The currently available levonorgestrel intrauterine contraceptive system contains 52 mg levonorgestrel. Since its introduction into the United States in 2001, it has contributed considerably to the increase in the use of intrauterine contraception. This has been the result of its safety, convenience, and its effectiveness as a contraceptive and as a treatment for heavy menstrual bleeding.1
Many authorities2–6 have supported use of intrauterine contraceptives in nulliparous women; however, a recent survey demonstrated that more than 60% of U.S. clinicians only infrequently offer intrauterine contraceptives to nulliparous women.7 In many European countries, intrauterine contraceptives are reserved for women who have completed their families. Additionally, a recent study performed in community family planning clinics in the United States reported that 19% of attempts at intrauterine contraceptive placement in nulliparous women were unsuccessful.8
Intrauterine contraceptive systems with 13.5 mg levonorgestrel (total content) and with 19.5 mg levonorgestrel (total content) were developed. They had smaller reservoirs of levonorgestrel and smaller T-frames, which allow placement using a narrower tube than the existing product. Thus, they may be suitable for women with a narrower cervical canal,2 smaller uterine cavity, or both.9
This article reports the results of a 3-year, Phase III, multicenter, single-blinded, prospective clinical trial of those two levonorgestrel contraceptive systems 13.5 mg and 19.5 mg. The primary outcome was pregnancy rates; other outcomes included bleeding patterns, ease and pain of placement, safety, continuation rates, and user satisfaction.
MATERIALS AND METHODS
This multicenter, open-label, randomized, two-arm, parallel-group, Phase III study of two levonorgestrel intrauterine contraceptive systems containing 13.5 mg and 19.5 mg, respectively (clinicaltrials.gov; NCT00528112), was conducted at 138 centers across 11 countries (Argentina, Canada, Chile, Finland, France, Hungary, Mexico, The Netherlands, Norway, Sweden, and the United States).10 The protocol and its amendments were reviewed and approved by each study site's independent ethics committee or institutional review board. The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonisation guideline E6: Good Clinical Practice. The Consolidated Standards of Reporting Trials (CONSORT) guidelines for randomized controlled trials were followed. All women provided written informed consent before study entry.
The trial, initiated in August 2007, randomized women to treatment with the 13.5 mg levonorgestrel intrauterine contraceptive system or 19.5 mg levonorgestrel intrauterine contraceptive system for 3 years. However, after results suggested a potentially longer duration of use for the higher-dose intrauterine contraceptive system, women in that arm were given an opportunity to continue using their system in an extension study for up to 2 more years (5 years in total).10 The results of the 3-year study, which was completed in July 2011, are reported here.
The current levonorgestrel intrauterine contraceptive system has a T-frame measuring 32 mm×32 mm and is placed using a tube that measures a 4.8 mm diameter in the United States. Both experimental levonorgestrel intrauterine contraceptive systems had a T-frame measuring 28 mm×30 mm and both were placed using identical 3.80-mm diameter placement tubes.
Healthy nulliparous and parous women aged 18–35 years (inclusive) were invited into the study if they had regular menstrual cycles (21–35 days) and requested contraception. At the screening visit, participants were tested for Chlamydia trachomatis using a swab sample from the cervix and if they tested positive, they were also tested for Neisseria gonorrhea (both tests used DNA probes). Women who tested positive for either infection were not eligible for enrollment until the infection had been successfully treated. The exclusion criteria were consistent with the contraindications for use of the existing levonorgestrel intrauterine contraceptive system that were in place at the time of protocol development with the exception that no maximum or minimum uterine dimensions were specified. Women were excluded if they had had a vaginal or cesarean delivery or abortion within 6 weeks before screening. Further exclusion criteria included: known or suspected pregnancy; lactation; infected abortion or postpartum endometritis within 3 months before screening; distortion of the uterine cavity (eg, as a result of leiomyomas) that, in the investigator's opinion, was likely to cause problems with placement, retention, or removal of an intrauterine system; unexplained abnormal uterine bleeding; history of ectopic pregnancy; genital malignancy or untreated cervical dysplasia; previous or current pelvic inflammatory disease; or genital infection (until successfully treated).
Randomization to 13.5 mg or 19.5 mg systems was set up centrally by the study statistician using a computerized randomization program, was performed in blocks of four using a one-to-one allocation ratio, and was balanced for study sites. A set of numbered randomization cards and a randomization list were prepared for each study site. The cards, used in ascending order, informed the investigator to which treatment each participant was to be allocated. Women were blinded to treatment allocation, but it was not possible to blind investigators because of discernible differences in the length of the hormone reservoirs of the two intrauterine systems. Study treatment was disclosed to women at 30 months.
