Determining the Impact of Combined Hormonal Contraceptives on Ulipristal Acetate
Phase: PHASE4
Conditions: Contraception
Sponsor: Oregon Health and Science University

OHSU IRB# 11784 
Protocol Version 2.13.2017 
 
 
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Official Title:  
Determining the Impact of Combined Hormonal Contraceptives on Ulipristal Acetate 
 
 
Principal Investigator: 
Alison Edelman, MD, MPH 
 
Professor, Department of Obstetrics and Gynecology 
Oregon Health & Science University  
 
 
 
 
 
NCT No: 
NCT02577601 
 
 
 
Protocol Version Date: 
February 13, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Determining the impact of combined hormonal contraceptives on ulipristal acetate 
PI: Alison Edelman MD, MPH, Dept. OB/GYN 
Funding: Investigator initiated, Society of Family Planning 
 
Specific Aim:  
1. To define whether starting COCs in close succession (2days) following the administration of 
the anti-progestin, ulipristal acetate, interferes with its efficacy as an EC.  
2. To determine if differences exist between obese and normal BMI women in the 
pharmacokinetics of ulipristal acetate-based EC (pilot data) 
 
Background 
 
The availability of highly effective options for emergency contraception (EC) is critical for 
women wanting to avoid pregnancy following an act of unprotected intercourse.  An anti-progestin, 
ulipristal acetate (UPA; ellaTM), has emerged as one of the most effective oral options1.  In vitro 
studies have shown that UPA binds to the genomic progesterone receptor (PGR) with high affinity2-5, 
leading to the theoretical clinical concern that using UPA in close succession with hormonal 
contraception may adversely impact the effectiveness of either or both methods. A pharma-
sponsored trial under review for publication studied the impact of UPA on the ability of combined oral 
contraception (COC) to suppress ovulation.  Moreover, that study was not designed to determine 
COC’s impact on UPA (personal communication, S Cameron, 3/2015). This knowledge gap places 
women at further risk for unplanned pregnancy.  A woman choosing to take UPA and wanting to 
initiate a hormonal method can either (1) delay initiation of a hormonal contraception for 14 days or 
until her next menstrual cycle8,9 and continue to be at risk for pregnancy using a less effective barrier 
method or (2) immediately initiate the method and possibly decrease the effectiveness of UPA.  
Discussions during the CDC Working Group for US Selected Practice Guidelines for Contraceptive 
Use (Atlanta, GA 10/2011) as well as the recent WHO Medical Eligibility Steering committee meeting 
(2014) noted that this issue should be a priority in light of increasing UPA use.  
Our proposal has been designed to address this gap in knowledge and will focus on the impact 
of COCs on UPA’s main mechanism of action. Our hypothesis is that starting COCs shortly after 
UPA use adversely impacts UPA’s ability to delay ovulation. Our primary aim is to define whether 
starting COCs 2 days following the administration of the anti-progestin, UPA, interferes with its 
efficacy as an EC.  The goal of this aim is to obtain evidence to support or refute the current 
recommendation to have women using UPA for EC to wait to delay initiation of their hormonal 
method. Our proposed studies focus on the interaction of COCs and UPA as COCs are one of the 
most commonly used hormonal methods.  
 
Glasier et al11 demonstrates that there may be differences in the effectiveness of UPA EC in 
women of varying BMIs. Drug therapeutics or how well a drug works is based on several key 
pharmacokinetic parameters – specifically for EC, maximum concentration and time to maximum 
concentration are considered critical. We would like to perform a substudy within this proposal to 
obtain pilot data to determine if there is a difference in pharmacokinetic parameters between obese 
and normal BMI women taking UPA-EC.  
 
Methods: 
Study design: Prospective cohort study. Women will act as their own controls. 
Study Population: Women (total=34) of reproductive-age with a BMI of 18.5-28 will be recruited from 
the Portland area. To account for screen fails and dropouts, we plan to enroll up to 60.  Individuals 
will be recruited through several different venues using IRB approved materials including flyers, 
internet recruiting, and the CWH website.  Individuals meeting inclusion and exclusion criteria for the 

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study will be enrolled following completion of informed written consent. The only contraindication for 
use of UPA-based EC is known current pregnancy but participants will also be exposed to COCs.  
Study inclusion and exclusion criteria include: 
 
Major inclusion criteria include:  
 Generally healthy women aged 18 to 35 with regular menses (every 21-35 days).  
 BMI of 18.5-28 
o Additional substudy group of 5 women will have BMI >28 
 Proven ovulation with a screening serum progesterone of >3ng/mL 
 Willing to use condoms (if sexually active with a male partner), willing to not have sex 
with men during the study, or have had a tubal ligation (or have a partner who has had a 
vasectomy) or have a copper IUD. 
 
