- Email: [email protected]
A 12-month multicenter, randomized study comparing the levonorgestrel intrauterine system with the etonogestrel subdermal implant
ORIGINAL ARTICLE: CONTRACEPTION 1 2 3 4 5 6 7 8 9 10 11 12 a b c d 13 Q9 Dan Apter, M.D., Ph.D., Paula Briggs, M.B.Ch.B., Marjo Tuppurainen, M.D., Julia Grunert, 14 Q1 Eeva Lukkari-Lax, M.D., Ph.D.,e Sarah Rybowski, M.B.B.S.,f and Kristina Gemzell Danielsson, M.D., Ph.D.g 15 a €a € ka €riasema Cantti Oy, Kuopio, and e Bayer Oy, Espoo, Finland; b May Logan VL-Medi Clinical Research Center, Helsinki, c La 16 Centre, Bootle, United Kingdom; d Bayer Pharma AG, Wuppertal, Germany; f Bayer HealthCare Pharmaceuticals, Whippany, 17 New Jersey; and g Division of Obstetrics and Gynecology, Department of Women's and Children's Health, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden 18 19 20 21 22 Objective: To compare the levonorgestrel intrauterine system (LNG-IUS 8), which has an average levonorgestrel release rate of 23 8 mg/24 hours during the first year (total levonorgestrel content 13.5 mg; Jaydess/Skyla), with the etonogestrel (ENG) subdermal implant (total content, 68 mg) with regard to the 12-month discontinuation rate (primary outcome). 24 Design: Randomized, open-label, phase III study. 25 Setting: Thirty-eight centers in six European countries. 26 Patient(s): Study population of 766 healthy nulliparous and parous women aged 18–35 years. 27 Intervention(s): The LNG-IUS 8 or the ENG implant. 28 Main Outcome Measure(s): Discontinuation rate, by treatment group, at Month 12. 29 Result(s): The 12-month discontinuation rates were 19.6% and 26.8% in the LNG-IUS 8 and ENG implant groups, respectively. The 30 Q4 7.2% difference was statistically significant (95% confidence interval 13.2%, 1.2%). Fewer women in the LNG-IUS 8 group than in the ENG implant group discontinued because of increased bleeding (3.2% vs. 11.3%) or adverse events (14.3% vs. 21.8%). At 31 12 months, more women in the LNG-IUS 8 group than in the ENG implant group were ‘‘very/somewhat satisfied’’ with their 32 bleeding pattern (60.9% vs. 33.6%) and reported a preference to use their study treatment after study completion (70.1% vs. 58.5%). 33 Conclusion(s): The LNG-IUS 8 was associated with a significantly lower 12-month discontinuation rate compared with the ENG 34 implant; mainly because ENG implant users frequently discontinued due to increased bleeding. More LNG-IUS 8 users than ENG 35 users reported being ‘‘very/somewhat satisfied’’ with their bleeding pattern, and reported a 36 preference to continue using their study treatment after the study. Use your smartphone Clinical Trial Registration Number: NCT01397097. (Fertil SterilÒ 2016;-:-–-. Ó2016 by 37 to scan this QR code American Society for Reproductive Medicine.) 38 and connect to the Key Words: LNG-IUS, etonogestrel implant, contraception, discontinuation, LARC 39 discussion forum for this article now.* 40 Discuss: You can discuss this article with its authors and with other ASRM members at http:// 41 fertstertforum.com/apterd-lng-ius-8-eng-implant/ * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace. 42 43 44 45 he high global incidence of unin46 Received January 5, 2016; revised February 23, 2016; accepted February 24, 2016. tended pregnancy (1) could be 47 D.A. has taken part in advisory boards and is a speaker for Bayer HealthCare and Merck. P.B. serves on advisory boards and has been an invited speaker for Bayer, MSD, Pfizer, HRA Pharma, and addressed through more wide48Q2 Q3 Gideon Richter. M.T. serves on advisory boards for MSD, Amgen, and Roche, and has been an spread use of highly effective long49 invited speaker for Bayer and MSD. J.G. is an employee of Bayer Pharma AG. E.L.-L. is an employee of Bayer Oy. S.R. is an employee of Bayer HealthCare. KGD serves on advisory boards acting reversible contraception (LARC) 50 and has been an invited speaker at scientific meetings for Bayer AG, MSD/Merck, HRA Pharma, methods (2), which are suitable for a 51 ExcelGyn, and Gideon Richter. K.G.D. has nothing to disclose. wide range of women regardless of Funded by Bayer Pharma AG. VL-Medi Clinical Research Center, Helsinki, has received grants from 52 Bayer HealthCare Pharmaceuticals for conduct of phase II and III trials on LNG-IUS 8 and LNGage or parity (3). Through provision of 53 IUS 13 (D.A.). Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden, has counseling on LARC methods, as well received grants for conducting phase II, phase III, and the current clinical trials of LNG-US 8 54 and LNG-IUS 13 (K.G.D.). as appropriate access to these methods, 55 Reprint requests: Dan Apter, M.D., Ph.D., VL-Medi Clinical Research Center, Helsinki, Finland 00100 unintended pregnancy rates (PRs) could 56 (E-mail: dan.apter@vlmedi.fi). be reduced (4, 5). 57 Fertility and Sterility® Vol. -, No. -, - 2016 0015-0282/$36.00 A smaller, lower dose LARC 58 Copyright ©2016 American Society for Reproductive Medicine, Published by Elsevier Inc. method is available: the levonorgestrel http://dx.doi.org/10.1016/j.fertnstert.2016.02.036 59
A 12-month multicenter, randomized study comparing the levonorgestrel intrauterine system (LNG-IUS 8) with the etonogestrel subdermal implant
