Conditions: Obesity
Keywords: Obesity Body weight Emergency contraception Levonogestrel Ulipristal acetate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: yes

Brief summary:
Obese women are significantly more likely than their normal BMI counterparts to experience failure of orally-dosed emergency contraceptives. The PI's preliminary data provides evidence for testing a dose escalation strategy in an effort to provide improved efficacy from orally-dosed emergency contraceptives in obese women. The overall project will be focused on both levonorgestrel (LNG) - and ulipristal acetate-containing emergency contraception but this protocol registration is for the LNG aspect of the study procedures.

Detailed description:
Emergency contraception (EC) provides a woman with an additional line of defense against unintended pregnancy following an act of unprotected intercourse. Orally-dosed EC works by delaying ovulation and reduces the risk of pregnancy for a single act of unprotected intercourse by 50-70%. Unfortunately, obese women are significantly more likely than their normal BMI counterparts to experience failure of orally-dosed EC and in some instances EC is equivalent to placebo.

The PI's preliminary data provides evidence for testing a dose escalation strategy in an effort to provide improved efficacy from orally-dosed EC in obese women. The hypothesis is that increasing the dose of orally-dosed EC agents will normalize the pharmacokinetics resulting in the expected treatment effect (delay in follicle rupture) in obese women. In the overall proposal, the investigators plan to perform detailed pharmacokinetic and pharmacodynamic studies of ulipristal acetate-based EC in obese women and expand upon the preliminary findings of levonorgestrel-based EC. This protocol registration is for the LNG aspect of the study procedures focused on the pharmacodynamics of LNG dose escalation

Arms:
arm 1: Levonorgestrel 1.5 mg orally x 1 dose. Timing of dosage depends on ovarian follicle measurements. arm 2: Levonorgestrel 3mg orally x 1 dose. Timing of dosage depends on ovarian follicle measurements.

Interventions: intervention 1: Levonorgestrel-based emergency contraception 1.5 mg intervention 2: Levonorgestrel-based emergency contraception 3.0mg
Intervention descriptions: intervention 1: Evaluating pharmacodynamic outcomes in obese women using 1.5mg versus 3.0mg of LNG-based EC intervention 2: Evaluating pharmacodynamic outcomes in obese women using 1.5mg versus 3.0mg of LNG-based EC

Protocol document:
Prot_SAP_000.pdf: 
Protocol v6.0 – 6.25.2021 
 
Page 1 of 12 
Template Revised: 1.22.2014 
 
Improving the effectiveness of orally dosed emergency contraceptives in women of varying 
weights/BMIs  
PI: Alison Edelman MD, MPH, Dept. OB/GYN 
Funding: Investigator initiated, National Institutes of Health 
 
Specific Aim:  
1. To determine if dose escalation for emergency contraception containing levonorgestrel results 
in improved pharmacodynamics outcomes for obese women. 
2. To compare the pharmacokinetic parameters and pharmacodyanmic profile of emergency 
contraception containing ulipristal acetate between obese and normal BMI women, and to 
determine if dose escalation improves how well it works in obese women. 
 
Background 
Emergency contraception (EC) provides a woman with an additional line of defense against unintended 
pregnancy following an act of unprotected intercourse. Orally-dosed EC [levonorgestrel (LNG) or ulipristal 
acetate (UPA)] works by blocking ovulation and reduces the risk of pregnancy for a single act of unprotected 
intercourse by up to 90% [1–3]. Unfortunately as the majority of U.S. women are either overweight or obese, 
LNG-based EC has diminished or no efficacy, the equivalent of taking a placebo pill [4–6]. Prevention and 
planning of pregnancies is critical as obese pregnant women are at higher risk of pregnancy complications 
endangering their own health and the development and post-natal health outcomes of the fetus [7]. Prior 
research from our group and others has proven that obesity adversely impacts the pharmacokinetics (PK) of 
contraceptive steroid hormones in combined (estrogen and progestin) oral contraceptive pill users [8,9]. In 
particular, drug half-life and clearance are affected. These changes in turn, cause a lower maximum 
concentration (Cmax) and a time delay in achieving Cmax and steady state [8–11]. This prior work provides 
insight into a possible mechanism for EC failure in obese users. As a single-dose therapy, EC is reliant on 
achieving a rapid peak level at a critical time point prior to the LH surge [12,13]. The PK profile following oral 
administration of LNG-EC is similar to that of LNG-based oral contraceptives, just a magnitude higher due to 
differences in the dosage [14]. We suspected that a critical level of the drug sufficient to block the LH surge is 
not being achieved in obese EC users. To test this, we performed preliminary studies and demonstrated that 
Cmax levels following oral administration of LNG-based EC are 50% lower in women of obese relative to 
normal body mass index (BMI) (15). 
 
We also tested an alternative dosing strategy in an effort to counteract these PK changes and demonstrated 
that obese women taking double the approved LNG EC dose normalized the PK profile to that of normal BMI 
women. Although a “take two” strategy could be rapidly implemented into clinical practice, we have no data on 
the resulting end-organ effects. Further studies are needed to document if PK normalization results in 
improved pharmacodynamic (PD) outcomes. Another alternative treatment strategy is to use a UPA-based EC 
instead. UPA is slightly more effective than LNG-based EC as it has a longer window of action (e.g. effective 
until LH peak vs. LH rise) [2]. However, published data demonstrate a possible decline in efficacy for obese 
women [4]. Detailed PK and PD studies for UPA have yet to have been performed in obese women but 
unpublished data from a colleague at Columbia University also demonstrated PK differences (personal 
communication 4-2016).  
 
The overall goal of this research is to improve EC effectiveness and quality of clinical care for obese women. 
We hypothesize that increasing the dose of LNG- and UPA-based EC will normalize PK (specifically the time 
needed to reach a therapeutic drug level) and PD outcomes (follicle rupture) in obese women who weigh 80kg 
or greater. In this application we propose to expand our model for LNG- to UPA-based EC, assess the 
pharmacodynamic outcomes of these alternative dosing regimens (“take two”) in obese women and to assess 
the safety and acceptability of these regimens in this population.  
 
Methods: 
Study design: This is a 2-part study: Part 1 will be focused on LNG-EC and Part 2 will be focused on UPA-EC. 
Eligible women can take part in both aspects of the study and in no particular order. If they do chose to enroll 


Protocol v6.0 – 6.25.2021 
 
Page 2 of 12 
Template Revised: 1.22.2014 
in both aspects of the study, then the screening visit does not need to be repeated unless it has been greater 
than 12 months since the original screening visit.  
 
Part 1 LNG-EC is a randomized control trial. Part 2 UPA-EC is a randomized cross-over study with an 
additional non-randomized control arm. 
 
This study will be conducted at Oregon Health & Science University (OHSU) in Portland, OR and a subcontract 
site, Eastern Virginia Medical School (EVMS) in Norfolk, Virginia. EVMS will be overseen by their own IRB.  
 
Study Population: Generally healthy, ovulatory women of reproductive-age (18-35yo) will be recruited from the 
Portland area. To account for screen fails and dropouts, we plan to enroll up to 80 women in Part 1 and 92 
women in Part 2 (80 obese, 12 normal BMI).   
 
Individuals will be recruited through several different venues using IRB approved materials including but not 
limited to flyers, internet recruiting, and the CWH website.  Individuals meeting inclusion and exclusion criteria 
for the study will be enrolled following completion of informed written consent. The only contraindication for 
use of LNG-EC or UPA-EC is a known current pregnancy.   
 
       Study inclusion and exclusion criteria include: 
Major inclusion criteria include:  
 
Generally healthy women aged 18 to 35 with regular menses (every 21-35 days).  
 
Have a BMI of < 25mg/k2 and a weight of less than 176 lbs  
           OR have a BMI of >30 mg/k2 and a weight of 176 lbs or more. 
 
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, 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 diabetes, polycystic ovarian syndrome, or uncontrolled 
thyroid disorder 
 
History of bariatric surgery 
 
Initiating or participating in a weight loss program 
 
Pregnancy, breastfeeding, or seeking pregnancy 
 
Recent (8 week) use of hormonal contraception 
 
Current use of drugs that interfere with metabolism of sex steroids 
 
Smoking or vaping 
 
Chronic marijuana use (3-4 days per week or more) 
 
Recruitment and Informed Consent: Attempts to enroll a diverse study population will be made through 
placement of IRB approved recruitment material in the community. Women who express interest in 
participating will be telephone screened to assess initial eligibility. Participants may also complete the 
Women’s Health Research Unit contact form found online. This will allow study staff to contact potential 
participants about the study. In order to collect protected health information (PHI) prior to participants signing 
consent, a Waiver of Authorization (WoA) will be requested. Participants will also be asked whether or not they 
prefer to receive a secure or non-secure emails from the study team. Secure emails would be sent when 
message includes PHI while non-secure would be for study visit reminders. 
 
Information collected through the telephone screen and the online WHRU contact form will be stored in a 
locked office, with access limited to study staff. For subjects electing to enroll in the study, this information will 
become a part of their protected research record. For subjects choosing not to enroll, all PHI will be stored 
confidentially with the research study information in a locked cabinet and archived with other study-specific 
documents at the close of the trial. All potential participants that contact the department for research studies 


Protocol v6.0 – 6.25.2021 
 
Page 3 of 12 
Template Revised: 1.22.2014 
 
will be added to a password-protected log listing their contact information, only accessible through OHSU 
password-protected computers by study staff. Telephone screens and the log containing potential participants’ 
information are saved to ensure that our department has a record of contact with the participant and to monitor 
our recruitment outreach efforts. Confidentiality of personal health information will be maintained according to 
HIPAA requirements for research and all data will be kept in locked files or in a password-protected document 
on a password protected computer.    
 
Women will be screened for eligibility and if they meet the basic criteria and agree to participate, they will 
undergo informed written consent. Study participants may also be asked to review the consent with study staff 
over the phone or video conference in order to limit time spent in clinic during the COVID-19 pandemic. In this 
case, a copy of the consent form will be emailed to study participants prior to the consenting process. After 
fully reviewing the consent with a participant and answering all study-related questions, study staff will note on 
the verbal consent memo both the date and time that the virtual consent was obtained or denied. In the case 
that verbal consent is given, participants will wet-sign the consent form and the attestation of verbal consent 
memo when coming in for required in-person activities. 
 
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 may be stored in the 
Women’s Health Research Unit repository (IRB# 6748) for possible future research if the participant opts to 
participate in the repository.  
 
Compensation: Women will be compensated for study participation via ClinCard debit card or check. If they 
discontinue early, they will receive a prorated amount based on the number of visits completed. The 
compensation amount will depend on the part of the study women participate in and is listed as follows: 
 
UPA Obese full PK:  up to $1520  
 
UPA Obese no PK: up to $1220 
 
LNG obese: up to $620 
 
UPA Normal BMI control: up to $720 
Participants who participate in the PK portion of the study will also receive a $10 gift card to OHSU cafes.  
 
 
 
PART 1. LNG-EC (obese BMI and a weight of 176 lbs or more), randomized controlled trial 
 
Specific Aim: To determine if dose escalation for emergency contraception containing levonorgestrel results 
in improved pharmacodynamics outcomes for obese women. 
 
Hypothesis: A dose increase of LNG-EC will provide greater follicle delay/inhibition in obese women. 
 
Rationale: Dose escalation is a commonly used strategy in pharmacotherapuetics [16]. We have already 
tested this strategy in our preliminary studies and demonstrated that we can normalize the LNG peak level in 
obese women by doubling the dose. It remains unknown if this improved drug level will translate into better 
end-organ suppression. However, we have had prior success with improved end organ suppression with dose 
escalation in our studies of oral contraceptives in obese women [11] thus we have confidence in this strategy 
for EC. The findings of our proposed studies, whether positive or negative, will provide critical information as 
we will have either proven or disproven if this potential solution works. 
 
Part 1 LNG-EC: 
The study flow for Part 1 is depicted in the graphic below. Part 1 will be performed as an open-label 
randomized control trial. Randomization will occur in a 1:1 fashion utilizing a computer generated random 
permuted block randomization scheme with block size 4, 6 and 
8.  
 
Demographic information will be obtained including but not 
limited to race, ethnicity, parity, and prior contraceptive use. After 


Protocol v6.0 – 6.25.2021 
 
Page 4 of 12 
Template Revised: 1.22.2014 
confirmation of ovulation via an elevated P4 of 3ng/mL or greater in the screening cycle.  
Subjects will be randomized to treatment group [LNG-EC 1.5 mg (ECx1) or LNG-EC 3mg (ECx2)] and undergo 
a treatment cycle.  
 
During the treatment cycle, subjects will undergo every other day visits starting on cycle day 6-8 followed by 
daily visits for up to 7 days once a dominant follicle measuring 15mm or greater in one diameter is visualized  
(see procedure flow below). Daily visits will cease prior to 7 days if evidence of follicle rupture (disappearance 
of or greater than 50% reduction in size of the dominant follicle) occurs. At each visit, subjects will undergo 
blood sampling via a single venipuncture for P4, E2 and LH levels and high-resolution transvaginal 
ultrasonography (TUS) (GE Ultrasound OR, 9900 Innovation, Voluson eBT11) to monitor follicular 
development and evidence of ovulation.  
 
During the treatment cycle, study medication will be dosed on the day a ≥15 mm follicle is visualized. Women 
will be randomized to either LNG ECx1 (1.5mg LNG) or LNG ECx2 (3mg LNG). Study medications will be 
given by study staff and ingestion will be directly observed. Prior to ingesting study medication, women will 
undergo urine pregnancy testing to confirm non-pregnant status.  
 
Study end will be at the onset of menses at the end of the treatment cycle (defined as two consecutive days of 
spotting/bleeding). We estimate up to 12 visits in the treatment cycles depending if delay in ovulation occurs. 
Subjects will have the option to undergo a washout cycle and participate in the studies detailed in Part 2; if they 
chose to do so, they will not have to undergo another screening visit or control cycle.  
 
Procedure flow: 
 
Data Analysis & Sample Size: All analyses will be performed on an intention-to-treat (ITT) basis. To 
demonstrate equality between treatment arms at baseline, we will compare participant demographics using two 
sample t-test or chi-square test, and descriptive statistics such as mean, median and percentages within each 
group will be reported. The primary outcome analysis will compare the proportion of women with no 
follicular rupture (yes/no) between the treatment groups using a Chi-square test. As mentioned 
previously, follicle rupture will be defined as the disappearance of or >50% reduction of size of the leading 
follicle [2,17]. 
 
Confirmation of the timing of ovulation will be supported by LH, P4, and E2 levels. If necessary, we will address 
any unanticipated imbalances between the treatment groups after randomization by adjusting for these  
confounders in analysis using a logistic regression. 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 EC ingestion during the treatment cycle within each group. Additionally, the proportion of inhibition of 
follicular rupture by LH status (no surge, start of LH surge, or after LH peak) [2,17] for each cycle will by 
compared between treatment groups using fisher’s exact test. Mean LH, P4, and E2 levels over time will be 
plotted by treatment group. Time from treatment intake to follicular rupture will be assessed by a survival 
 
Visit 0 
(Screening Visit) 
 
Treatment Cycle 
Starting Cycle 1 day 
6-8 
Consent, Screening tests and 
medical history  
X 
 
blood draws 
X 
X 
ultrasound 
 
X 
Study Medication & urine 
pregnancy test 
 
X* 
Total time 
2 hour 
30 min/visit 
*Visit number study medication w ill be taken depends on ultrasound findings. 


Protocol v6.0 – 6.25.2021 
 
Page 5 of 12 
Template Revised: 1.22.2014 
 
 
analysis using Kaplan-Meier curve and log-rank test. All statistical analyses will be performed with the SAS 
version 9.4 (Cary, NC, USA). 
 
We believe that the difference between groups will be large (50% or greater) given that LNG ECx1 in obese  
women appears to be equivalent to placebo (normal ovulation) as well as the large PK differences we found in  
our preliminary studies. However, we have chosen a more conservative difference (30%) in which to base our 
sample size calculations to ensure we have the ability to capture a range of differences. A sample size of 62  
will achieve 80% power to detect a 30% difference in the proportion of cycles that demonstrate inhibition of 
follicular rupture (yes/no) using a two-sided Z test with a 5% significant level assuming 90% rate of normal time 
to ovulation in LNG ECx1 dose group. We plan to screen up to 80 women to account for screen failures 
and enroll a total of 70 women to account for drop out. 
 
Part 2 UPA-EC, obese BMI and a weight of 176 lbs or more and normal BMI and a weight of less than 
176 lbs, randomized cross-over trial. 
 
Specific Aim: To compare the pharmacokinetic parameters and pharmacodyanmic profile of emergency 
contraception containing ulipristal acetate between obese and normal BMI women, and to determine if dose 
escalation improves how well it works in obese women. 
 
Hypothesis: The peak drug level of UPA-EC is lower in obese women than in normal BMI women which 
adversely impacts the therapeutic effect and dose escalation will improve drug efficacy for obese women.  
 
Rationale: Published data indicate a possible decline in the efficacy of UPA-EC for obese BMI women [4]. This 
lack of clarity is leading to concern among clinicians that no orally-dosed EC agent is effective in women of 
higher weight or BMI. UPA is metabolized differently than LNG. LNG is highly protein bound and our studies 
have established that obesity adversely impacts LNG clearance, half-life and specific to LNG EC, peak levels 
[9,10]. UPA, unlike LNG, binds distinctly to alpha-acid glycoproteins and high density lipoproteins. Obesity is 
known to alter serum/plasma profiles of both drug-binding proteins: Alpha-acid glycoprotein levels are usually 
doubled [19], and dyslipidemia of obesity is often characterized by low HDL [20]. The net effect of obesity 
induced changes in UPA binding proteins is unknown yet, however could be speculated as high degree of 
binding resulting in reduced concentration of pharmacologically relevant drug. Detailed PK and PD studies for 
UPA in an obese cohort have not been performed. We propose to perform these studies as a randomized 
cross-over study. This design will reduce variability in the PK data as obese subjects will act as their own 
controls for comparisons between ECx1 and ECx2. We have also chosen to include a small control group 
of normal BMI subjects in order to verify the accuracy of our PK findings. 
 
Part 2 UPA-EC: 
The study flow for Part 2 is depicted in the graphic to the right. 
Part 2 will be performed as an open-label randomized cross-over 
study. Randomization will occur in a 1:1 fashion utilizing a 
computer generated random permuted block randomization 
scheme with block size 4, 6 and 8. 
 
Demographic information will be obtained including but not limited 
to race, ethnicity, parity, and prior contraceptive use. If subjects 
did not participate in Part 1, they will undergo confirmation of 
ovulation via an elevated P4 of 3ng/mL or greater in the screening 
cycle. =. 
 
During the treatment cycles, subjects will undergo every other day 
visits starting on cycle day 6-8 followed by daily visits for up to 7 days once a dominant follicle measuring 
15mm or greater in one diameter is visualized. Daily visits will cease if evidence of follicle rupture occurs, either 
disappearance of or greater than 50% reduction in size of the dominant follicle. At each visit, subjects will 
undergo blood sampling via a single venipuncture for P4, E2 and LH levels and transvaginal ultrasonography 


Protocol v6.0 – 6.25.2021 
 
Page 6 of 12 
Template Revised: 1.22.2014 
(TUS). The TUS will be performed using a high-resolution transvaginal ultrasonography (GE Ultrasound OR, 
9900 Innovation, Voluson eBT11) to monitor follicular development and evidence of ovulation. During the 
treatment cycles, study medication will be dosed on the day a 15 mm follicle is visualized. Both the normal and 
obese BMI groups will undergo treatment cycle 1 and receive a standard dose of UPA EC (30mg) or ECx1. 
After at least one washout cycle, only the obese group will complete treatment cycle 2 and receive a double 
dose of UPA EC (60mg). Study medications will be given by study staff and ingestion will be directly observed. 
Prior to ingesting study medication in each treatment cycle, women will undergo urine pregnancy testing. Study 
end will be at the onset of menses at the end of the treatment cycle (defined as two consecutive days of 
spotting/bleeding). We estimate that approximately up to 12 visits in the treatment cycles depending if delay in 
ovulation occurs. 
 
During each treatment cycle, PK parameters will be obtained via serum samples through an indwelling 
catheter. IV placement in obese women can be challenging. We will enlist the assistance of OHSU’s NIH 
funded CTSA nursing staff or IV therapy, if necessary, to place IVs in our obese cohort in order to ensure the 
least traumatic process for our subjects. We plan to obtain samples at 0.5, 1, 1.5, 2, 3, 4, 24, 48, 72, 96, and 
120 hours for our normal controls in treatment cycle 1 and a subset of the obese cohort (n=30) in both 
treatment cycle 1 and 2.The IV will be left in place for the closely spaced samples and then single samples via 
phlebotomy will be obtained on the samples timed at 24 hours and later. This extended sampling scheme will 
allow us to determine a more accurate area under the curve by having observed rather than estimated values. 
Furthermore a prolonged sampling scheme will enable estimation of additional PK parameters that can lead to 
mechanistic insights.  
 
Of note, Eastern Virginia Medical School will not be recruiting or enrolling participants for the Part 2 – UPA 
Normal BMI cohort as enrollment of the 12 participants for this group is complete.  
 
Procedure flow for obese BMI study groups 
 
 
 
 Screening 
Visit 
(1 visit) 
Treatment 
Cycle 1 
Starting Cycle 
day 6-8 (up to 
12 visits) 
Washout 
Cycle 2  
(no visits) 
Treatment 
Cycle 3 
Starting Cycle 
day 6-8 (up to 
12 visits) 
Consent, Screening tests 
and medical history  
X 
 
 
 
Phone or email contact 
 
 
X 
 
Blood draws 
X 
X 
 
X 
Ultrasound 
 
X 
 
X 
Study Medication & urine 
pregnancy test 
 
X* 
 
X* 
Longer series of blood 
draws (over 5 hours) 
 
X** 
 
X** 
Total time 
2 hours 
30 min/visit 
for all but 2 
visit which will 
be 2 or 5 
hours 
 