Major exclusion criteria include:  
 Known intolerance or allergy to any of the study medication 
 Known metabolic disorders including polycystic ovarian syndrome or uncontrolled 
thyroid disorder 
 Overweight or obese BMI (except for additional substudy group of 5 women) 
 Any CDC Medical eligibility criteria category 3 or 4 for COC use12.  
 Pregnancy, breastfeeding, or seeking pregnancy; recent (8 week) use of hormonal 
contraception 
 Current use of drugs that interfere with metabolism of sex steroids 
 Smokers.  
 
General methods: Subjects will undergo a referent cycle (Cycle 1, UPA only), followed by a washout 
cycle (Cycle 2) and finally UPA with COCs dosed 2 days later (Cycle 3, treatment cycle) (see Table 
1).  Due to the extensive number of visits, blood draws, and exams, the patients will be compensated 
for their time.  Subjects will either receive compensation through the Greenphire debit card system or 
as a check. During the referent and treatment cycles (Cycle 1 and 3, respectively), subjects will 
undergo every other day visits starting on cycle day 6 followed by daily visits for up to 7 days once a 
dominant follicle measuring 15mm or greater in one diameter is visualized.  At each visit, subjects will 
undergo blood sampling via a single venipuncture for P and LH levels and transvaginal 
ultrasonography (TUS).  Study medication will be dosed on the day a 15 mm follicle is visualized. 
Women will be given a single dose of 30 mg UPA orally in Cycle 1 or a single dose of 30 mg UPA 
orally followed 2 days later by a COC (0.150 mg levonorgestrel/30 μg of ethinyl estradiol) in Cycle 3. 
Prior to ingesting study medication, women will undergo urine pregnancy testing. Women can choose 
to continue the COC for the entire 21 days or they can discontinue after 7 days. Women will have a 
washout cycle between the referent and treatment cycles where they will remain in contact with study 
staff for scheduling and retention purposes but will not have any scheduled study visits.  Study end 
will be at the onset of menses (defined as two consecutive days of spotting/bleeding). 
 
 
 
 
 
 
 

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Table 1. Study flow (n = 34) 
 
+ing 
Cycle 1 Referent cycle 
UPA only 
Cycle 2 
Washout 
Cycle 3 
UPA+COC 2 days later 
Study 
Procedures 
Luteal 
phase 
ovulation 
testing 
-Starting day 6 until 15 
mm follicle: every other 
day P, LH, & TUS  
-15 mm follicle: study 
medication dosed and 
daily P, LH, & TUS for 
up to 7 days 
 
-Starting day 6 until 15 
mm follicle: every other 
day P, LH, & TUS  
-15 mm follicle: study 
medication dosed and 
daily P, LH, & TUS for 
up to 7 days 
-COCs dosed 2 days 
after study medication  
 
Data Analysis &Sample Size:  
The primary outcome will be the difference in the proportion of women with a delay in follicular rupture 
up to 5 days (yes/no) between their referent and treatment cycles13. Follicle rupture will be defined as 
the disappearance or >50% reduction of size of the leading follicle.  Confirmation of ovulation will be 
supported by LH and P levels. Demographics will be reported and descriptive statistics will be utilized 
to report LH and P levels [mean (standard deviation], follicular diameter [median (range)], and cycle 
day [median (range)] on the day of UPA ingestion during the referent and treatment cycles.  
Additionally, inhibition of follicular rupture will be plotted by LH status (no surge, start of LH surge, or 
after LH peak; defined in Brache et al.13) for each cycle as well as mean LH and P levels over time 
and the time of treatment to follicular rupture.  
A sample size of 34 will achieve 82% power to detect a 15% difference in the proportion of 
cycles that demonstrate at least a 5-day delay in follicular rupture (yes/no) using a two-sided exact 
binomial test with a 5% significant level. We plan to recruit up to 60 women to account for drop out. 
We based this assumption on the overall effect of UPA which causes persistence of the dominant 
follicle for at least 5-days in 58% of cycles13. If COCs adversely impact UPA by 15% then UPA’s 
efficacy would be similar to that of a levonorgestrel-EC which would be clinically significant.   
 
