or bone loss. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Heping Zhang, PhD
Phone
203-785-5185
Email
heping.zhang@yale.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Weinberg, PhD
Organizational Affiliation
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Hugh Taylor, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Heping Zhang, PhD
Organizational Affiliation
Yale University
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Nanette Santoro, MD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Emily Jungheim, MD
Organizational Affiliation
Northwestern University
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Steven Young, MD, PhD
Organizational Affiliation
Duke University
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Abisola Tepede, PharmD
Organizational Affiliation
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Official's Role
Study Director
Facility Information:
Facility Name
University of Colorado Department of Obstetrics & Gynecology
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Katherine Kuhn
Phone
303-724-5276
Email
katherine.kuhn@cuanschutz.edu
First Name & Middle Initial & Last Name & Degree
Nanette Santoro
Facility Name
Yale School of Medicine Dept.of Ob/Gyn & Reproductive Sciences
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michele Frank
Phone
203-785-6949
Email
michele.frank@yale.edu
First Name & Middle Initial & Last Name & Degree
Hugn Taylor
Facility Name
Northwestern University Department of Obstetrics and Gynecology
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jessica Almgren-Bell
Phone
312-503-4118
Email
jessica.almgrenbell@nm.org
First Name & Middle Initial & Last Name & Degree
Emily Jungheim
Facility Name
Johns Hopkins, Division of Reproductive Science and Women's Health Research
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gaelle Massoud,
Phone
410-583-2763
Email
gmassou1@jhmi.edu
First Name & Middle Initial & Last Name & Degree
James Segars
Facility Name
Duke Fertility
City
Morrisville
State/Province
North Carolina
ZIP/Postal Code
27560
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tifani Panek
Phone
773-706-4202
Email
tifani.panek@duke.edu
First Name & Middle Initial & Last Name & Degree
Steven Young

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
35715184
Citation
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.
Results Reference
derived
PubMed Identifier
34363198
Citation
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.
Results Reference
derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs