Study of the Safety, Efficacy and Cycle Control of a Contraceptive Vaginal Ring
Condition: Contraception
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this study is to evaluate the one-year data on the contraceptive efficacy and
      safety of the 150/15 NES/EE CVR as the basis for regulatory approvals of this CVR as a new
      delivery system for contraception.
    

Detailed description: 
      There continues to be a need to develop additional long-term user controlled contraceptives.
      Consistent with this need, contraceptive vaginal rings (CVR) delivering synthetic estrogen
      and progestin hormones have been developed to provide certain advantages over available
      methods of hormonal contraception. Scientists at the Population Council (PC) have performed
      preliminary 1-year studies on an investigational CVR that releases effective doses of
      synthetic estrogen and progestin hormones. This CVR contains ethinyl estradiol (EE), an
      approved, marketed hormonal product and Nestoroneâ (NES), an investigational, new chemical
      entity for which there are considerable clinical data from NES formulations used in
      transdermal systems, implants and CVRs. A potent 19-nor progesterone derivative, NES is not
      active orally, but is effective when administered via non-oral routes such as vaginal rings,
      implants, and transdermal systems. The CVR delivery system currently under investigation
      contains low doses of both steroids (15µg EE and 150µg NES respectively), provides a
      relatively steady release rate without requiring daily administration or attention to provide
      the desired contraceptive effect and achieve regular menstrual cycles. Because this CVR does
      not require daily oral intake of steroids, it avoids the daily high concentrations of
      steroids to which the liver is exposed when there is repetitive, once a day administration
      via the oral route. After insertion of the CVR into the vagina, steroids are rapidly absorbed
      by vaginal tissues, pass into the general circulation, achieve a steady state by day 4, and
      ultimately inhibit ovulation. In the beginning of the first cycle, however, there is a
      "burst" effect that lasts about 48 hours and is caused by accumulation of steroids on the
      silastic walls of the ring following storage subsequent to manufacturing. Based on in vitro
      studies with this CVR and preliminary pharmacokinetic studies, this effect decreases
      significantly in subsequent cycles. Pharmacokinetic studies to confirm this finding are
      ongoing. After three weeks of use, the user removes the ring for a week to induce withdrawal
      bleeding, and then reinserts it on a three-weeks-in/one-week-out cyclic regimen.

      The progestin used in this new contraceptive system, NES, is a 19-nor progesterone
      derivative. It was selected for its high anti-ovulatory potency at low doses and its
      potential to decrease side effects usually observed with 19-nor testosterone derived
      progestins. In vitro studies have demonstrated that it binds selectively to progesterone
      receptors, and does not bind to androgen receptors. Although it binds to the glucocorticoid
      receptor, in vivo assays indicate no biological activity at low doses. NES also does not bind
      to estrogen receptors, and based on studies conducted in women using implants containing NES
      alone, it does not modify greatly the lipid profiles. When combined with estrogen, further
      data was obtained in a Phase 2, open label study comparing effects of the NES/EE CVR on
      estrogen-dependent liver proteins vs. those of an OC that used an androgenic progestin (LNG).
      Data revealed a significant increase in HDL associated with the CVR versus a decrease with
      the OC. In addition, data from this study demonstrated that when NES is administered
      vaginally with EE in the CVR, the impact on hepatic metabolism is similar to administration
      of EE via the oral routes with both hormonal products producing similar increases in
      angiotensinogen. The CVR, however, resulted in a significantly greater increase in SHBG and
      significantly greater decrease in protein S suggesting that due to its non-androgenic
      properties, NES does not counterbalance the EE effects on hepatic factors and that EE has an
      impact on liver proteins whether delivered vaginally or orally. Therefore, the same cautions
      and contraindications that apply to OCs relative to risks for thromboembolic events are
      likely to apply to CVRs containing EE and NES. Since there is no single marker that is known
      to predict such events, clinical experience and surveillance of women using new hormonal
      methods are required to clarify this question.

      The dose selected for the CVR in the present study is based on a one-year randomized, Phase 2
      clinical trial comparing three different doses, i.e. 150/15, 150/20 and 200/15µg on a 21/7
      days in/out schedule. All doses showed efficacy, good bleeding control and a satisfactory
      safety profile, therefore the lowest effective dose, 150/15µg, was selected. Luteal activity
      [progesterone >10nmol/L (>3ng/ml)] occurred in 14 (12%) of 114 monitored cycles for the 50
      women who comprised the group using 150/15µg dose. In a second study of 6 months duration,
      150/15µg rings were used on the 21/7 vs. a 26/4-day regimen. In these two studies, users of
      the 150/15µg rings with the 21/7 schedules were observed for a total of 61.5 woman years. No
      pregnancies occurred in the 150/15µg 21/7 groups. Overall in the two studies that used this
      regimen, fewer than 10% of cycles measured for progesterone levels had any indication of
      luteal activity [progesterone >10nmol/L (>3ng/ml)], suggesting that this ring and this
      schedule suppresses ovulation to an effective degree. Weight was significantly correlated
      with luteal activity with women weighing >90kg showing increased rates of luteal activity.
    

Intervention name(s): 150 mg of Nestorone and 15 mg of ethinyl estradiol (150/15 NES/EE CVR)
Intervention type(s): Drug
Intervention description(s): 150 mg of Nestorone and 15 mg of ethinyl estradiol (150/15 NES/EE CVR), administered via vaginal ring, used on a 21/7 days in/out schedule for no more than one year.
Intervention MeSH terms: Ethinyl Estradiol; ST 1435; Estradiol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Contraception; Vaginal Ring