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intrauterine system (LNG-IUS). Its total content is 13.5 mg (average, 8 mg/24 hours during the first year; LNG-IUS 8; Jaydess/Skyla, Bayer Pharma AG) (6). This device is placed with a narrower insertion tube than LNG-IUS total content of 52 mg (average, 20 mg/24 hours during the first year; LNG-IUS 20; Mirena, Bayer Pharma AG) (3.80 mm (7) vs. 4.40 mm (8), respectively) and may appeal to a wider range of women. In a pivotal phase III study, LNG-IUS 8 was highly effective in both nulliparous and parous women, in younger (%25 years) and older (26–35 years) women, and was associated with a favorable safety profile (7). The etonogestrel (ENG) subdermal implant (total content, 68 mg; Nexplanon, Merck Sharp & Dohme) (9), which is bioequivalent to the previous ENG subdermal implant (total content, 68 mg; Implanon, Merck Sharp & Dohme) (10), is preloaded into a novel applicator to facilitate insertion (10). The ENG implant is a highly effective contraceptive method with a favorable 3-year safety profile in women aged 18–40 years (9). This phase III trial was conducted to compare the use of LNG-IUS 8 with the ENG implant in nulliparous and parous Q5 women.
MATERIALS AND METHODS Study Design This multicenter, randomized, open-label study (ClinicalTrials.gov: NCT01397097) was conducted between September 2011 and June 2013 at 38 centers in Australia, Finland, France, Norway, Sweden, and the United Kingdom. The protocol and its amendment were reviewed and approved by each study site's Independent Ethics Committee or Institutional Review Board. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all subjects before study entry.
Inclusion and Exclusion Criteria Healthy nulliparous and parous women aged 18–35 years (inclusive) requesting contraception were recruited. Women were required to have a normal or clinically insignificant cervical smear (i.e., not requiring further follow-up) within 6 months before screening and to have regular menstrual cycles (21–35 days). Women were excluded if they had had a vaginal delivery, cesarean section, or abortion within 6 weeks before screening. For further exclusion criteria, see Supplemental Material (available online).
Treatment Groups and Randomization Treatment allocation was performed with a computergenerated randomization list provided by the sponsor's randomization management. Each randomization number was assigned to either the LNG-IUS 8 or the ENG implant and randomization numbers were distributed in sets in a 1:1 format to each group. Randomization envelopes were prepared for each study site, consisting of complete randomization sets. Eligible women were assigned to envelopes in ascending order to ensure the randomization as planned.
After 12 months, women had the option to continue using their study treatment for an additional 2 years (total, 3 years). However, only women using LNG-IUS 8 were followed beyond 12 months. The data reported here are from the 12month randomized study only.
Study Treatment The LNG-IUS 8 and the ENG implant were evaluated. Up to two placement attempts were permitted per woman; if both attempts failed, the woman was withdrawn from the study. Use of local anesthesia or oral analgesics was permitted at the investigators' discretion. Women were allowed to use barrier methods for protection against sexually transmitted infections and were required to record this form of back-up contraception.
Study Visits and Evaluations Scheduled study visits took place at screening, randomization (for LNG-IUS 8 placement or ENG implant insertion), and months 1, 6, and 12 (end of study [EOS]). Pregnancy tests were performed at screening, randomization, and Month 12/EOS. For premature discontinuations, all examinations were to be performed within 4 weeks of the premature discontinuation date. During this visit, reasons for premature discontinuation were assessed by the investigator using a case report form. Investigators cited the reason ‘‘lost to follow-up’’ only in cases when there was no possibility of contacting the woman anymore. Overall satisfaction with study treatment was assessed at Months 6 and 12/EOS by the subject and entered into a case report form by the investigator. User satisfaction with study treatment was assessed by subjects using a five-point Likert item questionnaire, with the options of ‘‘very satisfied,’’ ‘‘satisfied,’’ ‘‘neither satisfied nor dissatisfied,’’ ‘‘dissatisfied,’’ and ‘‘very dissatisfied.’’ The questionnaire was completed by subjects at Months 6 and 12/EOS in a quiet, private environment. Overall satisfaction rate was defined as the percentage of women in each treatment group reporting they were ‘‘very satisfied’’ or ‘‘satisfied’’ with treatment. Women recorded daily bleeding in diaries as ‘‘none,’’ ‘‘spotting’’ (need for panty liners only), ‘‘light’’ (need for sanitary protection but less than normal menstruation), ‘‘normal’’ (relative to the woman's own experience), or ‘‘heavy’’ (more than normal menstruation in the woman's own experience). Adverse events, including those of special interest (pelvic inflammatory disease, uterine perforation, ectopic pregnancy [EP], expulsion, and ovarian cysts [>3 cm in diameter on ultrasound or abnormal, nonfunctional cysts]), were also recorded. Vaginal ultrasound examinations were not routinely scheduled but may have been performed by the investigator if thought to be necessary to evaluate symptoms of ovarian cyst or other pelvic pathology.
Study Outcomes The primary outcome was discontinuation rate, by treatment group, at Month 12. Secondary outcomes included discontinuations by reason at Month 12, Pearl index (PI), overall user satisfaction, user satisfaction and bleeding questionnaire VOL. - NO. - / - 2016
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results, bleeding profile, and safety profile in the LNG-IUS 8 and ENG implant groups.
Statistical Analyses and Determination of Sample Size Based on data from previous studies, 12-month discontinuation rates of approximately 14% for LNG-IUS 8 (7, 11) and 19.8% for the ENG implant (12) were assumed. A sample size of 760 women was determined to provide 90% power to demonstrate noninferiority for LNG-IUS 8 compared with the ENG implant in discontinuation rates (primary objective; with a 3% noninferiority margin) at a one-sided a-level of 2.5%. The overall 12-month discontinuation rate in each treatment group was determined using Kaplan-Meier analysis. The 12-month discontinuation rates were compared for noninferiority and superiority of LNG-IUS 8 versus the ENG implant. These tests were performed by comparing the upper limit of the 95% confidence interval (CI) for the difference in proportions (i.e., the 12-month discontinuation rate of LNGIUS 8 minus the 12-month discontinuation rate of the ENG implant) with 3% (the noninferiority margin) and 0 (the superiority margin). For noninferiority, the upper limit of the 95% CI for the difference in proportions had to be >3%. For superiority, the upper limit of the 95% CI for the difference in proportions had to be >0. Superiority testing was only performed if noninferiority could be established. Twelve-month discontinuation rates, by reason for discontinuation, were also assessed. Women in each treatment group selected a reason for discontinuation from a predetermined list. The PR was expressed as the PI (number of pregnancies per 100 woman-years); 95% CI calculations assumed that the number of pregnancies followed a Poisson distribution. The cumulative failure rate was calculated for each treatment group using Kaplan-Meier analysis. Times during which women used concomitant contraception were subtracted from exposure times used for the calculations. Overall user satisfaction with study treatment was analyzed by the last observation carried forward method, which accounted for women who prematurely discontinued. Satisfaction ratings reported at premature discontinuation were assigned to the closest missing visit (for Months 6 and 12) and subsequently carried forward. Bleeding patterns during 12 months were evaluated using 90-day and 28-day reference intervals (RIs). The modified intention-to-treat set comprised all women for whom at least one placement attempt with LNG-IUS 8 or insertion attempt with the ENG implant was made. The full analysis set comprised all women for whom an LNG-IUS 8 or ENG implant was successfully placed or inserted.
RESULTS Study Subjects Of 952 subjects screened for inclusion, 766 were randomized; 385 to LNG-IUS 8 and 381 to the ENG implant (Supplemental Fig. 1, available online). The LNG-IUS 8 placement was attempted in 382 of 385 women (modified intention-to-treat) and was successful at the first attempt in 375 women
(98.2%). Four women had a second placement attempt, which was successful in three women (378/385 women [98.2%] in total) (full analysis set). The ENG implant insertion was successful in all 381 women. Therefore, all were included in the full analysis set and modified intention-to-treat. Local anesthesia was administered to 14.9% of LNG-IUS 8 users and 99.5% of ENG implant users. However, data were missing for 160 LNG-IUS 8 users and two ENG implant users. Baseline characteristics are summarized in Table 1.
Study Discontinuations The 12-month discontinuation rates in the LNG-IUS 8 and ENG implant groups were 19.6% and 26.8%, respectively, and noninferiority was demonstrated. The upper 95% CI of -1.2% for the difference in proportions was <3% (the noninferiority margin; P¼ .0004) (Table 2). In additional superiority analyses, the 12-month discontinuation rate was significantly lower with LNG-IUS 8 than with the ENG implant. The upper 95% CI for the difference in proportions was <0 (P¼ .0092) (Table 2). The most common reason for discontinuation at Month 12 was bleeding pattern alteration, mainly attributable to ‘‘increased bleeding’’ (11.3% in the ENG implant group, 3.2% in the LNG-IUS 8 group; Table 2).
Contraceptive Efficacy Three pregnancies (one intrauterine [IUP], one EP, and one biochemical [transient serum b-hCG increase]) were reported—all within the LNG-IUS 8 group. In all three cases the LNG-IUS 8 was still in situ, and estimated conception dates were 88, 310, and 349 days after LNG-IUS 8 placement.
