Approximately one-half of U.S. pregnancies are unintended. Current contraceptive methods serve well for many women but not well for others, especially women with special health considerations such as obesity, hypertension, or diabetes. Recent data indicate that one-third of reproductive-age women have obesity, putting them at increased risk of venous thromboembolism (VTE), hypertension, and diabetes. As their risk factors increase, these women have contraindications to most hormonal contraceptive methods, yet they face even higher risks from pregnancy. Options are limited for those women wishing to avoid pregnancy. New or improved safe and effective contraception is needed. The Contraceptive Development Program (CDP) is developing methods designed to address unmet needs for safety, acceptability, and effectiveness.
Contraceptive Vaginal Rings (CVRs)
Nestorone®/Estradiol CVR (NES-E2 CVR): One ring for 3 months of protection
In partnership with the Population Council, CDP has developed a novel ring that delivers progestin to effectively block follicular development and deliver 17-ßestradiol to support bone health, but with low potential for increasing VTE risk, even for women who have obesity. The ring used continuously (no removal interval) for 90 days appeared safe and effectively inhibited ovulation. Most women liked the ring, but some experienced unacceptable bleeding. A pilot study implementing a ring-out period (2 or 4 days) demonstrated that a short ring-out period could cause regular, predictable bleeding in most women. The ring appears to be safe and effective, including in women who have obesity. By either continuous or cyclical use of the ring, a woman may produce predictable and acceptable bleeding which, depending on her response, could be amenorrhea, occasional bleeding over a 90-day period, or a cyclical interval of bleeding resulting from removal of the ring for a 2-, 3-, or 4-day period.
ClinicalTrials.gov Identifier: NCT03432416
Status: A contraceptive efficacy trial of the NES/E2 CVR has completed follow-up. Data analysis will begin in 2022. Preliminary results indicate that the method is highly effective and that women may control bleeding patterns by using the ring continuously or by removal of the ring for a brief time (2-4 days) to induce a regular short bleeding interval.
Related Publications (from earlier studies):
- Chen, M. J., Creinin, M. D., Turok, D. K., Archer, D. F., Barnhart, K. T., Westhoff, C. L., Thomas, M. A., Jensen, J. T., Variano, B., Sitruk-Ware, R., Shanker, A., Long, J., & Blithe, D. L. (2020). Dose-finding study of a 90-day contraceptive vaginal ring releasing estradiol and segesterone acetate. Contraception, 102(3), 168–173. PMID: 32416145
- Tiedeken, M., Westhoff, C. L., Cohen, A., Cremers, S., Sitruk-Ware, R., Blithe, D. L., & NICHD Contraceptive Trials Network Vaginal Ring Group (2019). Bone turnover markers in women participating in a dose-finding trial of a contraceptive vaginal ring releasing Nestorone and estradiol. Contraception, 99(6), 329–334. PMID: 30871934
- Jensen, J. T., Edelman, A. B., Chen, B. A., Archer, D. F., Barnhart, K. T., Thomas, M. A., Burke, A. E., Westhoff, C. L., Wan, L. S., Sitruk-Ware, R., Kumar, N., Variano, B., & Blithe, D. L. (2018). Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: Pharmacokinetics from a dose-finding study. Contraception, 97(5),422-427. PMID: 29409834. PMCID: PMC5948142
Multipurpose Prevention Technologies (MPT)
Most contraceptive methods do not protect against HIV infection. MPTs are designed to protect against pregnancy and against infection from pathogens, like HIV, transmitted through sexual contact.
Dapivirine/Levonorgestrel (LNG) Vaginal Ring: One ring for 3 months of protection
Research showed that women with high HIV-transmission risk had a lower incidence of HIV acquisition if they consistently used a vaginal ring delivering dapivirine. A new ring that delivers both dapivirine and LNG is designed to provide protection against pregnancy and HIV acquisition.
ClinicalTrials.gov Identifier: NCT05041699
Status: A study of a vaginal ring containing dapivirine and LNG is being conducted in collaboration with the International Partnership for Microbicides with support from the NIH Office of AIDs Research. The clinical trial to evaluate the pharmacokinetics and safety of 90 days' use of vaginal rings containing dapivirine and LNG is actively recruiting.
