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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
United States Agency for International Development (USAID)
World Health Organization
Information provided by (Responsible Party):
Population Council
ClinicalTrials.gov Identifier:
NCT00263341
First received: December 6, 2005
Last updated: September 25, 2012
Last verified: September 2012
  Purpose

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.


Condition Intervention Phase
Contraception
Drug: NES/EE CVR
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Population Council:

Primary Outcome Measures:
  • Efficacy [ Time Frame: At all visits ] [ Designated as safety issue: No ]
    Primary endpoint: The Pearl Index for women 35 years of age derived from using all cycles for which back up contraception is not used will be the primary efficacy endpoint. This index will be calculated for the women participating in Protocol 300 B and will then be pooled with data from women 35 years who participate in 300 A (CCN006).

  • Safety [ Time Frame: At all visits ] [ Designated as safety issue: Yes ]
    Each subject's health status will be monitored carefully throughout the trial. Baseline data collected at the screening visit will consist of the medical and gynecologic history and physical examination findings including breast and pelvic exam (to include Pap test and STI screening for chlamydia and gonorrhea). These assessments will be repeated at the 6th cycle visit (with the exception of the Pap, and STI screening). Baseline data obtained from clinical chemistries and a CBC will be used to monitor liver and renal function, lipid levels and hematologic status.


Estimated Enrollment: 1000
Study Start Date: December 2005
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: NES/EE CVR
    This is a Phase 3, multicenter, open-label study of a 21/7-day regimen of the 150/15 NES/EE CVR, in healthy women followed on an outpatient basis up to one year (13 cycles) of treatment over one year. Because of the stop treatment date of December 31, 2008 for all participants, women enrolling or re-enrolling in 2008 may not complete a full 13 cycles of treatment. Subjects may also participate in a 6 month follow-up period after the 300B study. The ring is designed to last for 12 months.
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00263341

Locations
United States, California
Women and Children's Hospital, LAC/USC Medical Center
Los Angeles, California, United States, 90033
University of California, San Francisco General Hospital, Department of Obstetrics & Gynecology
San Francisco, California, United States, 94110
United States, Illinois
University of Chicago Hospitals
Chicago, Illinois, United States, 60637
United States, New York
Montefiore Medical Center/Albert Einstein College of Medicine
Bronx, New York, United States, 10461
United States, Ohio
Columbus Center for Women's Heatlh Research
Columbus, Ohio, United States, 43213
Australia
FPA Health
Ashfield, Australia
Brazil
University of Campinas, Department of Obstetrics & Gynecology
Campinas, Sao Paulo, Brazil
Chile
Instituto Chileno de Medicina Reproductiva
Santiago, Chile
Dominican Republic
Profamilia
Santo Domingo, Dominican Republic
Finland
Family Federation of Finland
Helsinki, Finland
Hungary
University of Szeged, Department of Obstetrics & Gynecology
Szeged, Hungary
Sweden
Karolinska Institutet, Department of Woman and Child Health, Division of Obstetrics & Gynecology
Stockholm, Sweden, SE 17176
Sponsors and Collaborators
Population Council
United States Agency for International Development (USAID)
World Health Organization
Investigators
Study Director: Ruth Merkatz, Ph.D. Population Council
  More Information

No publications provided

Responsible Party: Population Council
ClinicalTrials.gov Identifier: NCT00263341     History of Changes
Other Study ID Numbers: Protocol 300
Study First Received: December 6, 2005
Last Updated: September 25, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Population Council:
Contraceptive agents
Female contraception
Progestins

Additional relevant MeSH terms:
Contraceptive Agents
ST 1435
Estradiol
Ethinyl Estradiol
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Contraceptive Agents, Female

ClinicalTrials.gov processed this record on July 20, 2014