The systems were placed during the first 7 days of the woman's menstrual cycle in conformance with the instructions provided by the study sponsor. The use of local anesthesia, oral analgesics, or cervical dilation was permitted at the discretion of the investigator. Up to two placement attempts were permitted per participant and if both attempts failed, the woman was withdrawn from the study. After the procedure, ultrasonography was used to confirm correct intrauterine placement.
Study visits took place at screening, at baseline for randomization and placement of the system, at 3 months after placement, then every 3 months until the end of year 1, and every 6 months thereafter until the end of the 3-year study period. At each study visit, a gynecologic examination was performed, including a vaginal ultrasonographic examination to evaluate the position of the intrauterine system and to assess endometrial thickness, ovarian size, and the presence of ovarian cysts. Pregnancy tests were performed at screening, baseline, the end of the 3-year study, and when clinically indicated.
In vaginal bleeding diaries, women graded their bleeding daily as “none,” “spotting” (no need for sanitary protection or need for panty liners only), “light” (need for sanitary protection but less than associated with normal menstruation in the woman's experience), “normal,” or “heavy” (more than normal menstruation in the woman's own experience).
Investigators rated placements as “easy,” “slightly difficult,” or “very difficult” and women rated their pain on placement as either “none,” “mild,” “moderate,” or “severe” from their own perspectives and based on their own perceptions of what these terms meant. These scales were chosen because they were considered simple for investigators and women to understand and use and for consistency with the previous Phase II trial.
Additional outcomes included the use of cervical dilation, local anesthesia, or analgesia (each at the physicians' discretion); system position by ultrasonography; adverse events; and serious adverse events. Total or partial expulsions were reported as adverse events. A protocol amendment specified that a “partial expulsion” required that the system was located at least in part in the cervical canal and clarified that it was not necessary to remove an intrauterine system unless at least a portion of it extended into the cervical canal.
Body weight was measured at baseline and annually thereafter. Bone mineral density, measured by dual-energy X-ray absorptiometry at the lumbar spine and the total hip, was evaluated at baseline and annually thereafter in a subset of 205 women who were treated at two study centers in Finland.
At the final study visit, women were asked to complete a user questionnaire in which they rated their satisfaction with study treatment and their menstrual bleeding pattern as: “very satisfied,” “somewhat satisfied,” “neither satisfied or dissatisfied,” “dissatisfied,” or “very dissatisfied.” Women who did not experience any bleeding were asked to rate their bleeding as “not applicable.” When asked about their preference for use of contraception after the study, women were asked to choose from the following options: “continue with 13.5 mg or 19.5 mg system,” “use a different hormonal contraceptive,” “use a different contraceptive method,” “discontinue use of all types of contraception,” or “do not know.”
The European Medicines Agency guideline states that sufficient women should be recruited to give a Pearl Index with a two-sided 95% confidence interval (CI) such that the difference between the upper limit of the CI and the point estimate (expressed as pregnancies per 100 woman-years) does not exceed 1.11 The sample size for this study was calculated to fulfill this requirement in each of the two treatment groups for the third year of the study. The assumptions were as follows: the true Pearl Index was 1.0, the annual dropout rate was 15%, and exposure time was reduced by 2% owing to use of concomitant “back-up” contraception. The relevant exposure time in the third year was calculated to be 923 woman-years; 1,410 women were required in each treatment group to ensure sufficient exposure time in the third year of treatment.11 Efficacy and safety analyses were based on all randomized women for whom placement of a study intrauterine system was attempted (full analysis set).
The pregnancy rate was expressed as the Pearl Index (number of pregnancies per 100 woman-years). Pearl Index and corresponding CI calculations assumed that the number of pregnancies followed a Poisson distribution. As a secondary analysis, the cumulative failure rate was calculated using the Kaplan–Meier method. Exposure calculations were based on the time from placement until expulsion or removal of the system or the end of 3 years. Months during which women reported using concomitant contraception (eg, condoms) or sex steroid hormones were not included in the total number of months of treatment exposure (the denominator for the Pearl Index). However, if a pregnancy occurred during such a month, the pregnancy was counted in efficacy calculations. Women who had a failed placement attempt were assumed to have an exposure time of 1 day and, therefore, were included in the efficacy analysis. Pregnancies that occurred after removal or detection of an expulsion were not included in the Pearl Index calculation; pregnancies that occurred before detection of expulsion were included.
In total, 3,661 women were screened for inclusion in the study; 2,885 of whom were consented, enrolled, and randomized. Successful placement was achieved in 1,426 and 1,445 women in the 13.5 mg intrauterine contraceptive system and 19.5 mg intrauterine contraceptive system groups, respectively. The disposition of the women is summarized in Figure 1.