An iterative process was used by the Program for Appropriate Technology (PATH) to design a novel female condom that would be effective and acceptable to users. The Contraceptive Clinical Trials Network (CCTN) undertook a pivotal contraceptive efficacy trial to determine effectiveness for up to six cycles of use. The efficacy of the female condom was similar to that of male condoms.
Status:A clinical study report to support regulatory approval is in progress.
Long-Acting Reversible Contraceptives (LARCs)
LARCs are the most effective and most highly acceptable methods of contraception for women. CDP has two LARC methods in the pipeline, both under evaluation in the CCTN: 1) LNG butanoate, a novel progestin-only, long-acting injectable; and 2) a new intrauterine device (IUD) for nulliparous women.
LNG butanoate: A novel long-acting injectable method
LNG is effective as a contraceptive and is not associated with the increased VTE seen with products containing ethinyl estradiol. Progestin-only contraception methods are often prescribed for women who have conditions, including obesity, that increase risk of VTE. Injections of long-acting LNG esters, such as LNG butanoate, may improve compliance over progestin-only pills, which require daily intake within a narrow timeframe. LNG butanoate injections successfully suppressed ovulation; however, duration of action was fewer than 3 months in some women, particularly in women who have obesity. Modifications are underway to prolong the duration of action. A new formulation and manufacturing process has allowed an increase in concentration while preventing aggregation. The newly formulated drug allows preparation of more concentrated material; thus, higher doses in a lower volume, making intramuscular and subcutaneous injection easier. The ongoing trial (CCN021) is a dose-finding study to determine an effective dose for ovulation inhibition of 3 months or longer.
ClinicalTrials.gov Identifier: NCT04143659
Status: A multisite study to evaluate the pharmacokinetic and pharmacodynamic profile of intramuscular or subcutaneous injections of LNG butanoate for female contraception is actively recruiting in 2022.
Related Publication (from earlier study):
Edelman, A. B., Cherala, G., Li, H., Pau, F., Blithe, D. L., & Jensen, J. T. (2017). Levonorgestrel butanoate intramuscular injection does not reliably suppress ovulation for 90 days in obese and normal-BMI women: A pilot study. Contraception, 95(1), 55–58. PMID: 27475035. PMCID: PMC5140699
Mini Copper IUD for Nulliparous Women
The copper IUD has almost no contraindications for use, making it a safe option for women with health risks who wish to avoid pregnancy. Increased bleeding and cramping associated with the copper IUD has deterred many clinicians from recommending this method to nulliparous women, especially adolescents. A mini copper IUD may be less likely to cause increased bleeding in this population compared with the currently available copper IUD. In collaboration with the Bill & Melinda Gates Foundation and FHI 360, a study is underway to compare the mini copper IUD with ParaGard® in nulliparous women. Outcomes are to determine contraceptive effectiveness, continuation rate, expulsion rate, bleeding characteristics, and pain.
ClinicalTrials.gov Identifier: NCT03124160
Status: Enrollment began in 2017. Follow-up for 3 years of use is ongoing in the CCTN. Study completion and initiation of data analysis is scheduled for 2022.
Other Program-Supported Efforts
Creation of a Novel Database to Facilitate Contraceptive Target Discovery
CDP’s Dr. Min Lee led development of a new tool for contraceptive and infertility research. This searchable, downloadable Contraceptive Infertility Target DataBase (CITDBase) provides a portal for investigators to mine existing transcriptomic and proteomic resources for identifying high-quality contraceptive/infertility targets in male and female reproductive tissues.
Sinha, S., Knapp, M., Pywtorak, J., McCain, G., Wingerden, K., VanDervoort, C., Gondek, J. M., Madrid, P., Parman, T., Gerrard, S., Long, J. E., Blithe, D. L., Moss, S., & Lee, M. S. (2021). Contraceptive and Infertility Target DataBase: a contraceptive drug development tool for targeting and analysis of human reproductive specific tissues. Biology of Reproduction, 105(6), 1366–1374. PMID: 34514504