Elagolix for Fertility Enhancement Clinical Trial (EFFECT)
Phase: PHASE2
Conditions: Endometriosis, Unexplained Infertility
Sponsor: Wake Forest University Health Sciences

Official Title:  Elagolix for Fertility Enhancement Clinical Trial (EFFECT) 
NCT04039204
IRB-Approved Date: 6/1/2023

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Study Title: Elagolix for Fertility Enhancement Clinical Trial (The EFFECT Trial) 
Principal Investigator: Bruce A Lessey MD, PhD (Wake Health) 
Co-Investigators: Steven L. Young MD, PhD (University of North Carolina, Chapel 
Hill) and Ruth Lathi, MD, Stanford University 
Sponsor or funding source: (e.g. NIH, NICHD) 
Background, Rationale and Context 
Endometriosis is defined as the presence of endometrial glands and stroma outside the 
endometrial cavity. It affects at least 176 million women worldwide and over 10 million in 
the U.S.A., result in in an annual U.S. cost of over $22 billion. The impact on IVF has 
not been well studied, since most women with the disease are not counted, and those 
included in meta-analyses have already been surgically treated.  Recent work from our 
laboratory has identified two endometrial proteins, BCL6 and SIRT1, that are associated 
with endometriosis and together cause progesterone resistance, the sine quo non of 
endometriosis (Evers-Hoeker et al 2017; Yoo et al, 2018). The over-expression of BCL6 
has been shown to be associated with IVF failure (Almquist 2018; Figure 1) and had a 
high sensitivity and specificity for detection of endometriosis (Ever-Hoeker et al, 2017).  
Recurrent IVF implantation failure has also been shown to be treatable with suppression 
of menses using leuprolide acetate, letrozole, or both together (Surrey et al., 2017; 
Miller et al., 2012; Steiner et al., 2019).  Furthermore, treatment of women with elevated 
BCL6 with surgery or medical suppression for 2 months prior to embryo transfer 
(Lupron) improves outcomes compared to controls (Likes et al, 
2019).  
Figure 1: BCL6 and IVF success. The darker staining for 
BCL6 
provides 
an 
indication 
for 
the 
presence 
of 
endometriosis. When women entering an IVF cycle were 
tested, those positive for BCL6 (> 1.4 HSCORE) had a 
significantly decreased pregnancy rate compared to women 
with low BCL6.(Almquist et al., 2018). 
Elagolix (Orilissa) is a new generation FDA approved orally active GnRH 
antagonist that is rapidly reversible, for the treatment of endometriosis and pelvic 
pain (Taylor et al., NEJM 2018). There have been no randomized controlled trials 
examining the efficacy of elagolix for the treatment of endometriosis-associated 
infertility. Given the recent study in Fertility and Sterility demonstrating that IVF 
outcome prediction using BCL6 and subsequent preliminary data showing benefit 
using surgery and GnRH agonist therapy (Likes et al., 2019), and data on 
recurrent implantation failure responding to GnRH agonist and aromatase 
inhibitors (Steiner et al., 2019), there is adequate rationale to examine the use of 
this orally active, non-peptide compound (elagolix) for menstrual suppression prior 
to frozen embryo transfer in women who test positive for SIRT1 and BCL6 and 
therefore has suspected endometriosis.  In addition, during the conduct of this 
RCT to study elagolix treatment to study pregnancy outcomes and miscarriage 

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(primary and secondary outcomes), we are collecting blood (estradiol and 
cytokine measurements) to study the effect of medical suppression on 
inflammatory biomarkers in blood as well.  
 
Objectives 
To perform a prospective, open label randomized controlled trial for women who 
failed IVF with euploid embryos who have suspected endometriosis based on 
elevated elevated SIRT1/BCL6, comparing 2 months of elagolix (200 mg BID) to 
oral contraceptives (orthocylen; OPCs).  
Primary clinical objective is to determine methods to improve clinical pregnancy 
rates in these subjects who later undergo frozen embryo transfer with euploid 
(genetically tested) embryos.  
 
Justification 
The study will examine whether elagolix is superior to OCPs for fertility 
enhancement prior to frozen embryo transfer in women with unexplained prior 
implantation failure with euploid embryos. We will only use 200 mg twice a day 
dosing of elagolix, since the once daily approved dose of 150 mg does not reliably 
prevent ovulation and menstruation (Taylor et al., 2017). In women with 
menstruation, breakthrough bleeding or ovulation, a lower dose will efficiently 
eliminate the inflammatory changes that we are hoping to suppress. Further, we 
the goal of our study is to mimic depot leuprolide acetate which is completely 
suppressive of menstruation; thus the 200 mg BID dose, which is FDA approved 
for treatment of moderate to severe pelvic pain, will be used. It is possible that 
elagolix treatment will not be superior to OCPs. There has not been a head to 
head comparison of either elagolix or leuprolide acetate for endometriosis related 
symptoms of pain or infertility, so this type of comparison is needed.  
 