30 min/visit for 
all but 2 visit 
which will be 2 
or 5 hours 
*Visit number study medication w ill be taken depends on ultrasound findings. 
**The study visit on the day the study medication is taken w ill last 2 hours (curtailed PK) or 5 hours (full PK) 
 


Protocol v6.0 – 6.25.2021 
 
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Template Revised: 1.22.2014 
Procedure flow for Normal BMI control group 
Data Analysis & Sample Size: To ensure equality between treatment arms at baseline, we will compare 
participant demographics using t-test or chi-square test and descriptive statistics, such as mean, median and 
percentages within each group will be reported. The primary outcome analysis will compare the proportion of 
women with a delay in follicular rupture of at least 6 days (yes/no) between obese women taking UPA ECx1 
versus ECx2 using McNemar’s test. Only the women who have completed the two treatment cycles will be 
included in this portion of the analysis. Although we expect absence or ignorable “period” effect, we will further 
describe the difference between ECx1 and ECx2 with odds ratios using the generalized estimation equation 
adjusted for period and any other confounders using all available data. We will check the accuracy of our 
findings against a normal BMI control group using standard dosing, ECx1 using chi-square test. Follicle rupture 
will be defined as the disappearance of or >50% reduction of size of the leading follicle. Confirmation of 
ovulation will be supported by LH, P4, and E2 levels. 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 EC ingestion during the treatment cycle. Additionally, inhibition of follicular rupture will be plotted by LH 
status (no surge, start of LH surge, or after LH peak) [2,17] for each cycle as well as mean LH, P4, and E2 
levels over time and the time of treatment to follicular rupture. 
 
PK parameter analysis. UPA PK parameters will be generated by noncompartmental methods using 
WinNonLin (Pharsight, Mountain View, CA). Cmax and time to maximum Cmax will be observed values. Area 
under the curve (AUC) will be calculated from Time 0 to 120hr (AUC0-120) using the linear trapezoidal rule 
and then extrapolated to infinity which provide a more accurate calculation of drug clearance (Rowland 1980). 
Drug half-life (t1/2), oral clearance (CL), and volume of distribution (VD) will be generated using standard 
pharmacokinetic calculations (t1/2 =0.693/λz where λz is the terminal elimination rate constant; 
CL=dose/AUC0-infinity; VD=CL// λz). Descriptive statistics will be generated for each parameter 
[mean(standard deviation)], concentration-time curves will be generated for all of the doses and their 
respective BMI groups. Depending on the normality of the data, parametric or nonparametric testing will be 
performed for each parameter between the normal and obese BMI ECx1 groups and paired statistics will be 
utilized to compare obese BMI ECx1 and ECx2. 
 
We also plan to perform analyses to compare PD outcomes in obese users ingesting LNG and UPA, 
ECx1 and ECx2. UPA and LNG are the only two orally-dosed EC agents available on the market. A logical sub 
analysis is the comparison of the different dosing strategies to help guild future studies or even clinical 
management of orally-dosed EC in obese women if dose escalation appears effective. We will utilize the data 
collected in Aim 1 and 2. The proportion of women with a delay in follicular rupture (yes/no) in 4 different 
treatment regimens obtained in the trial in aim1 and 2 will be compared and test if there’s significant difference 
 
 
Screening Visit 
(1 visit) 
Treatment Cycle 1 
Starting Cycle day 6-8  
(up to 12 visits) 
Consent, Screening tests and 
medical history  
X 
 
blood draws 
X 
X 
ultrasound 
 
X 
Study Medication & urine 
pregnancy test 
 
X* 
Longer series of blood draws 
(over 5 hours) 
 
X** 
Total time 
2 hour 
30 min/visit for all but 1 visit which 
will be 5 hours 
*Visit number study medication w ill be taken depends on ultrasound findings. 
**The study visit on the day the study medication is taken w ill last 5 hours 
 


Protocol v6.0 – 6.25.2021 
 
Page 8 of 12 
Template Revised: 1.22.2014 
between LNG ECx2 and UPA LNG ECx2 using Chi-square test. Due to exploratory purpose of these analyses, 
the analysis will be descriptive but given the projected sample size (35 per group in Part 1 and 80 per group in 
Part 2) we will achieve more than 80% power with 5% of significance level to detect 23% difference in delay in 
follicular rupture. In addition, one of the secondary outcomes of time from treatment intake to follicular rupture 
will be compared among treatment groups using survival analysis. 
 
