Clinical trial NCT04173169: Pre-IVF Treatment With a GnRH Antagonist in Women With Endometriosis
Official title: Pre-IVF Treatment With a GnRH Antagonist in Women With Endometriosis - A Prospective Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infertility
Endometriosis
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: University of Colorado, Denver
name: Northwestern University
name: University of North Carolina
First posted: 2019-11-21
Enrollment: 103
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility 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 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.

Primary outcomes:
measure: Live birth rate
timeFrame: Up to 15 months
Secondary outcomes:
measure: Fertilization rate
timeFrame: Up to 9 months
measure: Number of embryos transferred
timeFrame: Up to 9 months
measure: Implantation rate
timeFrame: Up to 9 months
measure: Biochemical pregnancy rate
timeFrame: Up to 9 months
measure: Clinical pregnancy rate
timeFrame: Up to 10 months
measure: Miscarriage rate
timeFrame: Up to 10 months
measure: Overall pregnancy complication rate
timeFrame: Up to 15 months
measure: Gestation age at delivery
timeFrame: Up to 15 months
measure: Infant birth weight
timeFrame: Up to 15 months
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Department of Obstetrics & Gynecology
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine Dept.of Ob/Gyn & Reproductive Sciences
state: Connecticut
city: Chicago
country: United States
facility: Northwestern University Department of Obstetrics and Gynecology
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins, Division of Reproductive Science and Women's Health Research
state: Maryland
city: Morrisville
country: United States
facility: Duke Fertility
state: North Carolina
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: David Weinberg, PhD
role: STUDY_DIRECTOR
affiliation: Yale University
name: Hugh Taylor, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Heping Zhang, PhD
role: STUDY_DIRECTOR
affiliation: University of Colorado, Denver
name: Nanette Santoro, MD
role: STUDY_DIRECTOR
affiliation: Northwestern University
name: Emily Jungheim, MD
role: STUDY_DIRECTOR
affiliation: Duke University
name: Steven Young, MD, PhD
role: STUDY_DIRECTOR
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Abisola Tepede, PharmD
role: STUDY_DIRECTOR
References:
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.
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.