TABLE 1 Baseline characteristics (modified intention-to-treat seta). Variable
LNG-IUS 8 (n [ 382)
Mean age, y (range) 24.8 (18–35) 23.6 (15.3–46.0) Mean BMI, kg/m2 (range) Nulliparous, n (%) 291 (76.2) Mean duration of menses (d) 5.0 Mean cycle length (d) 28.5 Mean uterine depth (cm) 7.2 Contraceptive method used at screening, n (%) Oral hormonal 169 (44.2) contraception Barrier methods 131 (34.3) Vaginal hormonal 27 (7.1) contraception LNG-IUS 11 (2.9) Implants 6 (1.6) Transdermal hormonal 5 (1.3) contraception IUD 5 (1.3) Other 0 None 28 (7.3)
ENG implant (n [ 381) 25.0 (18–35) 24.3 (16.4–44.0) 275 (72.2) 5.0 28.7 Not relevant 175 (45.9) 127 (33.3) 23 (6.0) 10 (2.6) 11 (2.9) 7 (1.8) 4 (1.0) 1 (0.3) 23 (6.0)
Note: BMI ¼ body mass index; ENG ¼ etonogestrel; IUD ¼ intrauterine device; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year). a Modified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
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ORIGINAL ARTICLE: CONTRACEPTION 355 TABLE 2 356 357 Discontinuations at 12 months and by selected reasons of interest 358 (full analysis seta). 359 LNG-IUS 8 ENG implant 360 Reason for discontinuation (n [ 378) (n [ 381) 361 Premature discontinuation 74 (19.6) 102 (26.8) 362 (any reason), n (%) 363 Difference in the proportions 7.2%b (95% CI 13.2%, 1.2%) Non-AE-related reason, n (%) 20 (5.3) 19 (5.0) 364 Wish for pregnancy 3 (0.8) 4 (1.0) 365 AE-related reason, n (%) 54 (14.3) 83 (21.8) 366 LNG-IUS 8 expulsion 3 (0.8) Not relevant ENG implant site infection Not relevant 0 367 or expulsion 368 Bleeding pattern alterations 16 (4.2) 44 (11.5) 369 12 (3.2) 43 (11.3) Increased bleedingc 370 1 (0.3) 0 Decreased bleedingc 3 (0.8) 1 (0.3) Unspecified or irregular 371 c bleeding 372 Note: AE ¼ adverse event; CI ¼ confidence interval; ENG ¼ etonogestrel; LNG-IUS 8 ¼ levo373 norgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year); MedDRA ¼ Medical Dictionary for Regulatory Activities. 374 a Full analysis set: all women who had a successful placement/insertion. b 375 P¼ .0004 for noninferiority; P¼ .0092 for superiority. c MedDRA preferred term. 376 Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016. 377 378 379 The IUP resulted in elective abortion, and the EP was medi380 cally managed. The PIs for LNG-IUS 8 and the ENG implant 381 were 0.9 (95% CI 0.2–2.6) and 0.0 (95% CI 0.0–1.2), respec382 tively. The relevant exposure duration was 333.6 woman383 years in the LNG-IUS 8 group and 312.7 woman-years in 384 the ENG implant group. Kaplan-Meier estimates for the 12385 month cumulative failure rates when using LNG-IUS 8 and 386 the ENG implant were 1.0% and 0, respectively. 387 388 389 Overall User Satisfaction 390 Q6 At all time points (Months 6, 12, and 12/EOS), overall treat391 ment satisfaction was significantly higher with LNG-IUS 8 392 than with the ENG implant (95% CIs for the two treatments 393 do not overlap at any time point; Table 3). At Month 12, 394 395 396 TABLE 3 397 398 Overall satisfaction with study treatment (last observation carried 399 forward analysis; full analysis seta). 400 LNG-IUS 8 ENG implant 401 Satisfaction rate, % Satisfaction 402 n (95% CI)c n rate, % (95% CI)c Visitb 403 Month 6 365 82.7 (78.5, 86.5) 369 71.3 (66.4, 75.8) 404 Month 12 327 86.5 (82.4, 90.1) 319 75.9 (70.8, 80.5) 405 Month 12/EOS 369 80.2 (75.8, 84.2) 372 66.1 (61.1, 70.9) 406 Note: CI ¼ confidence interval; ENG ¼ etonogestrel; EOS ¼ end of study; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first 407 year). a 408 Full analysis set: all women who had a successful placement/insertion. b For women who discontinued prematurely, assessments of the premature discontinuation 409 visit were assigned to the closest missing visit for Months 6 and 12. For Month 12/EOS, assessments were carried forward from the previous visit. 410 c Satisfaction rate: combined percentages of women reporting that they were ‘‘satisfied’’ or 411 ‘‘very satisfied’’ in response to the following question ‘‘How satisfied are you with the birth control method used during the study?’’ 412 Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016. 413
among the 327 and 319 women in the LNG-IUS 8 and ENG implant groups, respectively, who completed the overall satisfaction questionnaire, 53.8% and 49.5% were ‘‘very satisfied,’’ 32.7% and 26.3% were ‘‘satisfied,’’ 6.7% and 10.3% were ‘‘neither satisfied nor dissatisfied,’’ 5.8% and 11.9% were ‘‘dissatisfied,’’ and 0.9% and 1.9% were ‘‘very dissatisfied,’’ respectively.
Further User Satisfaction and Bleeding Questionnaire Outcomes At 12 months, in response to the question ‘‘If given a choice, after completion of the study, you would: continue with the study treatment; use a different hormonal contraceptive; use a different contraceptive method; discontinue use of all types of contraceptives; no need for contraceptive at this time; don't know,’’ 70.1% of LNG-IUS 8 users and 58.5% of ENG implant users stated that they would continue their study treatment beyond study completion, and 2.2% of LNG-IUS 8 users and 3.3% of ENG implant users stated they had no need for contraception at that time. In response to the question ‘‘Since your last study visit, when you had menstrual bleeding, how satisfied were you with your menstrual bleeding pattern?,’’ at 12 months, 60.9% of LNG-IUS 8 users were ‘‘very satisfied’’ or ‘‘somewhat satisfied’’ with their bleeding pattern compared with 33.6% of ENG implant users. Among women who were amenorrheic, in response to the question ‘‘How satisfied were you with the absence of menstrual bleeding?,’’ 78.7% of LNG-IUS 8 users and 77.7% of ENG implant users reported being ‘‘very satisfied’’ with bleeding absence at Month 12.
