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Evaluation of a new, low-dose levonorgestrel intrauterine contraceptive system over 5 years of use

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Abstract

Objective

To evaluate the efficacy and safety of a new, low-dose levonorgestrel intrauterine contraceptive system (LNG-IUS 12) for up to 5 years of use.

Study design

In this Phase III study, 2885 nulliparous and parous women aged 18–35 years were randomized to LNG‐IUS 8 or LNG-IUS 12 for 3 years. After 3 years, women using LNG-IUS 12 could continue for up to 2 additional years (5 years total). The primary outcome was occurrence of pregnancy (Pearl Index). Secondary outcomes included safety, bleeding, dysmenorrhea, discontinuations, and user satisfaction.

Results

From August 2007 through May 2008, out of 2885 women who were enrolled, 1453 were randomized to LNG-IUS 12. Placement was attempted in 1452/1453 (full analysis set). Mean age at baseline was 27.1 years; 39.5% were nulliparous. The cumulative 5-year Pearl Index (PI) was 0.29; the 5-year cumulative failure rate was 1.4%. The 5-year PI for ectopic pregnancy was 0.18. Over 5 years, 55.3% of women reported study drug-related treatment-emergent adverse events (TEAEs). Crude incidences of pelvic inflammatory disease, uterine perforation, and complete/partial LNG-IUS 12 expulsion were 0.6%, 0.2%, and 3.7%, respectively. Women using LNG-IUS 12 generally experienced less frequent bleeding over time. The incidence of amenorrhea during the last 90-day reference interval (end of Year 5) was 22.6%. Overall, 870 (59.9%) and 550 (37.9%) women completed 3 and 5 years of treatment, respectively; 77.8% of women who entered the extension phase completed 5 years of use. Over 5 years, 22.6% discontinued due to TEAEs, including 13 women who discontinued due to pregnancy; 76 discontinued due to bleeding problems including amenorrhea; and 163 discontinued due to desire for pregnancy, 71.2% of whom conceived within 12 months.

Conclusion

In this study including parous and nulliparous women, LNG-IUS 12 was highly effective over 5 years of use and associated with a favorable safety profile. LNG‐IUS 12 offers women a low-dose contraceptive option for up to 5 years.

Introduction

To reduce the incidence of unintended pregnancy, clinical practice guidelines advocate the use of long-acting reversible contraception (LARC): highly effective methods independent of user compliance [1], [2], [3], [4]. Levonorgestrel intrauterine systems (LNG-IUSs) are a subset of LARC; available versions include: LNG-IUS 8 (Jaydess®/Skyla®; Bayer HealthCare) [5] and LNG20 (Levosert™/Liletta™; Medicines360/Actavis) [6], which are currently indicated for contraception for up to 3 years, and LNG-IUS 20 (Mirena®; Bayer HealthCare) [7], which is approved for up to 5 years of use for contraception.

A new LNG-IUS (LNG-IUS 12) has been developed for up to 5 years of use with an average release rate of ∼12 μg/24 h over the first year. LNG-IUS 12 has a narrower hormone reservoir, and smaller T-frame (28 × 30 mm) compared with LNG-IUS 20 and LNG20. Consequently, LNG-IUS 12 is placed using a narrower placement tube, which is equivalent in diameter to the placement tube used for LNG-IUS 8 [8], [9], [10]. Smaller placement systems may be more suitable for women with a narrower cervical canal and/or smaller uterine cavity, such as nulliparous women. This may broaden the appeal of LNG-IUSs to a wider range of women and help increase LARC uptake.

This article reports the final results of a 5-year Phase III trial evaluating the efficacy and safety of LNG-IUS 12 in nulliparous and parous women.

Section snippets

Materials and methods

This randomized, open-label, double-arm Phase III study (clinicaltrials.gov: NCT00528112) was conducted at 138 centers in 11 countries. It was originally designed as a 3-year study, and women who met eligibility criteria were randomized 1:1 to use either LNG-IUS 8 or LNG-IUS 12 for 3 years. Preliminary results showed that the efficacy of LNG-IUS 8 was well within the acceptable range over 3 years. Additionally, pharmacokinetic (PK) modeling predicted that LNG release rates with LNG-IUS 12 at

Results

Between August 2007 and May 2008, 2885 women were randomized and 1453 were allocated to LNG-IUS 12 (Fig. 1). The FAS included 1452 women for whom placement was attempted. Placement was successful in 1445/1452 women (99.5%), with no difference in success rates between nulliparous and parous women. Baseline characteristics were similar between women in the FAS and those who entered the extension period (Table 1).

The unadjusted 5-year PI was 0.29; PIs in each individual year were equal to or less

Discussion

In this study in nulliparous and parous women, LNG-IUS 12 was shown to be a highly effective contraceptive method for up to 5 years of use. Consistent contraceptive efficacy was observed over time, as demonstrated by the continuously low unadjusted PIs for each year. The efficacy of LNG-IUS 12 (5-year cumulative failure rate of 1.45%) was similar to that of the higher-dose LNG-IUS 20 (0.7% at 5 years) [7], which is indicated for up to 5 years of contraceptive use [7].

LNG-IUS 12 was well

Financial disclosure

Study funded by Bayer HealthCare. Medical writing support funded by Bayer HealthCare.

Condensation

LNG-IUS 12 is a highly effective low-dose intrauterine system with a favorable safety profile providing 5 years of contraception to parous and nulliparous women.

Acknowledgments and disclosures

Medical writing support was provided by Paul Richard Wilson, Helen Attisha, and Laura Miller of Chameleon Communications, with the financial support of Bayer HealthCare.

Kristina Gemzell-Danielsson serves on advisory boards and has been an invited speaker at scientific meetings for Bayer AG, MSD/Merck, HRA Pharma, Exelgyn, and Gedeon Richter on an ad hoc basis. Her institution has received grants for conducting the Phase II and Phase III clinical trials of LNG-IUS 8 and LNG-IUS 12. Dan Apter’s

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Clinical Trial Registration: ClinicalTrials.gov NCT00528112

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