A sample size of 73 will achieve 80% power to detect a 20% difference in the proportion of cycles that 
demonstrate at a delay in follicular rupture (yes/no) using a two-sided McNemar test with a Bonferroni-adjusted 
2.5% significant level. We estimate that 40 women will choose to participate in Aim 2 after completing Aim 1 
studies and plan to screen an additional 58 women to account for screen failures for a total enrollment of 80 
women to account for drop out. We believe that the difference between groups will likely be smaller given the 
clinical information (50% or less). We have chosen a difference of 20% in which to base our sample size 
calculations. We have consciously chosen not to enroll an adequately sized normal BMI group to detect the 
same amount of difference (20%) given that there are published PK/PD standards. We are utilizing this group 
to verify the accuracy of our findings under our environment, the targeted 10 total number of subjects (after 12  
screening) in the control arm would achieve the 80% power to detect 47% difference in follicular rupture given 
the 73 of women taking UPA ECx1 using two-sided Z test with 2.5% significance level. The total number of 
subjects in the control arm was chosen as a convenience sample but this number of subjects should supply us 
with an adequate amount of data to ensure that our PK/PD results are similar to published values in a normal 
BMI cohort. 
 
Protection of human subjects: 
1. Risks to Subjects  
Human Subjects Involvement and Characteristics 
Reproductive-aged (18-35 year old), ovulatory, healthy women with a normal or obese BMI with no 
contraindications to the study medications and not at risk for or seeking pregnancy will constitute the target 
population for this study.  
 
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. De-identified pharmacokinetic data will be analyzed by our consulting pharmacokinetic specialist, Dr. 
Ganesh Cherala.  
 
Sources of Materials 
The sources of research material for the clinical portion of this proposal will be new specimens obtained purely 
for this research protocol.  The study investigators and/or research assistants/nurses will perform all study 
procedures.   
 
Potential Risks 
One key contraindication exists for both of the emergency contraceptives used in this study and that is current 
pregnancy.  Current pregnancy 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 rarely can cause nausea. This information will be 
reviewed with participants and if necessary, an anti-emetic can be provided.  
 
Our research plan describes using EC in accordance with FDA-labeling (single dosing) as well as doubling the 
dose.  In regard to LNG-EC, LNG is considered one of the safest progestins among contraceptive steroid 
hormones with no associated serious adverse events and no upper dose limit known to cause toxicity [PHS 
1,2]. We experienced no serious adverse events during our preliminary studies of LNG-ECx2.  In regard to 
UPA-EC, UPA is similarly safe and well tolerated over a wide range of dosages and duration of treatment 
(published studies report on maximum dosing as follows: up to 200mg unmicronized UPA single and 50mg 
micronized UPA for 10 days)  [PHS 3-5]. In reality, as EC only covers a single act of intercourse and there is 
no limit on the number of times per month EC can be used, a woman could take multiple doses of EC in close 
proximity with little adverse consequences except for the affect the timing and duration of a woman’s next 
menstrual period [PHS 6].   


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Women may feel some pain when their blood is drawn through venipuncture or when an indwelling catheter is 
placed but there is minimal risk involved.  There is a small chance the needle will cause bleeding, a bruise, or 
an infection.   
 
Risk of pregnancy is always present in women who are sexually active.  Current recommendations for 
contraceptive-use in obese women are no different than for normal BMI women.  Women who are not at risk 
for pregnancy due to the use of permanent contraception (male or female) 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.   
 
There are no known harmful effects of a vaginal probe ultrasound but participants may experience slight 
vaginal discomfort.  Care will be taken to ensure that participants are treated with respect and the exam made 
as comfortable and efficient as possible to limit exposure time. 
 
Other potential risks include stigmatization or embarrassment due to issues surrounding body weight.  
Counseling resources are available through the Center for Women’s Health at OHSU and within the 
community.  A resource list will be available to study participants upon request.  A referral will be made upon a 
study participant’s request or because of investigator concern but only after discussion and permission from 
the participant.  
 
2. Adequacy of Protection Against Risk 
Recruitment and Informed Consent 
Attempts to enroll a diverse study population will be made through placement of IRB approved flyers in the 
community, community outreach (newsletters and print ads) and through the availability of foreign language 
interpreters and research staff (see Inclusion of women and minorities).  Women may also learn of the study 
through their routine visits in clinics or by working at OHSU. We also intend to utilize an EPIC Cohort search to 
identify and contact potential participants via phone, email, letter, and/or MyChart messages. We will also be 
using TrialSpark for recruitment through social media. 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 and OCTRI Scientific Advisory Committee prior to 
initiation of the study. 
 