Bleeding Profiles In both treatment groups, the mean and median number of bleeding days decreased over time during use (Supplemental Fig. 2, available online). The mean number of combined bleeding and spotting days was higher in the LNG-IUS 8 group than in the ENG implant group in the first 90-day RI. However, during the second 90-day RI, the number of bleeding and spotting days in the LNG-IUS 8 group reduced to a similar number to that of the ENG implant group. For the fourth 90-day RI, the mean number of bleeding days (excluding spotting) was 8.8 days in the ENG implant group and 6.5 days in the LNG-IUS 8 group. Furthermore, the median length of bleeding and spotting episodes by 28-day RI decreased more substantially with LNG-IUS 8 than with the ENG implant over time during use (17 days and 6 days [RI 1]; 5 days and 2 days [RI 12], for LNG-IUS 8 and the ENG implant, respectively). For the fourth 90-day RI, the incidence of amenorrhea was 28.5% in the ENG implant group compared with 9.3% in the LNG-IUS 8 group, and the incidence of prolonged bleeding was 15.9% in the ENG implant group and 4.8% in the LNGIUS 8 group (Table 4). In addition, the incidence of ‘‘normal bleeding’’ (bleeding that does not meet the World Health Organization criteria for amenorrhea, prolonged bleeding, frequent bleeding, infrequent bleeding, or irregular bleeding) in the LNG-IUS 8 group increased from 10.8% in RI 1 to >30% in VOL. - NO. - / - 2016
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TABLE 4 Bleeding patterns according to World Health Organization criteria for menstrual bleeding patterns and 90-day RIs (modified intention-to-treat seta). LNG-IUS 8
b
Amenorrhea (%) Infrequent bleeding (%)c Frequent bleeding (%)d Prolonged bleeding (%)e Irregular bleeding (%)f Normal (none of the above) (%)g
ENG implant
First 90-d RI
Second 90-d RI
Fourth 90-d RI
First 90-d RI
Second 90-d RI
Fourth 90-d RI
0.00 20.5 19.9 38.6 48.6 10.8
3.9 16.6 13.3 15.1 29.9 35.3
9.3 24.8 9.7 4.8 24.5 31.4
3.8 37.3 8.7 36.1 34.1 15.3
20.1 33.2 9.1 23.8 31.0 6.0
28.5 28.9 10.0 15.9 27.8 4.8
Note: ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year); RI ¼ reference interval. a Modified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. b Amenorrhea was defined as no bleeding/spotting throughout the 90-day RI. c Infrequent bleeding was defined as one or two bleeding/spotting episodes per 90-day RI. d Frequent bleeding was defined as more than five bleeding/spotting episodes per 90-day RI. e Prolonged bleeding was defined as bleeding/spotting episodes lasting >14 days. Women with prolonged bleeding may also be included in one of the other categories (excluding amenorrhea). f Irregular bleeding was defined as three to five bleeding/spotting episodes and fewer than three bleeding/spotting-free intervals of R14 days. g Normal bleeding was defined as none of the above categories. Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
subsequent RIs, whereas in the ENG implant group, the incidence decreased from 15.3% in RI 1 to 4.8% in RI 4.
Safety Both LNG-IUS 8 and the ENG implant were associated with a favorable safety profile. The incidence of treatment-emergent adverse events (TEAEs) was 84.3% and 79.5% in the LNG-IUS 8 and the ENG implant groups, respectively. Among LNG-IUS 8 users, the most frequently reported TEAEs were dysmenorrhea (33.5%), uterine spasms (16.2%), procedural pain (13.6%), headache (11.3%), and acne (9.9%), whereas among ENG implant users, they were acne (15.5%), headache (12.3.%), dysmenorrhea (12.3%), nasopharyngitis (9.2%), and cervical dysplasia (8.9%). Serious TEAEs were reported by 2.4% of women in each treatment group (9 events in each treatment group); two of these events (one EP and one pregnancy of unknown location [biochemical pregnancy]) were considered by the investigator to be study drug-related in the LNG-IUS 8 group and one of these events (cerebral infarction) was considered by the investigator to be study drug-related in the ENG implant group. The discontinuation rate owing to TEAEs was 15.4% and 21.8% in the LNG-IUS 8 and ENG implant groups, respectively. Study drug-related TEAEs leading to discontinuation are shown in Supplemental Table 1, available online. Adverse events of special interest are summarized in Supplemental Table 2, available online. Ovarian cysts were reported in 10 women in the LNG-IUS 8 group and 3 women in the ENG implant group. These were considered study drug-related in eight women in the LNG-IUS 8 group and in all three women in the ENG implant group.