Methods and Measures 
 
Patients with at least one unexplained IVF failure after transfer of a normal euploid 
embryo who previously test positive for BCL6 and SIRT1 will be eligible to 
participate. Each will undergo initial endometrial biopsy, blood draw in the mid-
secretory phase. Data will be evaluated separately to estimate the prevalence of 
positive BCL6 and/or SIRT1 in this group of women with failed euploid embryo 
transfer.  Results of the biopsy will be shared with the patient and the clinicians 
performing the FET cycle, indicating whether they will be eligible for enrollment in 
the study.  Inclusion criteria will include, therefore, over-expression of endometrial 
proteins SIRT1 and BCL6 and the availability of frozen euploid embryos for a 
future FET. Each subject who agrees to enroll will be randomized to one of two 
treatment arms (elagolix 200 mg BID or an oral birth control pill for two months).   
After completion of 2 months of treatment, blood collection will be performed on all 
subjects. The treatments will not be blinded to the patient and the researchers. All 
subjects at the conclusion of treatment will undergo immediate entry into a 

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standardized frozen embryo cycle (FET) cycle using a single euploid embryo. 
Eight days after embryo transfer, serum hCG levels will be obtained on day 8 after 
the FET. Outcomes will be recorded including estradiol, progesterone and hCG 
measurements and documentation of pregnancy outcomes based on ultrasound. 
The outcome variables will include 1) cancellation; 2) not pregnant; 3) biochemical 
pregnancy; 4) ongoing pregnancy (sac with cardiac activity) and 5) live birth rate.  
Miscarriage rate will be calculated based pregnancy loss/number of pregnancies 
(not counting biochemical pregnancy).   
FET cycles will begin without intervening menstruation. Subjects will begin estrace 
2 mg for 4 days, going to 4 mg for 4 days and then back to 2 mg for 4 days. 
Progesterone in oil IM injections will be started when the lining is > 6 mm and has 
a trilaminar appearance. Transfer will occur 126 hours after the start of 
progesterone, which is continued until 10 weeks gestation if pregnant. If the hCG 
test is negative, POI will be discontinued.  
If the FET is delayed for any reason, whatever treatment the subject is on 
(elagolix or OCPs) will be extended for up to 2 weeks to avoid interruption in 
treatment prior to embryo transfer.  
 
Design 
A prospective randomized open label controlled trial. Primary outcome will be live birth 
rate, with secondary outcomes including pregnancy rates, miscarriage rates, measures 
of inflammation, after treatment at the time of frozen embryo transfer. 
 
Programmed FET Cycle 
i. Patients will be advised to call within a week of stopping the last dose 
of treatment 
ii. On day 3 after stopping, patients should begin taking estradiol 2mg PO 
BID 
iii. First monitoring visit should be scheduled for cycle day 9-11 and 
should include E2, P4, LH, and pelvic ultrasound 
1. If endometrium is > 7mm and trilaminar, initiation of 
progesterone may be scheduled to facilitate FET on desired 
date 
2. If endometrium is < 7mm and/or not trilaminar, estradiol should 
be increased to 2mg PO TID and another monitoring visit should 
be scheduled in 4-5 days 
iv. Timing of progesterone start 
1. If endometrium is > 7mm and trilaminar, initiation of 
progesterone may be scheduled to facilitate desired FET date 
2. In all cases, progesterone should be initiated with the goal of 
126 hours of progesterone exposure prior to FET 
3. Progesterone to be utilized is progesterone in oil (PIO) 50mg IM 
daily 

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v. Consideration should be given to cycle cancellation in the following 
circumstances: 
1. Endometrium < 7mm after 2-3 weeks of exogenous estradiol 
2. Persistent non-trilaminar endometrium after 2-3 weeks of 
exogenous estradiol 
3. Presence of significant fluid in the endometrial cavity 
4. If follicular recruitment is noted, conversion to natural cycle FET 
may be considered 
 
Setting 
 
The EFFECT trial will be conducted at three academic teaching institutions with 
accredited Reproductive Endocrinology and Infertility (REI) programs involved in In Vitro 
Fertilization cycles.  Wake Forest will be the central IRB and provide data safety 
monitoring board (DSMB) capabilities for the study.  
 