Protection Against Risk 
The EC utilized in this study will be used in accordance with the FDA and at a dosage that is still considered to 
be safe.  Women will be informed of this off-label dosing but that we have specifically chosen a dose and 
length of exposure time to the drug or compound with extremely low potential for significant side effects or 
serious risks (see above potential risks). Women will undergo screening for any known contraindications to the 
study drugs chosen to trial in women.   
 
Women will have access to appropriate counseling for emotional distress regarding body weight issues. 
 
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 database.  All data will be kept in locked files or a 
password protected computer in the Principal Investigator’s (PI) office.  
 
Data and safety monitoring of plans for clinical trials 
The PI and study staffs are responsible for recording the data, and they will be verifying its accuracy 
throughout the process. The PI will be reviewing the data in-depth upon completion of Aim 1, Aim 2 and again 
at the study’s conclusion. The PI will also be overseeing that the study procedures are being carried out as per 
the approved protocol via close supervision of study visits and procedures and through frequent 
communication with the study staff. The PI will also be conducting an initial assessment and periodic 
assessments of the study and its procedures. If any safety concerns arise, a data safety monitoring board will 


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be convened to review the study.  As this study will be performed in conjunction with the Women’s Health 
Research Unit’s (WHRU), an independent chart audit to ensure data integrity and completeness will be 
performed after the first 5 subjects have been enrolled and then at regular 6 months intervals.     
 
The PI will adhere to OHSU’s Institutional Review Board (IRB) policies regarding protection of human subjects 
and the reporting of study deviations and adverse events. In the rare case of an adverse event, she will utilize 
the WHRU data safety monitoring board (DSMB) to review the event and rule on a course of action. The 
WHRU DSMB is made up of individuals knowledgeable about women’s reproductive health and therapies and 
will have no conflict of interest with the study or its outcomes.  
 
3. Data Storage 
 
Data for this project will be stored in OCTRI’s installation of REDCap, a highly secure and robust web-
based research data collection and management system. 
 
Features of REDCap that protect participants’ privacy and data security include: 
 
Physical Security: OCTRI’s REDCap software is housed on servers located in ITG’s Advanced 
Computing Center providing locked physical security 
 
Electronic Security: The REDCap servers are housed behind both the OHSU firewall and a second 
ACC firewall. All web-based data transmissions are encrypted with industry-standard SSL methods. 
 
Controlled User Access. REDCap employs a robust multi-level security system that enables 
researchers to easily implement “minimum necessary” data access for their research staff, including 
specification of data fields that are identifiers. This feature includes “single click” ability to provide 
completely deidentified (removing all identified data fields and shifting dates) for analysis or other 
purposes. User activities are logged to enable auditing of all data access. Access is integrated with 
OHSU’s network such that all users who are OHSU employees are authenticated against their 
OHSU network credentials. 
 
Data Integrity: REDCap is jointly managed to accordance with OSU Information Security Directives 
by ACC staff and members of OCTRI’s Biomedical Informatics Program, ensuring fidelity of 
database configuration and back-ups. User activities are logged to enable auditing of all data 
changes.  
 
4. Potential Benefits of the Proposed Research to the Subjects and Others 
There are no direct benefits to study participants. 
5. Importance of Knowledge to be Gained 
This study will increase the knowledge regarding obesity and failure of contraception.  It may help to increase 
awareness regarding an additional health concern specific to obese women and the need for individualizing 
birth control for this group to avoid unplanned pregnancies.  It may go beyond the identification of a problem, 
but also help in providing the potential mechanism of action and intervention for this phenomenon.   
 
References 
 
Task Force on Postovulatory Methods of Fertility Regulation. Randomised controlled trial of 
levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. 
The Lancet. 1998 Aug 8;352(9126):428–433. PMID 9708750 
2.  
Brache V, Cochon L, Deniaud M, Croxatto HB. Ulipristal acetate prevents ovulation more effectively than 
levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception 
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Apter D. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO 
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Lond Engl. 1999 Feb 27;353(9154):721. PMID: 10073517 
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Protection of Human Subjects (PHS) Citations 
 
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3.  Pohl O, Osterloh I, Gotteland J-P. Ulipristal acetate - safety and pharmacokinetics following multiple doses 
of 10-50 mg per day. J Clin Pharm Ther. 2013 Aug;38(4):314–320. PMID: 23550906 
4.  FDA. FDA Ella prescribing information [Internet]. [cited 2016 Jan 5]. Available from: 
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5.  Eurpean Medicines Agency. CHMP Assessment Report for Ellaone [Internet]. [cited 2016 Jan 5]. Available 
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_Public_assessment_report/human/001027/WC500023673.pdf 
6.  Update to CDC’s U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: Revised Recommendations 
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