DISCUSSION During 12 months of use, significantly fewer women discontinued LNG-IUS 8 than discontinued with the ENG implant. The higher discontinuation rate with the ENG implant was mainly attributable to bleeding pattern alterations (11.5% of ENG implant users discontinued for this reason compared
with 4.2% of LNG-IUS 8 users). Almost all discontinuations were associated with increased bleeding. This is consistent with the properties of the ENG implant, which are known to alter bleeding in an unpredictable manner (13, 14). The lower discontinuation rate with LNG-IUS 8 reflects increased user satisfaction compared with ENG implant users at all study visits. Overall user satisfaction at Month 12/EOS was 80.2% in the LNG-IUS 8 group and 66.1% in the ENG implant group. User satisfaction with LNG-IUS 8 in this study was similarly high to that reported for LNG-IUS 20 in the US-based contraceptive CHOICE study. Of the LNG- Q7 IUS 20 users, 85.7% reported that they were ‘‘very satisfied’’ or ‘‘somewhat satisfied’’ with treatment after 12 months of use (15). Furthermore, a prospective analysis examining use of LNG-IUS 20 and the ENG implant in women aged 20–35 years demonstrated a significantly higher 12-month continuation rate with LNG-IUS 20 than with the ENG implant (93% vs. 86%, respectively) (16). User satisfaction, assessed as the number of women reporting that they ‘‘definitely agree’’ or ‘‘somewhat agree’’ with the statement ‘‘I am satisfied with my contraceptive method,’’ was also higher with LNG-IUS 20 than with the ENG implant after 12 months (80% using LNG-IUS 20 vs. 65% using the ENG implant) (16). Although discontinuation rates were higher in the present study than with LNG-IUS 20 and the ENG implant in the study by Short et al. (16), overall satisfaction for both types of contraception was similar in both studies. This may be due to the higher proportion of young and nulliparous women in the present study who may more readily discontinue their contraceptive method than older, parous women, despite a similar level of user satisfaction. In addition, a numerically higher proportion of LNG-IUS 8 users than ENG implant users stated a preference to continue treatment after study completion, and the percentage of women who were satisfied with their bleeding pattern at Month 12 was greater in the LNG-IUS 8 group than in the ENG implant group. These results suggest that LNG-IUS is an appealing contraceptive option.
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ORIGINAL ARTICLE: CONTRACEPTION 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649
During the 12-month study, the mean number of bleeding and spotting days per 90-day RI and the median length of bleeding and spotting episodes per 28-day RI decreased over time during use. The overall reduction was more substantial with LNG-IUS 8 than with the ENG implant in both cases. Bleeding patterns according to World Health Organization criteria (17) demonstrated that amenorrhea increased over time during use. However, in all RIs, more women experienced amenorrhea in the ENG implant group than in the LNG-IUS 8 group. The frequency of prolonged bleeding decreased over time with both study treatments, but more substantially with LNG-IUS 8. The increase in amenorrhea and decrease in prolonged bleeding over time were consistent with the expected bleeding profile for LNG-IUS 8 (6, 11). In addition, the proportion of women experiencing ‘‘normal bleeding’’ increased over time with LNG-IUS 8 use and decreased over time with the ENG implant. Three pregnancies occurred during the 12-month study, all within the LNG-IUS 8 group, resulting in a PI of 0.9 compared with 0.0 for the ENG implant. However, this study was not powered to determine the PI accurately for either treatment, and the short relevant exposure times mean no definite conclusions regarding comparative efficacy of the two contraceptive methods can be made. Both LNG-IUS 8 and the ENG implant were well tolerated, with no new or unexpected safety events observed. However, the number of study drug-related TEAEs that led to study discontinuation was higher in the ENG implant group (LNGIUS 8, 14.7% vs. ENG implant, 21.0%). Ovarian cysts were reported in 10 women in the LNG-IUS 8 group and 3 women in the ENG implant group. Because reporting of ovarian cysts included women with complaints as well as those in whom cysts were detected without complaints on routine ultrasound at each study visit, the results may overstate the clinical importance of this event. Transvaginal ultrasound follow-up of 1,432 women during a 3-year phase III trial indicated that ovarian cysts associated with LNG-IUS 8 use are uncommon (18). The high spontaneous resolution rate for ovarian cysts reflects their physiologic/functional nature. More women in the ENG implant group than in the LNG-IUS 8 group reported acne as a TEAE (15.5% vs. 9.9%). The difference may be explained by the higher systematic activity of the progestin with the ENG implant compared with the LNG-IUS 8. Although this was a large, randomized phase III study, some additional limitations to those outlined exist. The study was open-label and, because 75% of women were nulliparous, this precludes subgroup analysis according to parity. Women compared their bleeding intensity satisfaction with their own previous menstrual experience, meaning that results were subjective, and bleeding data at baseline were not captured. Therefore, it was difficult to fully interpret data in the first RI. Furthermore, women's perceptions of bleeding patterns in the first 90 days after placement may have been affected because approximately 45% of women in each treatment group switched from using oral contraception, and thus may have experienced lighter bleeding patterns before entering in the study. In addition, the number of bleeding and spotting days was not adjusted for women who prematurely discontinued.
In conclusion, during 12 months of use, discontinuation rates were significantly lower with LNG-IUS 8 compared with the ENG implant. The higher discontinuation rate with the ENG implant was mainly due to increased bleeding. Accordingly, almost twice as many women in the LNG-IUS 8 group than in the ENG implant group reported being ‘‘very/somewhat satisfied’’ with their bleeding pattern, which may have contributed to more women in the LNG-IUS 8 group than the ENG implant group reporting a preference to use their study treatment after the study. Both LNG-IUS 8 and the ENG implant were highly effective and neither method was associated with any new or unexpected safety events. This study demonstrates that LARC methods are a suitable contraceptive option for nulliparous and parous women, and it provides further evidence that could be used by healthcare providers in contraceptive counseling. Increased use of LARC in the general population could substantially reduce unintended PRs. Acknowledgments: The authors thank the participating investigators and coordinators at the 38 study centers and Liisa Lindstr€ om and Heidi Wikstr€ om for management of the study. In the development of the manuscript, medical writing support was provided by Laura Miller, Claire Jessop, and Helen Attisha of Chameleon Communications, with financial support from Bayer Pharma AG.
