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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Infertility, Endometriosis

Intervention / Treatment
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* Drug: Elagolix 200 MG
* Other: Placebo or SOC IVF


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pre-IVF Treatment with 60 day course of oral GnRH antagonist<br>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<br>* Elagolix tablet<br>* Other names: Orlissa;|
| Other: Pre-IVF Treatment with 60 day course of Placebo or SOC IVF<br>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<br>* Sugar pill manufactured to mimic Elagolix 200mg<br>|

What is the study measuring?
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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 |