Compare Daily Ulipristal Acetate and Combined Oral Contraceptive Effects on Breast Epithelial Cell Proliferation
Condition: Contraception
Study type: Interventional
Phase: Phase 1

Summary: 
      Breast cancer accounts for almost a quarter of all cancers in women. In the United States
      (U.S.) in 2014, more than 230,000 women were diagnosed and 40,000 died of breast cancer.
      There is an urgent need to develop acceptable means of preventing breast cancer both for high
      risk and average risk women.

      The proposed study is a clinical trial in premenopausal women aged 18-39 to evaluate the
      capacity of daily Ulipristal Acetate (UPA) to reduce breast epithelial cell proliferation
      (increase in number of cells in the breast) and to measure its effect compared to that found
      with a combined estrogen-progestin oral contraceptive (COC). UPA is an anti-progestin in use
      as daily medication up to 12 months for the treatment of abnormally heavy bleeding at
      menstruation due to uterine fibroids, and is currently in trials in the U.S. to evaluate its
      use as a daily contraceptive.

      The investigators will use breast biopsies to compare breast cell proliferation, comparing
      biopsies at the end of 3 months treatment to biopsies taken at baseline in the 2 groups (UPA
      and COC). The investigators will also compare the changes in the 2 groups to each other. The
      comparison of the effect of UPA to that of a conventional COC is because of UPA's potential
      use as a daily contraceptive.

      Cell proliferation in the breast occurs throughout the menstrual cycle. The actions of
      hormones on the breast are rapid and an anti-progestin such as UPA, which will block the
      action of progesterone in the breast, would be predicted to quickly lower breast cell
      proliferation in premenopausal women. Effects of UPA on the uterus continue to be studied and
      are reassuring. COC use has not been found to lower breast cell proliferation and is not
      associated with any decrease in risk of breast cancer.

      The changes in breast cell proliferation will also be compared to changes seen on breast MRI.
      If the changes are highly correlated future studies will be able to be done without the need
      for breast biopsies.
    

Detailed description: 
      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.
    

Intervention name(s): Ulipristal Acetate; Combined Oral Contraceptive Pill
Intervention type(s): Drug; Drug
Intervention description(s): Daily use of Ulipristal Acetate; Daily use of Oral Contraceptive Pill
Other intervention name(s): Ella; Portia
Intervention MeSH terms: Contraceptive Agents; Ulipristal acetate; Contraceptives, Oral; Contraceptives, Oral, Combined
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: Ulipristal Acetate (UPA); Breast Cancer; Combined Oral Contraceptive (COC)