Substudy: UPA Pharmacokinetics 
Our control group (normal BMI) will be recruited from women enrolling in the main study. Up to 5 
women enrolled in the main study may choose to participate in this substudy. They may choose to 
participate in this substudy either during Cycle 1 or Cycle 3, whichever cycle is most convenient for 
them.  The substudy will be performed over 1 visit but this visit will take approximately 3 hours to 
complete. During this visit, women will undergo serial blood sampling from a “single stick” 
venipuncture or from an indwelling intravenous catheter – per the subject’s choice.  One tube (10mL) 
of venous blood will be collected at the following time intervals in conjunction with UPA ingestion (0, 
0.5, 1, 1.5, 2, 2.5 hours).  UPA will be ingested under fasting conditions and directly observed intake 
will occur.  Women volunteering for this substudy will be compensated for this additional time.  An 
additional 5 obese women will be recruited only to participate in this substudy as obesity is an 
exclusion criteria for the main study.  This group must meet the main study’s eligibility criteria except 
for BMI and confirmed ovulatory status by P value.  Serial blood sampling will be timed to occur 
during the follicular phase of the obese participant’s menstrual cycle. 
 
Human subjects protection: 

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Human Subjects Involvement and Characteristics. Reproductive-aged (18-35 year old), ovulatory, 
healthy women with no contraindications to the study medications and not at risk for or seeking 
pregnancy will constitute the target population for this study.  
 
Setting. All enrollment and clinical evaluations will be performed at OHSU in Portland, Oregon.  
Serum samples will be prepared at OHSU and analyzed at the ONPRC Endocrine Core Laboratory 
under the direction of Dr. David Erickson.  
 
Sources of Materials. The sources of research material for the clinical portion of this proposal will be 
new specimens (blood) and ovarian ultrasound data obtained purely for this research protocol.  The 
study investigators and/or research assistants/nurses will perform all study procedures. 
 
Potential Risks.  In regard to the UPA-based emergency contraceptive used in this study, the only 
contraindication to this medication is current pregnancy (CDC 2013) and this is an exclusion criterion 
for study participation.  The use of EC can affect the timing and duration of a woman’s next menstrual 
period and very rarely can cause nausea and/or headache. This information will be reviewed with 
participants and if necessary, an anti-emetic can be provided.  For the COC utilized in the study, we 
will use a COC that is commercially available and screen women according to the CDC Medical 
eligibility for contraceptive use guidelines.  We plan to use these medications in accordance with 
FDA-labeling.  
 
Women may feel some pain when their blood is drawn through venipuncture or the use of an 
indwelling venous catheter but there is minimal risk involved.  There is a small chance the needle will 
cause bleeding, a bruise, or an infection.   
 
There are no known harmful effects of a transvaginal ultrasound.  Women may experience slight 
vaginal discomfort. 
 
Risk of pregnancy is always present in women who are sexually active.  Women who are not at risk 
for pregnancy due to the use of permanent contraception (male or female), use of a copper IUD, or 
have a female partner will be eligible for the study.  Those women at potential risk of pregnancy will 
be asked to abstain or to use condoms for the duration of the study.   
 
Recruitment and Informed Consent. Attempts to enroll a diverse study population will be made 
through placement of IRB approved recruitment material in the community, community outreach such 
as receiving an emailed newsletter they have opted to receive, and through the availability of foreign 
language interpreters and research staff. Women may also learn of the study through their routine 
visits in clinics or by working at OHSU.  
 
Women will be screened for eligibility and if they meet the basic criteria and agree to participate, they 
will undergo informed written consent. The protocols and consent will be reviewed and approved by 
the OHSU IRB prior to initiation of the study. Information we collect and create in order to conduct 
and oversee this research study will be stored in the Women’s Health Research Unit repository (IRB# 
6748) for possible future research.  
Protection Against Risk.  Confidentiality of personal health information will be maintained according to 
HIPAA requirements for research.  All subjects will receive a study number to which all subsequent 
data will refer.  Personal identifiers will not be on questionnaires, data, abstract sheets, or in the main  

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database.  All data will be kept in locked files or a password protected computer in the Principal 
Investigator’s (PI) office. We will do our best to keep information confidential by keeping it coded and 
on password-protected computer.   
 