The two treatment groups were similar with regard to mean age, weight and body mass index, smoking status, number of births, and parity status (Table 1). Overall, 39% of women were nulliparous; 12% had had a cesarean delivery only (no vaginal deliveries), and 39% were aged 25 years or younger.
The 3-year Pearl Indices were 0.33 and 0.31 for the 13.5 mg system and 19.5 mg system, respectively (Table 2). The Pearl Indices for individual years demonstrated no discernible differences in pregnancy rates over time with either system (Table 2).
The Kaplan–Meier failure rates for 13.5 mg and 19.5 mg systems were 0.4% and 0.2%, respectively, for year 1; 0.3% and 0.4%, respectively, for year 2; and 0.2% and 0.4%, respectively, for year 3. Kaplan–Meier estimates for the cumulative failure rate over 3 years for the 13.5 mg and 19.5 mg systems were 0.9% and 1.0%, respectively. None of the on-treatment pregnancies were associated with birth defects.
Placement success rates, reasons for placement failure, use of cervical dilation, and administration of pain medications are summarized in Table 3. Overall, 99.5% of women had a successful placement of either system (allowing up to two attempts per woman) and placement was successful at the first attempt in 96.0% of women.
Table 3 also summarizes investigators' assessments of ease of placement and participants' perceptions of placement-related discomfort. Investigators rated placement as “easy” in 90% of women and “very difficult” in 1% of women. Only 8% of women rated their pain as “severe.”
Mean numbers of bleeding or spotting days by 30-day reference periods for the first year and by 90-day reference periods over 3 years are shown in Figure 2. Mean number of bleeding or spotting days decreased over time in both treatment groups (Fig. 2A–B). There were more spotting-only days than bleeding days in all reference periods (Fig. 2A–B).
Table 4 lists the adverse events reported by at least 2% of patients that were judged to be at least possibly related to study treatment. Treatment-related serious adverse events were reported by eight (0.6%) and 15 (1.0%) women in the 13.5 mg and 19.5 mg groups, respectively. All perforations and ectopic pregnancies were considered to be serious adverse events. There were no complete uterine perforations and only one partial perforation (a case of myometrial embedment with a 19.5 mg system). This woman had a hysteroscopy to evaluate abdominal pain and her intrauterine system was removed vaginally at a later date without complication. The crude incidence of complete or partial perforation across both treatment groups combined was therefore 0.03%.
Over the course of the 3-year study, three and seven ectopic pregnancies occurred in the 13.5 mg and 19.5 mg system groups, respectively, resulting in absolute ectopic pregnancy rates of 0.10 per 100 woman-years (95% CI 0.02−0.29) for the lower dose and 0.22 per 100-woman-years (95% CI 0.09−0.45) for the higher dose system. No pattern in the ectopic pregnancy rate over time was observed in either treatment group.
Two cases of pelvic inflammatory disease in the levonorgestrel intrauterine contraceptive system 13.5 mg group and four cases of pelvic inflammatory disease in the other group were classified as serious adverse events. A further four cases of pelvic inflammatory disease in the 13.5 mg system group and a further two cases of pelvic inflammatory disease in the 19.5 mg system group were classified as nonserious adverse events. Five of these 12 cases were diagnosed within 1 month of placement of an intrauterine system. All cases of pelvic inflammatory disease were diagnosed clinically based on the investigator's assessment.
The cumulative risk of at least partial expulsion over 3 years was 4.56% for the 13.5 mg system group and 3.58% for the 19.5 mg system group. Number of expulsions by treatment year is detailed in Figure 1.
Among 103 women evaluated in the 13.5 mg group and 102 women evaluated in the 19.5 mg group, no reduction in bone mineral density from baseline was observed at either the lumbar spine or total hip over 3 years in either treatment group. Mean (standard deviation) change in body weight from baseline was 0.2 kg (4.4 kg) at 12 months and 0.5 kg (6.0 kg) at 3 years for 13.5 mg system users and 0.6 kg (4.7 kg) at 12 months and 1.1 kg (6.3 kg) at 3 years for 19.5 mg system users (P=.03).
Epithelial cell abnormalities detected by cervical cytology tests were reported in 3.9% and 4.1% of women in the 13.5 mg system and 19.5 mg system groups, respectively, at the end of 3 years or at the last visit for women who discontinued early: 1.2% had atypical squamous cell of undetermined significance; 2.1% had low-grade and 0.7% high-grade squamous intraepithelial lesions. No cases of squamous cell carcinoma were diagnosed during the study.
