Improving the Effectiveness of Orally Dosed Emergency Contraceptives in Obese Women - PK and PD of 30mg and 60mg UPA
Phase: PHASE4
Conditions: Obesity, Contraception
Sponsor: Oregon Health and Science University

Title: Effectiveness of Orally Dosed Emergency Contraception in Obese Women – UPA 
NCT number: NCT02859337 
Document Date: March 1, 2016 
 
 

PROTOCOL FOR CT.GOV 
This randomized cross-over study was conducted at Oregon Health & Science University (OHSU) in 
Portland, OR, USA and Eastern Virginia Medical School (EVMS) Norfolk, VA, USA. The Institutional 
Review Board (IRB) at OHSU and EVMS approved the study protocol. We recruited healthy women 18-
35 years old who with regular menstrual cycles (21-35 days) with a BMI at or greater than 30 kg/m2 and a 
weight of 176 lbs or more (80 kg).  In addition to this, 12 women with a BMI <25 kg/m2 were also 
recruited as controls. All subjects were required not to be at risk for pregnancy (e.g. abstinent, non-
hormonal method of birth control, or non-sperm producing partner). Major exclusion criteria obtained via 
participant report, review of medical records, and clinical exam included sensitivity or allergy to UPA; 
treatment for infertility; metabolic disorders including uncontrolled thyroid dysfunction or polycystic 
ovarian syndrome or clinical evidence of androgen excess; a screening serum progesterone level <3 
ng/mL; impaired liver or renal function; actively seeking or involved in a weight loss program (weight 
stable) or prior bariatric surgery; pregnancy or seeking pregnancy; breastfeeding; recent (8 weeks) use of 
hormonal contraception; smoking, vaping, or chronic marijuana use.   
 
After an initial telephone screening, participants completed an in-person screening visit to collect baseline 
demographic and health information and a serum progesterone level during luteal phase to confirm 
ovulatory status (progesterone level ≥3 ng/mL), an inclusion criterion for participation. All participants 
completed written informed consent prior to any study procedures. The study was conducted over three 
menstrual cycles, Cycles 1 and 3 were treatment cycles interspersed by Cycle 2, a washout cycle. For the 
normal BMI control group, participants only underwent one treatment cycle. We did not have participants 
undergo a baseline cycle with ultrasound and hormone monitoring. Participants could request to space 
Cycle 1 and 3 longer than 1 cycle for personal scheduling conflicts or study staff had participants delay an 
additional cycle, if menses delay occurred in Cycle 2 but if spacing was longer than 3 months, then 
rescreening would need to take place (n = 0).  Additionally, our study procedures overlapped with the first 

six months of the COVID-19 pandemic resulting in suspended procedures for several months as directed 
by state and institutional mandates.  
 
Our monitoring procedures were as follows: day 6-8 of treatment cycles 1 and 3, participants came in 
every other day until a dominant follicle measuring ≥15 mm in at least one dimension was visualized. 7,9,10 
These visits consisted of follicular activity monitoring via transvaginal ultrasound and blood sampling for 
progesterone (P4), estradiol (E2), and luteinizing hormone (LH). After a pregnancy test was performed 
and the results were negative, the cohort with a BMI at or greater than 30 kg/m2 and a weight of 176 lbs 
were randomized to UPA 30 mg or 60 mg for Cycle 1 and then the other dose for Cycle 3. The OHSU 
research pharmacy maintained the computer-generated randomization scheme and kept treatment 
assignments in a locked database. Those in the control group, received a single dose of UPA (30 mg) 
during Cycle 1 only. Following dosing, all subjects were seen daily for blood sampling and ultrasound 
monitoring until evidence of follicle rupture (>50% reduction of mean size or complete disappearance of 
follicle) or for up to 7 days.4,7,9,10  
 
Participants could volunteer for additional study procedures to obtain PK samples. PK parameters were 
obtained via serum samples through an indwelling catheter. We obtained samples during treatment cycles 
at the time of dosing at 0.5, 2, 1.5, 2, 3, 4, 24, 48, 72, 96, and 120 hours. PK parameters were generated 
by noncompartmental methods using WinNonLin (Pharsight, Mountain View, CA). Cmax and time to 
maximum Cmax are observed values. Area under the curve (AUC) was calculated from Time 0 to 120 hr 
(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 EC 30 mg groups and paired statistics will be utilized to compare obese BMI 
30 versus 60 mg UPA groups. 
 
Our primary outcome was the difference in the proportion of subjects with no follicle rupture 5 days post-
dosing (yes/no) between dosing groups (30 mg vs 60 mg) in the BMI at or greater than 30 kg/m2 cohort. 
Our main secondary outcome was the timing (day) of follicle rupture between dosing groups in the BMI 
at or greater than 30 kg/m2 cohort. We also calculated these outcomes for our control group and 
descriptively compared it with the BMI at or greater than 30 kg/m2 cohort. If the date of follicle rupture 
was unclear by ultrasound imaging (e.g. collapse was seen but reduction of size was <50%), we utilized 
serum hormone levels to adjudicated day of rupture. Two investigators independently reviewed these 
cycles while being masked to dosing and if a disagreement occurred, a third investigator was engaged.  
 
Hormone assays were performed by The Endocrine Technologies Core (ETC) at the Oregon National 
Primate Research Center (ONPRC, Beaverton, Oregon (https://www.ohsu.edu/onprc/endocrine-
technologies-core) performed the hormone, UPA, and Monodemethyl-UPA assays. Serum E2, P4, and 
LH were analyzed by a Roche Cobas e411 chemiluminescence-based automated immunoassay platform 
(Roche Diagnostics, Indianapolis, IN). The sensitivities of the E2, P, and LH assays for the Roche e411 
are 5 pg/ml, 0.050 ng/ml, and 0.1 mIU/ml, respectively. The intra- and inter-assay variation with the 
Roche e411 in the ETC is consistently less than 7% for all assays. Quality control sample analyses were 
repeated prior to each assay run. Serum ulipristal acetate (UPA) and N-monodemethylated (NDM)-UPA 
concentrations were simultaneously determined by ultra-high performance liquid chromatography-heated 
electrospray ionization-tandem triple quadrupole mass spectrometry (LC-MS/MS) on a Shimadzu 
Nexera-LCMS-8050 instrument (Shimadzu Scientific, Kyoto, Japan). The lower limit of quantification 
for both UPA and NDM-UPA was 0.19 ng/ml. Samples with concentrations above 200 ng/ml were re-
analyzed after 1:5 dilution in 0 standard. Data processing and analysis were performed using 

LabSolutions Software, V5.72 (Shimadzu). Intra-assay coefficient of variation (CV) for UPA ranged from 
3.2-14.3% with an inter-assay CV of 6.3% (n=5 assays).  Intra-assay CV for NDM-UPA ranged from 2.9-
7.4% with an inter-assay CV of 4.5% (n=5 assays). Accuracy was 104.8% for UPA and 106.5% for 
NDM-UPA. The UPA and NDM-UPA assays were developed and validated largely following FDA 
guidelines for bioanalytical method validation [FDA Bioanalytical Method Validation Guidance for 
Industry, 2018] by assessing specificity, stability, precision, accuracy, extraction efficiency (recovery), 
calibration curve, sensitivity, and reproducibility.