Potential Benefits of the Proposed Research to the Subjects and Others. There are no direct benefits 
to study participants. 
 
Importance of Knowledge to be Gained. It is anticipated that the results from this study will determine 
whether close administration of a COC with UPA will inhibit the ability of UPA to function effectively as 
an EC. Since UPA works via its ability to serve as a PGR antagonist, the immediate administration of 
PGR agonists present in COCs will possibly increase the failure rate of UPA due to competing actions 
on PGR signaling. UPA effects include preventing or delaying the midcycle surge of LH that is critical 
for ovulation11 and the expression of progesterone (P) regulated genes in the ovulatory follicle 
necessary for its rupture2. Thus, it is necessary to establish whether the PGR agonists present in 
COCs will negate the ability of UPA to prevent the cellular processes crucial for ovulation and 
consequently fertilization. This information will be critical for determining when to initiate COCs in 
women seeking this form of birth control. In addition, our research team is one of only a very few 
studying molecular and associated clinical aspects of novel and established contraceptives 
We anticipate that the study results will provide evidence for direct clinical guidance regarding 
co-administration of COCs and UPA. We plan to disseminate the data through publication and 
presentations as well as highlighting the results to relevant governmental entities (e.g., CDC) and 
interested parties (e.g., HRA Pharma).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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References 
1. Glasier A, Cameron S, Fine P, Logan S, Casale W, Van Horn J, Sogor L, Blithe D, Scherrer B, 
Mathe H, Jaspart A, Ulmann A, Gainer E. Ulipristal acetate versus levonorgestrel for emergency 
contraception: a randomised non-inferiority trial and meta-analysis. Lancet 2010,375:555–562. 
2. Nallasamy S, Kim J, Sitruk-Ware R, Bagchi M, Bagchi I. Ulipristal blocks ovulation by inhibiting 
progesterone receptor-dependent pathways intrinsic to the ovary. Reprod Sci 2012,20:371-381. 
3. Conneely O. Progesterone receptors and ovulation. Handb Exp Pharmacol 2010:37–44. 
4. Akison L, Robker R. The critical roles of progesterone receptor (PGR) in ovulation, oocyte 
developmental competence and oviductal transport in mammalian reproduction. Reprod Domest Anim 
2012, 47:288–296. 
5. Hild S, Reel J, Hoffman L, Blye R. CDB-2914: anti-progestational/anti-glucocorticoid profile and post-coital 
anti-fertility activity in rats and rabbits. Hum Reprod. 2000;15:822-829. 
6. Edelman A, Jensen J, Hennebold J. A nonhormonal model for emergency contraception: 
prostaglandin synthesis inhibitor effects on luteal function and lifespan, a pilot study. 
Contraception 2010, 81:4961–500. 
7. Edelman A, Jensen J, Doom C, Hennebold J. Impact of the prostaglandin synthase-2 
inhibitor celecoxib on ovulation and luteal events in women. Contraception 2013;87:352-357. 
8. CDC MMWR.US Selective Practice Recommendations for Contraceptive Use, 2013. Vol 62, #5, June 21, 
2013: 35. 
9. FDA. Ella package insert. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf. 
Accessed 4/2/2015. 
10. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and 
characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27:383-91. 
11. Brache V, Cochon L, Jesam C, Maldonado R, Salvatierra A, Levy D, Gainer E, Croxatto 
H. Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays 
follicular rupture. Human Reproduction 2010, 25:2256–2263. 
12. CDC MMWR. US Medical Eligibility for Contraceptive Use, 2010. Vol 59. June 10, 2010. 
13. Brache V, Cochon L, Deniaud M, Croxatto H. Ulipristal acetate prevents ovulation more effectively than 
levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens. 
Contraception 2013;88:611-618. 
14. Glasier A, Cameron S, Blithe D, Scherrer B, Mathe H, Levy D, Gainer E, Ulmann A. Can we identify 
women at risk of pregnancy despite using emergency contraception? Data from randomized trials of 
ulipristal acetate and levonorgestrel. Contraception 2011;84:363-367. 
 

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