CDP Research: Increasing Contraception Options for Women

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 are obese, 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 CDP is developing methods designed to address unmet needs for safety, acceptability, and effectiveness.

Contraceptive Vaginal Rings (CVRs)

Nestorone®/Ethinyl Estradiol CVR: one ring for a full year of protection

In partnership with The Population Council, CDP has developed a novel ring that delivers the progestin, Nestorone®, to effectively block follicular development and deliver 17-ß estradiol to support bone health, but with low potential for increasing VTE risk, even for obese women. The ring used continuously (no removal interval) 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 ring-out period of 2 days could cause regular, predictable bleeding in most women. The ring appears to be safe and effective, including in obese women, based on inhibition of ovulation. 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-day period.

Status: Enrollment into a contraceptive efficacy trial of the Nes/E2 CVR began in 2018. Women will be randomized to continuous or cyclical use but can switch if not satisfied with her bleeding pattern.

Nestorone®/Estradiol CVR (Nes/E2 CVR): one ring for 3 months of protection

This multicenter, open-label randomized study is examining the efficacy, cycle control, and safety of a CVR delivering a daily dose of Nestorone® and estradiol (NES-E2 CVR). This effort is being conducted in collaboration with The Population Council.

ClinicalTrials.gov Identifier: NCT03432416

Related Publications (from earlier studies):

  1. Jensen JT, Edelman AB, Chen BA, Archer DF, Barnhart KT, Thomas MA, Burke AE, Westhoff CL, Wan LS, Sitruk-Ware R, Kumar N, Variano B, Blithe DL. Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: pharmacokinetics from a dose-finding study. Contraception. 2018; 97(5):422-427. PMID: 29409834. PMCID: PMC5948142.
  2. Archer DF, Thomas MA, Conard J, Merkatz RB, Creasy GW, Roberts K, Plagianos M, Blithe D, Sitruk-Ware R. Impact on hepatic estrogen-sensitive proteins by a 1-year contraceptive vaginal ring delivering Nestorone® and ethinyl estradiol. Contraception. 2016; 93(1):58-64. PMID: 26408374.
  3. Huang Y, Merkatz RB, Hillier SL, Roberts K, Blithe DL, Sitruk-Ware R, Creinin MD. Effects of a one-year reusable contraceptive vaginal ring on vaginal microflora and the risk of vaginal infection: An open-label prospective evaluation. Public Library of Science One. 2015; 10(8):e0134460. PMID: 26267119. PMCID: PMC4534458.

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 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.

Status: Irregular bleeding caused by continuous progestin use is the major reason that women discontinue a progestin only method. CDP is sponsoring a study to determine if use of the ring with a 2- day ring-free interval maintains sufficient levels of Dapivirine to effectively inhibit ovulation and cause regular bleeding.

The study, titled A Randomized, Phase 1, Open-Label Study in Healthy HIV-Negative Women to Evaluate the Pharmacokinetics, Safety and Bleeding Patterns Associated with 90-Day Use of Matrix Vaginal Rings Containing 200 mg Dapivirine and 320 mg Levonorgestrel, is being conducted in collaboration with the International Partnership for Microbicides, the Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute of Mental Health

ClinicalTrials.gov Identifier: NCT03467347

Woman’s Condom (WC)

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 6 cycles of use. The efficacy of the WC 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. The copper intrauterine device (IUD) has almost no contraindications for use, making it a safe option for women with health risks who wish to avoid pregnancy.

Mini-Copper IUD for Nulliparous Women

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 current copper IUD. In collaboration with Bill & Melinda Gates Foundation and FHI 360, a comparison 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.

Status: Enrollment began in 2017 and is ongoing in the CCTN.

ClinicalTrials.gov Identifier: NCT03124160

Levonorgestrel (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 pill intake within a narrow timeframe each day. LNG Butanoate injections successfully suppressed ovulation; however, duration of action was less than 3 months in some women, particularly in obese women. Modifications are underway to increase the particle size, which may prolong the duration of action.

Status: Product production and protocol development is ongoing.

Publication (from earlier study):
Edelman AB, Cherala G, Li H, Pau F, Blithe DL, Jensen JT. Levonorgestrel butanoate intramuscular injection does not reliably suppress ovulation for 90 days in obese and normal-BMI women: a pilot study. Contraception. 2017; 95(1): 55-58. PMID: 27475035. PMCID: PMC5140699.

Other Program-Supported Efforts

Westhoff CL, Chen BA, Jensen JT, Barnhart K, Thomas M, Teal S, Blithe D. Phase I/II pharmacokinetic and pharmacodynamic evaluation of two levonorgestrel-only contraceptive patches in a multicenter randomized trial. Contraception 2018. Epub 2018 Apr 18. PMID: 29679590

Brooks JP, Edwards DJ, Blithe DL, Fettweis JM, Serrano MG, Sheth NU, Strauss JF 3rd, Buck GA, Jefferson KK. Effects of combined oral contraceptives, depot medroxyprogesterone acetate and the levonorgestrel-releasing intrauterine system on the vaginal microbiome. Contraception 95:405-413, 2017. PMID: 27913230

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