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Singh S, Sedgh G, Hussain R. Unintended pregnancy: worldwide levels, trends, and outcomes. Stud Fam Plann 2010;41:241–50. National Institute for Health and Care Excellence. Long-acting reversible contraception (LARC). Available at: https://www.nice.org.uk/guidance/ cg30; 2005. Accessed February 4, 2016. World Health Organization. Medical eligibility criteria for contraceptive use. 5th ed. Geneva: World Health Organization. Available at: http:// www.who.int/reproductivehealth/publications/family_planning/Ex-SummMEC-5/en/; 2015. Accessed February 4, 2016. Harper CC, Rocca CH, Thompson KM, Morfesis J, Goodman S, Darney PD, et al. Reductions in pregnancy rates in the USA with long-acting reversible contraception: a cluster randomised trial. Lancet 2015;386:562–8. Winner B, Peipert JF, Zhao Q, Buckel C, Madden T, Allsworth JE, et al. Effectiveness of long-acting reversible contraception. N Engl J Med 2012;366: 1998–2007. Bayer HealthCare Pharmaceuticals Inc. Jaydess Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/28672; 2015. Accessed February 4, 2016. Nelson AL, Apter D, Hauck B, Schmelter T, Rybowski S, Rosen K, et al. Two low-dose levonorgestrel intrauterine contraceptive systems: a randomized controlled trial. Obstet Gynecol 2013;122:1205–13. Bayer HealthCare Pharmaceuticals Inc. Mirena (levonorgestrel-releasing intrauterine system) Prescribing Information. Available at: http://www.berlex. com/html/products/pi/Mirena_PI.pdf; 2015. Accessed February 16, 2016. Bahamondes L, Brache V, Meirik O, Ali M, Habib N, Landoulsi SA. 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls. Hum Reprod 2015;30: 2527–38. Everett M, Wokoma T. Non-oral contraceptive options: their efficacy and suitability. Prescriber 2012;23:40–9. Gemzell-Danielsson K, Schellschmidt I, Apter D. A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil Steril 2012;97:616–22. VOL. - NO. - / - 2016
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Fertility and Sterility® 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767
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Croxatto HB, Urbancsek J, Massai R, Coelingh Bennink H, van Beek A, Implanon Study Group. A multicentre efficacy and safety study of the single contraceptive implant Implanon. Hum Reprod 1999;14:976–81. Merck Sharp & Dohme. Nexplanon (etonogestrel) Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/ 23824/SPC/Nexplanonþ68þmgþimplantþforþsubdermalþuse/; 2014. Accessed February 16, 2016. Mansour D, Korver T, Marintcheva-Petrova M, Fraser IS. The effects of Implanon on menstrual bleeding patterns. Eur J Contracept Reprod Health Care 2008;13(Suppl 1):13–28. Peipert JF, Zhao Q, Allsworth JE, Petrosky E, Madden T, Eisenberg D, et al. Continuation and satisfaction of reversible contraception. Obstet Gynecol 2011;117:1105–13.
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Short M, Dallay D, Omokanye S, Hanisch JU, Inki P. Acceptability of the levonorgestrel releasing-intrauterine system and etonogestrel implant: oneyear results of an observational study. Eur J Contracept Reprod Health Care 2012;17:79–88. Belsey EM, Machin D, d'Arcangues C. The analysis of vaginal bleeding patterns induced by fertility regulating methods. World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction. Contraception 1986; 34:253–60. Nahum GG, Kaunitz AM, Rosen K, Schmelter T, Lynen R. Ovarian cysts: presence and persistence with use of a 13.5 mg levonorgestrel-releasing intrauterine system. Contraception 2015;91: 412–7.
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ORIGINAL ARTICLE: CONTRACEPTION 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885
SUPPLEMENTAL MATERIAL Exclusion Criteria Further exclusion criteria were known or suspected pregnancy; current lactation; infected abortion or postpartum endometritis within 3 months before screening; distortion of the uterine cavity, which may, at the investigator's discretion, cause problems with placement, retention, or removal of levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year) (LNG-IUS 8); acute, or a history of recurrent, pelvic inflammatory disease; abnormal genital bleeding of unknown origin; any acute lower genital infection (until successfully treated); or use of any long-acting injectable hormonal contraceptive within 10 months before randomization.
Study Treatment For women not switching from another hormonal contraceptive, placement of LNG-IUS 8 or insertion of the etonogestrel (ENG) implant was performed during the first 5 days of the woman's menstrual cycle. For women switching from other hormonal contraceptives, the timing of placement of LNG-
IUS 8 and insertion of the ENG implant was according to the local Summary of Product Characteristics for the reference drug (the ENG implant) (13).