Subjects selection criteria 
 
Only patients with previous IVF failure who are suspected or known to have 
endometriosis on the basis of elevated endometrial BCL6 and SIRT1 will be included in 
this study.  The selection criteria includes the use of these two biomarkers as which 
defines a specific study population of interest. This inclusion of biomarkers was part of 
an NIH proposal that was submitted to and funded by the NIH. SIRT1 is strongly 
induced by resveratrol which has been shown to reduce embryo implantation (Ochiai 
2019a) and endometrial decidualization (Ochiai  2019b), supporting the biology as 
outlined in this proposal. We hypothesize that suppression of endometriosis will have 
the effect of reducing cytokines associated with inflammation which is part of the 
endometriosis pathogenesis. Each participant will be required to have at least 1 euploid 
embryo (preimplantation genetic tested and normal) with intentions to transfer that 
embryo in a frozen embryo transfer (FET) cycle.  
 
• Inclusion Criteria 
1. Age – 18 to 42 
2.  Parity – G0 or greater 
3.  AMH ≥ 0.5 and ≤ 10 
4.  Planning to undergo FET and PGT-A within 1 year of enrollment 
5.  Must have blastocyst(s) by day 6 that were biopsied for PGT-A 
6.  Has a previous endometrial biopsy showing elevated BCL6 and SIRT1 
expression. 
7.  Endometrial thickness at time of transfer ≥ 6 and ≤ 14 
• Exclusion Criteria 
1. Uterine fibroids > 4 cm in size, if intramural  
2.  Polycystic ovary syndrome (PCOS) according with the Rotterdam criteria 
3.  Ovarian failure and subjects receiving donor oocytes/embryos 
4.  Failure to identify at least 1 euploid embryo for FET 

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5.  Anti-cardiolipid and/or lupus anti-coagulant abnormalities by history 
6.  Diabetes mellitus (Type I or Type II) 
7.  Untreated hypothyroidism 
8.  Hyperprolactinemia 
9.  BMI ≤ 17 and ≥ 40 
10.  Uncorrected uterine anomaly 
11.  Women with osteoporosis 
12.  Women with moderate or severe hepatic impairment defined by Child-Pugh 
Classes B (moderate) and C (severe) 
13.  Women using strong CYP3A inhibitors (e.g. ketoconazole, clarithromycin) 
14. Women at high risk of thromboembolic disorders including those that smoke, 
have cardiac valvular disease, atrial fibrillation, hypertension not controlled by 
medication, and a history of severe migraines.  
15. Severe renal disease with GFR < 15 ml/min. 
 
Sample Size 
 
Based on previous studies (Likes et al., 2019) we calculated that 50 patients (25 per 
arm) are required to have a 90% chance of detecting, as significant at the 5% level, an 
increase in the primary outcome measure from 11% live birth in the OCP group to 50% 
in the elagolix group. We decided to include 50 subjects per treatment arm (elagolix 
200 mg BID vs OCPs) for 2 months, because unlike the Likes study, we are not using a 
no treatment control arm, and OCPs may have some benefit over no treatment. Having 
a non-randomized, no treatment control group to follow will allow us some flexibility, 
however, in comparing outcomes over time. 
 
Enrollment may vary between sites, but we hope to recruit approximately 1/2 of the 
subjects at our site with the remainder at each of the other 2 sites (UNC and Stanford).  
We will perform interim analyses after 25 subjects per arm for safety assessment. 
Based on the 12 months of treatment in the original study (Taylor et al., 2017), safety 
concerns are minimal. Nevertheless, we will halt the study using the following stopping 
rules:  
1) If after 25 subjects per arm, the OCP ongoing pregnancy rate is higher than the 
treatment arm with elagolix 
2) There is no difference between the no treatment controls and the elagolix treatment 
are at 25 patients per arm 
 
We will perform an interim analysis after 25 subjects per arm to recalculate sample size 
requirements based on the outcomes at that point (Kuman and Chakraborty 2016). 
 
The choice to use oral contraceptives as a comparator group was made based on 
surveys of potential subjects who voiced concerns about being assigned to a placebo 
(no treatment) arm. It was felt, and the NIH reviewers agreed, that having an active 
comparator group would be acceptable.  OCPs, while a first line treatment for 
endometriosis, may not be as suppressive of endometriosis as traditional GnRH agonist 
therapy, although no head to head comparison studies are available.  Finally, the 

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choice to not compare 2 doses of elagolix is based on published results from the 
Taylor study (Taylor et al., NEJM, 2017) showing a high proportion of subjects in the 
150 mg per day dosing group that ovulated and/or menstruated. Bleeding, ovulation or 
menstruation is a clearly defined problem that would increase inflammation instead of 
decreasing it, which is the goal of this study. 
 
