EXECUTIVE SUMMARY

The copper T 380A intrauterine device (IUD), developed almost 50 years ago, was introduced in the United States in 1988. It is an extremely effective form of birth control, with a failure rate of 0.3%-0.6%. It measures 32 mm horizontally and 36 mm vertically.

• Researchers are conducting a clinical trial comparing the device with a newer, smaller copper IUD not sold in the United States. The device, the Mona Lisa NT Cu380 Mini, has been marketed in Europe since 2014 and is available in Canada, Germany, France, and eight other countries. It carries a labeled duration of use of up to five years. It measures 24 mm horizontally and 30 mm vertically.

• A Phase III trial of the VeraCept IUD, a novel copper IUD on a flexible frame, is underway. The VeraCept measures 32 mm horizontally and 30 mm vertically.


Today, 4.4 million women in the United States rely on an intrauterine device (IUD) for contraception.1 According to a 2018 analysis, this level of IUD use represents the greatest percentage of device use ever seen in the U.S. Almost 8% of all women, nearly 12% among women using contraception, and more than 16% of reversible contraception users named the IUD in a national survey.2 This uptick stands in sharp contrast to the less than 1% of women who used the device in 1995.

The copper T 380A was one of the few IUDs available for Americans in 1995. Introduced in the U.S. in 1988, it is an extremely effective form of birth control, with a failure rate of 0.3%-0.6%.3 The device features a 380 mm2 copper surface area supplied by a sleeve of solid copper on each of the arms, with copper wire wrapped around the 36 mm vertical stem. A monofilament polyethylene thread is tied through the base, creating two 10.5 cm tailstrings for device detection and removal. The device is designed to be used in women whose uterine cavities sound to a depth of 6-9 cm.3

The copper T 380A was designed nearly 50 years ago, notes David Hubacher, PhD, senior epidemiologist, product development and introduction at FHI 360 in Durham, NC.

“Over the past four decades, this product has become the predominant device that international donor agencies purchase for developing countries,” states Hubacher. “The product has become the standard-bearer for copper devices due to its high effectiveness.”

Research Underway on Copper Option

In collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, FHI 360 is leading a clinical trial comparing the standard copper T 380A with a newer, smaller copper IUD not sold in the United States. The study device measures 24 mm horizontally and 30 mm vertically, compared to the copper T 380A, which measures 32 mm horizontally and 36 mm vertically. The study’s primary outcome measure is to determine the pregnancy rate over three years.

The device, the Mona Lisa NT Cu380 Mini, has been marketed in Europe since 2014 and is currently available in Canada, Germany, France, and eight other countries. It is labeled for use up to five years.2

All contraceptive products produce side effects. The goal of this comparative study is to see if a smaller copper IUD shows similar efficacy to the copper T 380A with fewer side effects, notes Hubacher.

“Side effects of increased menstrual bleeding and pain are the main reasons why women stop using the copper T 380A. Nulliparous women tend to have higher removal rates compared to parous women,” says Hubacher. “Indeed, some previous research has shown that smaller IUDs may fit the uteri of nulliparous women better than the standard device.”

In its original U.S. clinical trials, the two-year cumulative discontinuation rate for the copper T 380A was 22%; by three years, the rate rose to 33%, and after five years, discontinuation was at 60%.4 In the CHOICE Project study, data indicated that at 24 months, 48 months, and 60 months, 23%, 35.8%, and 44.1%, respectively, of copper IUD users discontinued.5 In a 2019 case control review, 67 women were fitted with a mini IUD (mean age 23 years, 64% nulliparous) and 63 women were fitted with a standard IUD (mean age 25 years, 39% nulliparous). Data indicated that more women who used the standard-sized IUD complained of pain and bleeding, leading to higher discontinuation at one year.6

“This trial of predominately nulliparous women is the first comparative study involving a smaller copper IUD to be conducted in the U.S. in more than 35 years,” says Hubacher. “If participants experience fewer side effects and higher satisfaction with the smaller product, while simultaneously benefitting from high contraceptive efficacy, then this product will provide additional options for women seeking nonhormonal, long-acting contraception.”

