Elagolix for Fertility Enhancement Clinical Trial

Study Overview
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Brief Summary
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Studies suggest that undiagnosed endometriosis results in poor reproductive outcomes in the setting of In Vitro Fertilization and Embryo Transfer (IVF-ET). Biomarkers that predict endometriosis including B-cell lymphoma (BCL6) and Sirtuin 1 (SIRT1) are associated with reduced pregnancy rates following IVF-ET. Treatment with gonadotropin releasing hormone (GnRHr) receptor agonists (leuprolide acetate depot) has been shown to improve pregnancy rates following embryo transfer (ET). In this randomized controlled trial, a new generation GnRHr antagonist, elagolix, will be compared to oral contraceptives (OCPs) for suppression of suspected endometriosis prior to ET. Both groups will receive two months of treatment prior to frozen embryo transfer of a single euploid embryo. Outcomes will include pregnancy rate, miscarriage rate and ongoing and live birth rate following treatment. Patients experiencing unanticipated problems or who experience adverse events such that they do not tolerate the treatment they are assigned, will be allowed to discontinue treatment and be provided the opportunity to use the other treatment if they so choose. The outcomes of such cycles would be collected separately and included as observational data only and not included in the randomized data analysis. Alternatively, they can simply drop out of the study and resume medical therapy as appropriate or pursue frozen embryo transfer as previously planned.

Detailed Description
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Although meta-analyses have not demonstrated an effect of endometriosis on IVF outcomes, most women with endometriosis undergoing IVF have not been diagnosed or treated for their disease. Recent evidence suggests that biomarkers for endometriosis predict IVF failure and miscarriage. Further suppression of endometriosis prior to IVF has been shown to dramatically improve pregnancy rates in unexplained infertility with suspected endometriosis. Elagolix (Orilissa) is a new generation FDA approved orally active GnRHr antagonist that is rapidly reversible, for the treatment of endometriosis and pelvic pain. There have been no studies on the efficacy of elagolix for the treatment of endometriosis-associated infertility. Given the recent study in Fertility and Sterility demonstrating IVF outcome prediction using BCL6 as a biomarker for the presence of endometriosis and subsequent preliminary data showing benefit using surgery and GnRH agonist therapy, there is adequate rationale to examine the use of the orally active, non-peptide compound (elagolix) for estrogen suppression prior to frozen embryo transfer in women who test positive for BCL6 and an associated protein, SIRT1. In this multi-central randomized controlled trial (RCT), the EFFECT Trial, the investigators plan to recruit 100 subjects with prior unexplained IVF failure with positive endometrial BCL6/SIRT1 expression. To qualify all subjects will need to have a preimplantation genetic testing (PGT-A) tested euploid embryo and intentions to undergo frozen embryo transfer. Subjects will be randomized to receive elagolix (200 mg BID) or OCPs for 2 months prior to standardized FET. Primary study outcomes will be pregnancy outcome.

Official Title
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Elagolix for Fertility Enhancement Clinical Trial (EFFECT)

Conditions
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Endometriosis, Unexplained Infertility

Intervention / Treatment
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* Drug: Elagolix
* Drug: Oral Contraceptive


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Anti-Mullerian Hormone (AMH) > 0.5 and < 10 At least 1 euploid embryo for transfer Prior endometrial biopsy showing elevated BCL6 and SIRT1 expression Endometrial thickness > 5.9 and < 14 mm Exclusion Criteria: Uterine fibroids > 4 cm (intramural) Polycystic ovary syndrome (Rotterdam criteria) Ovarian failure and donor eggs or oocytes Positive lupus anticoagulant or positive anti-cardiolipin antibody testing Diabetes mellitus (Type I or II) Untreated hypothyroidism Untreated hyperprolactinemia BMI <17 or > 35 Uncorrected uterine anomaly

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 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: Crossover Assignment
Interventional Model Description: Subjects in the OCP group who fail FET but have remaining euploid embryos will be offered 2 additional months of elagolix followed by another FET
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Elagolix<br>Elagolix will be dosed at the higher dose used in pelvic pain trials, 200 mg twice a day for 2 months. | Drug: Elagolix<br>* This orally active, reversible GnRH antagonist will be used to suppress endometriosis by lowering estrogen levels for 2 months prior to FET<br>|
| Active Comparator: Oral contraceptives (Ortho Cyclen)<br>Elagolix will be compared to a less potent standard commonly used prior to IVF or embryo transfer, namely estrogen containing birth control pills. | Drug: Oral Contraceptive<br>* Oral contraceptive prescribed by physician.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing pregnancy rate | The number of viable pregnancies divided by number of frozen embryo transfers | 12 to 15 weeks | 
| Live birth rate | The number of live births divided by number of transfers | 9 months | 
| Number of subjects with categorical outcome of cancellation | based on ultrasound | 1 year | 
| Number of subjects with categorical outcome of not pregnant | based on ultrasound | 1 year | 
| Number of subjects with categorical outcome of biochemical pregnancy | based on ultrasound | 1 year | 
| Number of amniotic sacs | (0, 1, 2, 3) based on ultrasound | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Miscarriage rate | The number of subjects with a first trimester pregnancy loss divided by the number of pregnancies | 15 week |