Interventions and Interactions 
 
Visit 1: Screening and enrollment. Following initial screening of potential subjects 
with an IVF failure, a positive SIRT1 and BCL6 on endometrial biopsy and 
available euploid embryos for transfer, patients will meet with the research nurse 
who will review all inclusion and exclusion criteria and obtain informed consent 
from eligible patients.   
Visit 2  First day of menses. Patients will be instructed to call with the menses at 
which time an hCG measurement will be made to rule out pregnancy. Subjects 
will be prepared for their two treatment cycles. Patients will be randomized using 
computer generated assignments to receive either 200 mg of elagolix twice daily 
or daily OCPs (Ortho Cyclen). The medications will be formulated into 2 tablets 
per day to blind the subjects and researchers. The center will call and receive the 
treatment by means of an interactive voice-response system. The trials will be 
conducted in accordance with International Conference on Harmonisation 
guidelines and applicable regulations and ethical principles of the Declaration of 
Helsinki. All the women provided written informed consent for the study protocol. 
Women will be instructed to use two forms of non-hormonal contraception; 
monthly pregnancy tests were performed including an initial hCG test prior to 
beginning the medication. During the course of two months of treatment subjects 
will be encouraged to call in and speak to the research nurse or their clinician with 
any concerns or reports of side effects. Bone mineral or other safety parameters 
previously performed in the Elaris I-IV studies by Abbvie showed that we should 
not expect adverse events due to the brevity of the exposure. 
 
Visit 3: All subjects will be seen at 1 month time interval and adverse reactions to 
the medial treatments reviewed and recorded. The second month of medications 
will be dispersed at that time. Adverse events will be coded with the use of 
the Medical Dictionary for Regulatory Activities, versions 19.0. We will use 
Fisher’s exact test to compare the incidence of any adverse event in the elagolix 
group with the incidence in the OCP group. All reported P values will be 
considered two-sided, and confidence intervals for safety end points will be 
considered relevant at the 95% level. 
 
Visit 4:  After completion of 2 months of treatment with  elagolix or OCPs,  
subjects will return for collection of blood (serum and plasma) which will be 
collected, processed and stored at -80° C for later evaluation. Subjects will be 
prepared for the upcoming FET cycle. 
 

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Visit 5: Completion of the study. Patients will return periodically for standardized 
treatments as part of their FET cycle for endometrial preparation, ultrasound and 
embryo transfer as dictated by the clinicians in the practice. Outcomes will be 
recorded and extracted from their SART database for pregnancy included 
extended follow-up for live birth rate.  
 
Patients experiencing unanticipated problems with the protocol 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. 
 
Outcome Variables 
The following outcome data will be collected on each subject: 
1) BCL6/SIRT1 HSCOREs 
2) hCG level (first) 
3) Progesterone levels at first hCG measurement (ng/dl) 
4) hCG level (second) 
5) Pregnancy outcome (not pregnant, pregnant biochemical, pregnant 
miscarriage, pregnant ectopic, pregnant ongoing, pregnant delivered, 
pregnant 2nd or 3rd trimester loss) 
6) Categorical outcome (pregnant/not pregnant; summary designation) 
7) Comments related to overall outcomes 
8) Number of sacs (0, 1, 2, 3) 
 
 
Independent Variables 
The following demographic data will be collected on each subject: 
1) Age (based on date of birth) 
2) Weight 
3) BMI 
4) Gravidy/Parity  
5) Randomization group (elaglox, OCPs, non-randomized control) 
6) Embryo grade 
7) Number of remaining euploid embryos 
8)  PGT-A results (narrative) 
9)  Endometrial thickness  
10) Peak estradiol levels (pg/dl) 
11) Comments regarding embryo transfer 
12) Embryo transfer physician (name) 
13) Number of embryos transferred (confirm that 1 was transferred) 
 

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Analytical Plan 
Statistical analysis: Statistical analyses will be performed using the Student’s t-
test for data from the two groups. All data will be presented as means ± SEM. p < 
0.05 was considered statistically significant.  Fisher's exact test, relative risk, and 
95% confidence interval (CI) will be used for comparisons of categorical data.  
 
Independent Variables. 
Measurement of hormones. Estrogen, progesterone and hCG assays will be run 
by the hospital’s clinical laboratories using a competitive antibody technology. 
Venous blood will be drawn into serum separator tubes and taken immediately to 
the clinical lab for processing (available 24 hours per day).  
 
Results will be analyzed initially using descriptive statistics.  Comparison between 
groups will be done using chi square tests for proportions, and t-tests for continuous 
variables.  Regression analysis will be performed to identify independent outcome 
predictors.  Other inferential statistical analysis will be conducted as appropriate. 
 