More Devices in Research Pipeline

The Phase III trial of the VeraCept IUD, a novel copper IUD on a flexible frame, is underway. The IUD’s design accommodates the shape of the uterus with a lower total copper load for increased comfort and less bleeding. The flexible frame is made of nitinol, a nickel and titanium alloy.

During insertion, the 30 mm x 32 mm device is placed just inside the internal cervical os and bilaterally at the tubal ostia. For comparison, the copper T380 A measures 32 mm horizontally and 36 mm vertically.7 The VeraCept features 175 mm2 of copper surface area, which is less than the 380 mm2 in the copper T 380A.

The VeraCept underwent a Phase II trial of 286 women in 12 U.S. centers who provided 4,263 cycles evaluable for pregnancy. Sixty percent of women enrolled in the study were nulliparous. One pregnancy occurred during the 24 months of observation (Pearl Index 0.30; 95% confidence interval, 0.01-1.70). Placement was successful in 283 women, with a mean pain score at insertion reported at 1.44. At one year, 177 women elected to continue device use, with 135 (76.2%) continuing to use the IUD until 24 months. About 15% of women discontinued early due to adverse events.8

In a randomized, subject-blinded comparison of the VeraCept IUD and a copper T 380A, data indicate use of the VeraCept device resulted in less pain at insertion, fewer expulsions, and higher total continuation than the copper T 380A, with similar efficacy.9

The Phase III trial is designed as a prospective, multicenter, single-arm, open-label study for three years, with extension up to five years. Women who are postmenarcheal and premenopausal up to age 45, who are at risk for pregnancy, and who desire a long-term intrauterine contraceptive for birth control are eligible for the study. Estimated completion date is 2024.

Sebela Pharmaceuticals also has a 52 mg levonorgestrel (LNG)-releasing system, the LevoCept, under development. The device has a nitinol wire frame with a 32 mm arm span and a 30 mm vertical measurement. There are two similar 52 mg levonorgestrel IUDs currently available in the United States: Mirena and Liletta. The FDA recently approved Liletta for up to six years of effective use; the manufacturers of the Mirena have requested approval for a similar effectiveness window. Cumulative pregnancy rates for the available 52 mg IUDs are 0.1% to 0.2% in the first year.10

REFERENCES

  1. Kavanaugh ML, Jerman J. Contraceptive method use in the United States: Trends and characteristics between 2008, 2012 and 2014. Contraception 2018;97:14-21.
  2. Hubacher D, Kavanaugh M. Historical record-setting trends in IUD use in the United States. Contraception 2018;98:467-470.
  3. Nelson AL, Massoudi N. New developments in intrauterine device use: Focus on the US. Open Access J Contracept 2016;7:127-141.
  4. Wu JP, Pickle S. Extended use of the intrauterine device: A literature review and recommendations for clinical practice. Contraception 2014;89:495-503.
  5. Diedrich JT, Madden T, Zhao Q, et al. Long-term utilization and continuation of intrauterine devices. Am J Obstet Gynecol 2015;213:822.e1-e6.
  6. Akintomide H, Barnes P, Brima N, et al. Higher discontinuation rate with a standard-sized compared to a small-sized ‘gold standard’ copper intrauterine device: A case-control review. BMJ Sex Reprod Health 2019: doi: 10.1136/bmjsrh-2018-200296.
  7. Turok DK, Gawron LM, Lawson S. New developments in long-acting reversible contraception: The promise of intrauterine devices and implants to improve family planning services. Fertil Steril 2016;106:1273-1281.
  8. Turok D, Nelson A. Phase 2 efficacy, safety and tolerability results of the veracept low-dose copper intrauterine contraceptive: 24-month data. Contraception 2018;98:355.
  9. Reeves MF, Katz BH, Canela JM, et al. A randomized comparison of a novel nitinol-frame low-dose-copper intrauterine contraceptive and a copper T380S intrauterine contraceptive. Contraception 2017;95:544-548.
  10. Dean G, Schwarz EB. Intrauterine devices. In: Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology: 21st revised edition. New York: Ayer Company Publishers, 2018.