Compare Daily Ulipristal Acetate and Combined Oral Contraceptive Effects on Breast Epithelial Cell Proliferation

This will be a randomized controlled parallel group clinical trial with blinded evaluation to
be carried out at 2 academic medical centers: Columbia University Medical Center and Weill
Cornell Medical College. The investigators will screen healthy women aged 18-39 who meet
inclusion/exclusion criteria and will enroll them for the study.

After the informed consent process and study enrollment, study participation will begin with
a baseline cycle. The main goal of the baseline cycle is to identify the occurrence and the
timing of ovulation. Starting at about day 6 of the baseline cycle, participants will undergo
blood sampling for progesterone (P4) levels at intervals of every 2-3 days. An increase of P4
to greater than 3 ng/mL, confirmed by a second such value, will indicate ovulation and
eligibility to continue in the study. The participant's baseline breast MRI and biopsy (see
below) will be scheduled to occur in the mid luteal phase, about 7 days after the first
increase (>3 ng/mL) in P4. The investigators will randomly assign which breast has the first
biopsy, and women will return for a post-biopsy visit about 7 days later. At the post-biopsy
visit, the investigators will assess acceptability of the MRI and biopsy to the participants
using visual analog scales (VAS) as well as interview.

At the beginning of the next menstrual period, women will begin the treatment phase of the
study. They will receive random assignment to either UPA or COC at the study center and
receive their first dose and a 4-week supply of study drug. During cycles 1 and 2 they will
return to the study site every 2 weeks for assessment, blood draws and to receive the next
cycle of study drug. During the third cycle, they will return to the study site twice weekly
for more frequent testing and monitoring. Each cycle will be 28 days, corresponding to usual
COC packaging. At day 75-77 of treatment women will undergo the second breast MRI,
immediately followed by a biopsy of the contralateral breast to that biopsied at baseline. An
end-of-study visit, including checking the incision site and a repeat assessment of
acceptability of the MRI and biopsy to the participants, will occur about 7 days later.
Participants will also be asked to rate their preference for an MRI versus a biopsy, were it
possible to do a study with only one of these procedures.

Participants will have up to 24 study visits, and at each visit, participants will be asked
about adverse events and use of any concomitant medications. Participants will have a high
sensitivity urine pregnancy test at baseline and immediately preceding each MRI and preceding
the first dose of study medication. Any participant with a positive pregnancy test will be
immediately withdrawn from the study.

Breast Biopsies Breast biopsies will take place immediately following each breast MRI. Women
will receive 24-hour telephone follow-up, and make a visit within one week following each
breast biopsy to ensure that the biopsy site is healing without incident.

MRI For each participant, the baseline and follow-up MRI will be done using the same machine.
Each MRI study will undergo an immediate wet read to assure adequate quality and to identify
any unexpected pathology that would mandate clinical evaluation and withdrawal from the
study. A limited report indicating technical adequacy and absence of major clinical
abnormalities will be recorded in the patient record.

Breast MRI and breast biopsy visits will take place at the Center for Breast Imaging at
Columbia University Medical Center.

Inclusion Criteria:

1. Women between 18 and 39 years of age (inclusive).

2. In good health, with regular menstrual cycles between 21 and 35 days and with
intra-individual variation of less than or equal to 5 days.

3. Volunteers who are postpartum or who aborted in the first or second trimester must
have had two normal menstrual cycles (3 bleeding episodes) prior to screening.

4. No use of any other hormonal contraception within two normal menstrual cycles (3
bleeding episodes) prior to screening.

5. If previous use of injectable Depo Provera, subject must have had two normal menstrual
cycles (3 bleeding episodes) prior to screening.

6. Not at risk for pregnancy:

1. Using a copper intra uterine device (IUD), or

2. Willing to protect all further acts of intercourse with condoms, or

3. Not hetero-sexually active, or

4. Having undergone previous tubal ligation, or

5. Partner sterilized or vasectomized.

7. Body Mass Index (BMI) < 30 kg/m2 and not having previously undergone bariatric
surgery.

8. Diastolic blood pressure (BP) ≤ 90 mm Hg and systolic BP ≤ 140 mm Hg after at least 5
minutes in a sitting position. Hypertensive subjects who are treatment controlled may
obtain a waiver for participation.

9. Willing and able to follow all study requirements, including use of the study
medication and willing to give information related to study medication use as required
during the study, in the opinion of the investigator.

10. Able to give informed consent to participate in the study.

Exclusion Criteria:

1. Currently pregnant as confirmed by positive high-sensitivity urine pregnancy test.

2. Currently breast-feeding or within 30 days of discontinuing breast feeding at
screening.

3. Undiagnosed abnormal genital bleeding.

4. Known hypersensitivity to an active substance or any of the excipients of the study
treatments.

5. Abnormal clinical breast examination at screening.

6. Suspected hyperplasia or carcinoma of the endometrium.

7. Ovarian cyst > 25 mm observed on transvaginal or transabdominal ultrasound performed
on the first visit of the Baseline cycle.

8. History of any diagnostic or therapeutic breast biopsy

9. Any of the known contraindications to COC use:

1. History of or existing breast cancer, or other hormone sensitive neoplasia, or

2. History of or current ischemic heart disease or stroke, or

3. History of or current deep venous thrombosis or pulmonary embolism, or

4. Systemic lupus erythematosus with positive or unknown antiphospholipid
antibodies, or

5. History of or current benign or malignant liver tumor, or

6. Severe (decompensated) cirrhosis.

7. Headaches with focal neurological symptoms.

10. Hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose
malabsorption.

11. Known or suspected alcoholism or drug abuse.

12. Known human immunodeficiency virus (HIV) infection.

13. Smoking 15 cigarettes or more per day, if in the opinion of the investigator or
medically qualified designee, this would increase the risk for cardiovascular disease
and thromboembolism based on risk factors.