Elagolix for Fertility Enhancement Clinical Trial (EFFECT)

Elagolix for Fertility Enhancement Clinical Trial (EFFECT)

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.

Study Overview

• Status: Completed
• Conditions: Endometriosis; Unexplained Infertility
• Intervention / Treatment: Drug: Elagolix; Drug: Oral Contraceptive

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bruce A Lessey, MD, PhD; Phone Number: 336-716-6476; Email: blessey@wakehealth.edu
• Study Contact Backup: Name: Dan Angress; Phone Number: 310-227-6607; Email: dan@cicerodx.com

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Univesity Health Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 42 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Elagolix; Elagolix will be dosed at the higher dose used in pelvic pain trials, 200 mg twice a day for 2 months.	Drug: Elagolix; This orally active, reversible GnRH antagonist will be used to suppress endometriosis by lowering estrogen levels for 2 months prior to FET
Active Comparator: Oral contraceptives (Ortho Cyclen); 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; Oral contraceptive prescribed by physician.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: Stanford University; University of North Carolina, Chapel Hill
• Investigators: Principal Investigator: Bruce A Lessey, MD, PhD, Wake Forest University Health Sciences

Publications and helpful links

General Publications

• Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, Diamond MP, Surrey E, Johnson NP, Watts NB, Gallagher JC, Simon JA, Carr BR, Dmowski WP, Leyland N, Rowan JP, Duan WR, Ng J, Schwefel B, Thomas JW, Jain RI, Chwalisz K. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017 Jul 6;377(1):28-40. doi: 10.1056/NEJMoa1700089. Epub 2017 May 19.
• Surrey E, Taylor HS, Giudice L, Lessey BA, Abrao MS, Archer DF, Diamond MP, Johnson NP, Watts NB, Gallagher JC, Simon JA, Carr BR, Dmowski WP, Leyland N, Singh SS, Rechberger T, Agarwal SK, Duan WR, Schwefel B, Thomas JW, Peloso PM, Ng J, Soliman AM, Chwalisz K. Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies. Obstet Gynecol. 2018 Jul;132(1):147-160. doi: 10.1097/AOG.0000000000002675. Erratum In: Obstet Gynecol. 2018 Dec;132(6):1507-1508.
• Likes CE, Cooper LJ, Efird J, Forstein DA, Miller PB, Savaris R, Lessey BA. Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression. J Assist Reprod Genet. 2019 Mar;36(3):483-490. doi: 10.1007/s10815-018-1388-x. Epub 2019 Jan 4.
• Almquist LD, Likes CE, Stone B, Brown KR, Savaris R, Forstein DA, Miller PB, Lessey BA. Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study. Fertil Steril. 2017 Dec;108(6):1063-1069. doi: 10.1016/j.fertnstert.2017.09.017. Epub 2017 Nov 7.
• Littman E, Giudice L, Lathi R, Berker B, Milki A, Nezhat C. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril. 2005 Dec;84(6):1574-8. doi: 10.1016/j.fertnstert.2005.02.059.

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2022
• Primary Completion (Actual): August 9, 2023
• Study Completion (Actual): August 9, 2023

Study Registration Dates

• First Submitted: July 25, 2019
• First Submitted That Met QC Criteria: July 30, 2019
• First Posted (Actual): July 31, 2019

Study Record Updates

• Last Update Posted (Actual): January 9, 2024
• Last Update Submitted That Met QC Criteria: January 5, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Infertility; Endometriosis; Physiological Effects of Drugs; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptive Agents; Contraceptives, Oral
• Other Study ID Numbers: IRB00059474

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No