In the 13.5 mg system and 19.5 mg system groups, 21.9% and 19.1% of women discontinued for any adverse event over 3 years, including 1.0% and 1.2% who discontinued for serious adverse events and 4.7% and 4.9% who discontinued for disturbances in menstrual bleeding (including amenorrhea), respectively. In total, 57% and 60% of women completed 3 years of treatment with the 13.5 mg system and 19.5 mg system, respectively.
Overall, of 2,884 women in the full analysis set, 2,116 (1,053 and 1,063 women in the 13.5 mg system and 19.5 mg system groups, respectively) completed a user satisfaction questionnaire either at the end of 3 years (for women who completed the study) or at the final study visit (for women who discontinued prematurely).
For the levonorgestrel intrauterine contraceptive system 13.5 mg, 95% of those surveyed rated themselves as “very satisfied” or “somewhat satisfied” with study treatment; for the levonorgestrel intrauterine contraceptive system 19.5 mg, the corresponding percentage was 96%. In each of the respective groups, 77% and 76% of women stated that they were “very satisfied” or “somewhat satisfied” with their bleeding patterns. Finally, 77% and 82% of women in the 13.5 mg system and 19.5 mg system groups, respectively, stated that they would like to continue using their study treatment after the study (although at the time neither of the study intrauterine contraceptive systems was available for use outside of clinical trials).
This study confirmed that both the lower dose levonorgestrel intrauterine contraceptive systems provide consistent and reliable contraception for up to 3 years. This study evaluated the clinical performance of the two low-dose intrauterine contraceptive systems; only limited comparisons with the existing products are possible. The only randomized study to directly compare either study system with the existing levonorgestrel intrauterine contraceptive system was the Phase II study, which was not sufficiently powered to establish the Pearl Index or to demonstrate noninferiority of the experimental levonorgestrel intrauterine contraceptive systems compared with the marketed product. Nevertheless, in the Phase II study, the 95% CIs for the years 1, 2, and 3 and 3-year Pearl Indices for all three systems overlapped, indicating good contraceptive efficacy for both experimental systems in the cohort of nulliparous and parous women.12
Vaginal bleeding patterns in this study were found to be acceptable by more than three fourths of women using these systems. Over the entire study duration, only 4.7% and 4.9% of women using 13.5 mg system and 19.5 mg systems, respectively, discontinued because of bleeding changes. The number of bleeding and spotting days declined over time, and there were more spotting days than bleeding days in all reference periods. Although a large cohort of women was monitored over 3 years of treatment, there are limitations to the data: the number of bleeding and spotting days was not adjusted for women who prematurely discontinued; women compared their bleeding intensity with their own previous menstrual experience; and importantly, the number of bleeding and spotting days at baseline (before placement) was not captured.
The ease and pain of placement of these smaller levonorgestrel intrauterine contraceptive systems was verified by investigators and women, respectively. In the mixed cohort of nulliparous and parous women, 39% of whom were nulliparous and 12% of whom had previously had cesarean deliveries only, investigators rated placement of these smaller systems as “easy” in 90% of women. In addition, 65% of women reported their pain as either “none” or “mild.” In a previous study evaluating the ease of placement of the currently available device in 509 women (99.8% of whom were parous), 92% of investigators rated the procedure as “easy.”13 The previously reported Phase II study of these new devices, which was also conducted in a mixed cohort of nulliparous and parous women, showed that they were considered by investigators and women to be statistically significantly easier and significantly less painful to place, respectively, compared with currently used device.12
The reporting of ovarian cysts included those cysts detected because women had complaints as well as those that were detected on routine ultrasonographic studies at each study visit and, therefore, the results may overstate the clinical importance of this adverse event.
The absolute rates of ectopic pregnancy were low in both treatment groups: 0.10 per 100 woman-years (13.5 mg system) and 0.22 per 100 woman-years (19.5 mg system). In comparison, studies on the background incidence of ectopic pregnancy, based on data from two large managed care databases in the United States, have estimated ectopic pregnancy rates in the range of 1.8–2.5% of all pregnancies or 0.14–0.42 per 100 woman-years in women aged 20–39 years in the general population (including contraceptive users and nonusers).14,15
Only 2,116 of 2,884 women in the full analysis set completed the user satisfaction questionnaire and opinions among the women who discontinued the study before the survey was introduced were not captured, which limits the generalizability of those results.
Both levonorgestrel intrauterine contraceptives systems demonstrated very good, consistent contraceptive efficacy over 3 years and in this regard they belong among the top tier methods. A smaller T-frame and smaller hormone reservoir that allows placement with a narrower placement tube may help expand use among nulliparous women and parous women who have never delivered vaginally. Additionally, a lower dose system may appeal to women seeking lower exposure to synthetic hormones and a reduced likelihood of developing amenorrhea.