Human Subjects Protection 
 
Subject Recruitment Methods 
Subjects who failed IVF or FET with a previous endometrial biopsy showing elevated 
endometrial BCL6 and SIRT1 will be identified as part of ongoing care.  We do not 
discriminate on the basis of race or economic status, although we do have age and BMI 
cut-off criteria defined in the protocol.  Subjects will be approached in the privacy of the 
clinic and all conversations will be confidential. 
 
• We plan to use a recruitment flyers in the clinic to help motivate and identify 
willing subjects. A copy of this poster is provided with the submission material 
for IRB review. 
• Privacy will be protected and no records kept until subjects/patients agree to 
participate in the study?   
• If an individual declines participation including randomization any and all 
documents will be destroyed.  
 
Informed Consent 
 
Signed informed consent will be obtained from each subject by her physician or a clinic 
research nurse. Consent will be obtained in the CFEM clinical space where patients 
receive their care from the REI unit.  Other centers will use clinical research staff to 
consent patients in private offices under similar conditions.  
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that 
could directly identify subjects, and maintaining all study information in a secure 
manner.  To help ensure subject privacy and confidentiality, only a unique study 

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identifier will appear on the data collection form.  Any collected patient identifying 
information corresponding to the unique study identifier will be maintained on a linkage 
file, store separately from the data.  The linkage file will be kept secure, with access 
limited to designated study personnel.  Following data collection subject identifying 
information will be destroyed 3 years after completion of the study, consistent with data 
validation and study design, producing an anonymous analytical data set.  Data access 
will be limited to study staff.  Data and records will be kept locked and secured, with any 
computer data password protected.  No reference to any individual participant will 
appear in reports, presentations, or publications that may arise from the study. 
 
Data and Safety Monitoring 
The principal investigator and PIs at UNC and Stanford will be responsible for the 
monitoring of the data and safety of study participants.  The principal investigator will be 
assisted by other members of the study staff. A data safety monitoring board (DSMB) 
through WFBH will be established to oversee the entire project.  
 
Per FDA request, we will assess suicidal ideation as part of our safety evaluation. At 
each visit subjects will be asked whether they have had any thoughts of self-harm as 
part of their encounter or if there has been any change in thoughts that include suicide.  
This screening will be two part, since this drug has been well studied and suicide risk is 
considered very low (Taylor et al., 2017). If a subject reports having suicidal ideation, 
we will use the PHQ-9 survery, commonly used in primary care. This instrument has a 
sensitivity of 78% and specificity of 70% (Runeson et al, 2017) and refer the individual 
for psychiatric evaluation. Subjects will be withdrawn from the study based on the 
outcomes of these two steps if they appear to be affected by either treatment toward 
self harm. 
 
We will exclude subjects with moderate to severe hepatic or renal disease or 
osteoporosis. We have added to the consent information on avoidance of pregnancy.  
 
Any pregnancy resulting in live birth that arises while taking active drug (elagolix or 
OCPs) will be identified and followed up to 1 year for any problems that might arise as a 
result of exposure as an early fetus.  
 
Excessive or unexpected bleeding may be considered an adverse event since the 
purpose of this study is to achieve and maintain amenorrhea for subjects prior to their 
next frozen embryo transfer. 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or 
protocol changes will be promptly reported by the principal investigator or designated 
member of the research team to the IRB and sponsor or appropriate government 
agency if appropriate. 
 
 
 

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vitro fertilization outcomes: a cohort study. Fertility and sterility. 2017; 108: 1063-9. 
 
Evans-Hoeker E, Lessey BA, Jeong JW, et al. Endometrial BCL6 Overexpression in 
Eutopic Endometrium of Women With Endometriosis. Reprod Sci. 2016; 23: 1234-41. 
 
Kumar A, and Chakraborty BS. Interim analysis: A rational approach of decision making 
in clinical trials. J Advanced Pharmaceutical Tech and Res.2017; 7:118-122. 
 
Lessey BA, Lebovic DI, Taylor RN. Eutopic endometrium in women with 
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Med. 2013 Mar;31(2):109-24. 
 
Likes CE, Cooper LJ, Efird J, Forstein DA, Miller PB, Savaris R, Lessey BA. 
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Miller PB, Parnell BA, Bushnell G, Tallman N, Forstein DA, Higdon HL 3rd, 
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Ochiai A, Kuroda K, Ikemoto Y, Ozaki R, Nakagawa K, Nojiri S, Takeda S, 
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Steiner N, Shrem G, Tannus S, Dahan SY, Balayla J, Volodarsky-Perel A, Tan SL, 
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