Safety and Efficacy of a Contraceptive Vaginal Ring Delivering Nestorone® and Ethinyl Estradiol

A Multicenter, Open-label Study on the Efficacy, Cycle Control and Safety of a Contraceptive Vaginal Ring Delivering a Daily Dose of 150 ug of Nestorone® and 15 ug of Ethinyl Estradiol

The purpose of this 1-year study is to evaluate the efficacy and safety of a new contraceptive vaginal ring (CVR) delivering low doses of Nestorone (NES), a new, nonandrogenic progestin, and ethinyl estradiol (EE), an estrogen used in oral contraceptives. The CVR, which is made of silicone rubber, is designed to be used for 1 year (13 menstrual cycles) before replacement is required.

The objective of this study is to evaluate the contraceptive efficacy, cycle control, and safety of a reusable CVR delivering low daily doses of NES and EE for a 1-year (13-cycle) period.

Nestorone is a potent, nonandrogenic, 19-norprogesterone derivative, which is not active when given orally, but is highly active when delivered via non-oral delivery systems, such as CVRs, implants, or transdermal preparations. The high potency of NES makes it an excellent candidate for use in contraceptive delivery systems designed to be effective for prolonged periods. This characteristic of Nestorone has been utilized in the design of a contraceptive vaginal ring that releases low daily doses of both NES and EE and is effective for a 1-year (13-cycle) period. The NES/EE vaginal ring is a long-acting contraceptive device, but, unlike other long-term methods, it use is controlled by the woman without the need for medical intervention.

The efficacy of NES/EE vaginal ring in preventing pregnancy during a 1-year (13-cycle) period will be studied in women who have regular sexual activity and use no other form of contraception. The Pearl index for all women (18-<40) and Kaplan-Meier life table analyses will be assessed for all subjects and for subjects £ 35 years and will provide supportive analyses for demonstrating efficacy. Pearl indices will be based on all cycles and on all cycles for which back-up contraception is not used.

The number of bleeding/spotting days per cycle or reference period will be used to evaluate cycle control. Safety will be evaluated by regular assessments of blood pressure, pulse, and body weight and by laboratory testing and Pap smears at screening and termination, and by the frequencies of adverse events and serious adverse events. Additional safety evaluations will be obtained in a companion Phase 3 study conducted by the NIH (Protocol CCN006) with three substudies to evaluate 1) the effect of treatment on 4 hepatic proteins that may be associated with a risk for thromboembolism; 2) the effect of reusing the same CVR for 13 consecutive cycles on vaginal flora and the risk of infection; and 3) the effect of vaginal delivery of NES and EE on the endometrium.

A nested pharmacokinetics/pharmacodynamics/safety study is also being conducted in a subset of 39 patients. Blood samples are drawn during study cycles 1, 3, and 13 in order to assess ovulation suppression, measured by serum progesterone concentration, and the pharmacokinetics of NES and EE.

Inclusion Criteria:

Healthy women who meet the following criteria:

• 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 clinic catchment area or within a reasonable distance from the clinic.
• Do not meet any of the exclusion criteria.
• Signed informed consent prior to entry into the trial.

[For pharmacokinetics study only; 39 subjects already recruited]

- Willing to undergo frequent blooding sampling

Exclusion Criteria:

Contraindications for enrollment will be the same as those for use with combined hormonal contraceptives in addition to contraindications specific to this clinical trial including:

• 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 a chlamydia or gonococcus infection 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 < 35yrs 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 a familial defect in the blood coagulation system, which in the opinion of the PI, 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 history of medically diagnosed severe depression, which, in the opinions 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) 85 mm Hg and/or systolic BP 135 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-Provera [depo-medroxyprogesterone (DMPA)] unless suspended 6 months before treatment.
• Current use of implanted hormonal contraceptives, including Mirena® [progestin containing intrauterine system (IUS)], Jadelle®, Norplant® or Implanon® (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).