Study of the Safety, Efficacy and Cycle Control of a Contraceptive Vaginal Ring

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.

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.

Eligibility Criteria:
Inclusion Criteria:

* Healthy women, aged 18-\<40 years who wish to use a combined hormonal contraceptive.
* Women not intending to become pregnant for 13 months.
* Intact uterus and both ovaries.
* Prior history of regular menstrual cycles of 28 ± 7 days when not using hormonal contraception; if postpartum or postabortal, history of regular menstrual cycles of 21-35 days in length and at least one cycle (2 menses) with a cycle length consistent with her past cycles.
* Sexually active (currently) and willing to discontinue current contraceptive method to participate in the study.
* In the opinion of the investigator, able to comply with the protocol, e.g. live within the study site catchment area or within a reasonable distance from the site.
* Do not meet any of the exclusion criteria.
* Signed informed consent prior to entry into the trial.

Exclusion Criteria:

* Known hypersensitivity to estrogens or progestins.
* Known hypersensitivity to silicone rubber.
* Known or suspected pregnancy.
* History of infertility of \>1.0 year in woman or her male partner.
* History of vasectomy or sterility in male partner; tubal ligation (sterilization) in women
* Undiagnosed abnormal genital bleeding.
* Undiagnosed vaginal discharge or vaginal lesions or abnormalities. (Subjects diagnosed at screening with Chlamydia or gonorrhea may be included in the trial following treatment; partner treatment is also recommended. Investigators should make a determination if subjects are at high risk for reinfection, e.g. multiple sex partners, untreated partner, and whether such subjects can be included.)
* History of pelvic inflammatory disease since last pregnancy episode.
* History of toxic shock syndrome.
* Current abnormal Pap smear (women who have abnormal Paps but are ASCUS HPV negative may participate provided there is follow up for this finding per standard of care).
* Cystoceles or rectoceles or other anatomical abnormality that would preclude use of a vaginal ring.
* Women planning to undergo major surgery.
* Smoking in women who are 35 years and over or will be 35 years during the course of the trial; Women \< 35 years who smoke 15 cigarettes or more must be evaluated by the PI for inclusion based on risk factors that would increase their risk for CVD, e.g. lipid levels, glucose level, BP, BMI, family history of CVD at a young age.
* Breastfeeding.
* Current or past thrombophlebitis or thromboembolic disorders.
* History of venous thrombosis or embolism in a first-degree relative \<55 years of age suggesting familial defect in blood coagulation system, which in the opinion of the principal investigator, suggests use of a hormonal contraceptive could pose a significant risk.
* Cerebrovascular or cardiovascular disease.
* History of retinal vascular lesions, unexplained partial or complete loss of vision.
* Known or suspected carcinoma of the breast.
* Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia.
* Past history of any other carcinoma unless in remission for more than 5 years.
* Current or past medically diagnosed severe depression, which, in the opinion of the investigator, could be exacerbated by use of a hormonal contraceptive.
* Headaches with focal neurological symptoms.
* Severe constipation.
* History of cholestatic jaundice of pregnancy or jaundice with prior steroid use.
* Benign or malignant liver tumors; active liver disease.
* Diastolic blood pressure (BP) ³85 mm Hg and/or systolic BP ³135 mm Hg after 5-10 minutes rest.
* Known or suspected alcoholism or drug abuse.
* Abnormal serum chemistry values according to the physician's judgment.
* Participation in another clinical trial within last 30 days.
* Weight \>95 kg or \>209 lbs.
* Use of liver enzyme inducers on a regular basis.
* Use of monthly injectable contraceptives (e.g. cyclofem) unless suspended 2 months before initiation of treatment. Use of Depo-Proveraâ \[depo-medroxyprogesterone (DMPA)\] unless suspended 6 months before treatment.
* Current use of implanted hormonal contraceptives, including Mirenaâ \[progestin containing intrauterine system (IUS)\], Jadelleâ, Norplantâ or Implanonâ (subjects using any of these methods who request removal for reasons unrelated to the purpose of enrollment in this study may be considered for participation).
* Current use of a non-hormonal IUD. Subjects with IUDs who request removal for reasons unrelated to the purpose of enrollment in this study may be considered for participation.
* Known HIV infection.
* Women at high risk of contracting HIV, e.g. women with multiple sex partners who need to use condoms consistently, injection drug users. If women enrolled in the study do use condoms to protect against STIs, they should be instructed that this occasional use should be with non-N-9 containing condoms and they should record condom use in their diaries. Women found to have an STI at screening will be treated prior to inclusion in the study (with the exception of those infected with HIV).