A Comparative Pharmacokinetic Study of ORTHO EVRA (a Transdermal Contraceptive Patch) and CILEST (an Oral Contraceptive) in Healthy Female Volunteers
Condition: Contraception; Female Contraception
Study type: Interventional
Phase: Phase 1

Summary: 
      The objective of this study is to compare the levels of the hormones norelgestromin,
      norgestrel, and ethinyl estradiol in the bloodstream of healthy female volunteers
      administered ORTHO EVRAÂ® (a transdermal contraceptive patch) and CILESTÂ® (an oral
      contraceptive). The open-label treatment phase of the study consists of two 28-day cycles of
      one treatment, a washout period of 28 days, and crossover to two 28-day cycles of the other
      treatment.
    

Detailed description: 
      ORTHO EVRA® is a combination, monophasic transdermal contraceptive patch containing 6 mg of
      norelgestromin (NGMN) and 0.75 mg of ethinyl estradiol (EE), and delivering to the systemic
      circulation an average of 150 µg/day of NGMN and 20 µg/day of EE. CILEST® is an oral
      contraceptive tablet containing 250 µg of norgestimate (NGM) and 35 µg of ethinyl estradiol
      (EE). Although the multiple-dose pharmacokinetics of the active serum progestin and estrogen
      analytes following administration of the ORTHO EVRA® formulation and OrthoCyclen (same as
      CILEST®) has been evaluated previously in separate studies, the multiple dose
      pharmacokinetics has not been evaluated in a comparative manner in a single study. The
      present study is designed to directly compare the total exposure and pharmacokinetics, over
      comparable time intervals (Week 1 of Cycle 1 and Week 3 of Cycle 2), of NGMN, NG, and EE from
      ORTHO EVRA® and CILEST® in a single study, designed as a randomized, crossover study. Since
      EVRA® is worn for 7 days and CILEST® is a once-daily tablet, pharmacokinetics will be
      estimated over different time periods ORTHO EVRA® (7 days) and CILEST® (Days 1 and/or 7 of a
      7 day period) during each cycle. Pharmacodynamic parameters of estrogenicity are determined
      and compared to assist in the interpretation of the pharmacokinetic data.

      This is a single center, randomized, open-label, two-way crossover, pharmacokinetic study of
      ORTHO EVRA® and CILEST®. The subject population is to be comprised of 32 healthy female
      volunteers between the ages of 18 and 48 years and having a body mass index (BMI) between
      18.0 and 29.9 kg per meter squared. The study consists of a pretreatment phase (a screening
      period up to 21 days), an open-label treatment phase (two 28-day cycles of 1 treatment, a
      washout period of 28 days, and cross-over to two 28-day cycles of the other treatment), and a
      post-treatment phase (a follow-up or early withdrawal visit). Treatment Day 1 is the first
      day of menses, or within 5 days after the first day of menses. In one treatment period,
      subjects wear an ORTHO EVRA® patch on their abdomen or buttock (based on the randomization
      schedule) applied once weekly for 3 consecutive weeks during each of two 28-day cycles. ORTHO
      EVRA® will be applied and removed by the investigator (or designated study personnel), on
      Days 1 (application only), 8, 15, and 22 (removal only) of each cycle. In the other treatment
      period, subjects take CILEST® tablets once daily for the first 21 days of each cycle for two
      28-day cycles. CILEST tablets will be administered to the subject with 225 mL (7.5 oz) of
      water by the investigator or designated personnel on Days 1 through 8 of Cycle 1 and Days 18
      through 21 of Cycle 2. On days when the subject is not required to be at the study unit, the
      subject will self-dose at home (on Days 9 through 21 of Cycle 1 and Days 1 through 17 of
      Cycle 2). Neither the ORTHO EVRA® patch nor CILEST® tablets are used on Days 22 to 28 (the
      4th week) of any cycle, during which subjects may experience withdrawal bleeding. The total
      duration of the open-label treatment phase is approximately 5 months.

      The primary outcome of the study is a comparison of the total exposure and pharmacokinetics,
      based on comparable intervals, of NGMN, NG, and EE. Blood samples will be drawn during Week 1
      of Cycle 1 and Week 3 of Cycle 2 for analysis of plasma NGMN (total and anti and syn
      isomers), NG, and EE concentrations. Pharmacokinetic parameters, such as Cmax, tmax, and AUC
      will be estimated by non-compartmental methods. Safety is assessed by monitoring for the
      incidence and severity of adverse event reports, clinical laboratory tests, vital signs,
      physical and gynecological examination and an electrocardiogram (ECG). The expectation is
      that the ratios of exposure between these products and of the ratios of NG/NGMN between these
      products will be similar. However, the confidence intervals around these ratios are not
      required to fall within 80-125%. Treatment 1: ORTHO EVRA® transdermal patch, applied once
      weekly for 3 consecutive weeks of each cycle for two 28-day cycles. Treatment 2: CILEST®
      tablets, taken once daily by mouth for 21 consecutive days of each cycle, for two 28-day
      cycles. There is a 28-day washout between treatments.
    

Intervention name(s): EVRA® transdermal contraceptive patch containing 6 mg of norelgestromin and 0.75 mg of ethinyl estradiol (versus CILEST® tablets).
Intervention type(s): Drug
Intervention MeSH terms: Ethinyl Estradiol; Norelgestromin; Contraceptive Agents; Estradiol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Transdermal contraception; contraceptive; hormonal, steroid contraception; ethinyl estradiol; progesterone; EVRA; CILEST