Study Visits and Evaluation Women answered two further questions at Month 6 and Month 12/EOS. The first of these questions was ‘‘If given a choice, after completion of the study, you would .’’. The response options were ‘‘continue with the study treatment,’’ ‘‘use a different hormonal contraceptive,’’ ‘‘use a different contraceptive method,’’ ‘‘discontinue use of all types of contraceptives,’’ ‘‘no need for contraceptive at this time,’’ or ‘‘don't know.’’ For the second question, ‘‘Since your last study visit, when you had menstrual bleeding, how satisfied were you with your menstrual bleeding pattern?,’’ the response options were ‘‘very satisfied,’’ ‘‘somewhat satisfied,’’ ‘‘neither satisfied nor dissatisfied,’’ ‘‘dissatisfied,’’ ‘‘very dissatisfied,’’ or ‘‘no menstrual bleeding during study treatment.’’ The subset of women with absence of menstrual bleeding answered a further question, ‘‘How satisfied were you with the absence of menstrual bleeding?,’’ using the response options ‘‘very satisfied,’’ ‘‘somewhat satisfied,’’ ‘‘neither satisfied nor dissatisfied,’’ and ‘‘dissatisfied.’’
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Fertility and Sterility® 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003
SUPPLEMENTAL FIGURE 1 Screened (n=952)
Not randomized (n=186) Screening failure (n=161) Withdrew consent (n=20) Lost to follow-up (n=5)
Randomized (n=766)
LNG-IUS 8 (n=385)
ENG implant (n=381)
Modified intention-to-treat seta (n=382)
Modified intention-to-treat seta (n=381)
Full analysis setb (n=378)
Full analysis setb (n=381)
Completed the 12-month study (n=304)
Completed the 12-month study (n=279)
Disposition of women in the study. aModified intention-to-treat set: all women for whom at least one placement attempt was made. bFull analysis set: all women who had a successful placement/insertion. ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year). Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
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1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062
ORIGINAL ARTICLE: CONTRACEPTION
SUPPLEMENTAL FIGURE 2 45 Bleeding days (excluding spotting)
40 Mean number of days
1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121
Spotting-only days
35 30 25 20 15 10 5 0
LNGIUS 8
ENG implant
1
LNGIUS 8
ENG implant
2
LNGIUS 8
ENG implant
3
LNGIUS 8
ENG implant
4
90-day reference interval Mean number of bleeding and spotting days by 90-day reference intervalsa (modified intention-to-treat setb) in the LNG-IUS 8 and ENG groups. a The numbers of bleeding and spotting days were not recorded at baseline. bModified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year). Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
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1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180
Fertility and Sterility® 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239
1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298
SUPPLEMENTAL TABLE 1 Incidence (>1% in either treatment group) of study drug-related TEAEs leading to discontinuation of study treatment (modified intent to treat seta). MedDRA preferred term Any study drug-related TEAE (%) Acne Dysmenorrhea Abdominal pain, lower Menometrorrhagia Menorrhagia Metrorrhagia Vaginal hemorrhage Weight increased Mood altered Libido decreased
LNG-IUS 8 (n [ 382)
ENG implant (n [ 381)
14.7 2.9 2.1 1.6 1.0 0.8 0.8 0.8 0.3 0.3 0.0
21.0 5.2 0.0 0.0 1.8 3.7 2.6 2.9 1.8 1.6 1.3
Note: ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year); MedDRA ¼ Medical Dictionary for Regulatory Activities; TEAE ¼ treatment-emergent adverse event. a Modified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
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ORIGINAL ARTICLE: CONTRACEPTION 1299 1300 1301 1302 1303 Q8 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357
1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416
SUPPLEMENTAL TABLE 2 Adverse events of special interest (modified intention-to-treat seta). XXX
LNG-IUS 8 (n [ 382)
ENG implant (n [ 381)
Ectopic pregnancy (n) Expulsion (n) Uterine perforation (n) Pelvic inflammatory disease (n) Deeply inserted implant (n) Implant site complications (n) Implant site pruritus Implant site pain Implant site bruising Implant site hematoma Implant site erosion Implant site irritation Ovarian cysts (n)
1 3b 0 1 Not relevant Not relevant – – – – – – 10
0 0 Not relevant 0 0 25 9 6 3 2 1 1 3
Note: ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year). a Modified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. b All partial expulsions. Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
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A 12-month multicenter, randomized study comparing the levonorgestrel intrauterine system (LNG-IUS 8) with the etonogestrel subdermal implant
T
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60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118
ORIGINAL ARTICLE: CONTRACEPTION 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177
intrauterine system (LNG-IUS). Its total content is 13.5 mg (average, 8 mg/24 hours during the first year; LNG-IUS 8; Jaydess/Skyla, Bayer Pharma AG) (6). This device is placed with a narrower insertion tube than LNG-IUS total content of 52 mg (average, 20 mg/24 hours during the first year; LNG-IUS 20; Mirena, Bayer Pharma AG) (3.80 mm (7) vs. 4.40 mm (8), respectively) and may appeal to a wider range of women. In a pivotal phase III study, LNG-IUS 8 was highly effective in both nulliparous and parous women, in younger (%25 years) and older (26–35 years) women, and was associated with a favorable safety profile (7). The etonogestrel (ENG) subdermal implant (total content, 68 mg; Nexplanon, Merck Sharp & Dohme) (9), which is bioequivalent to the previous ENG subdermal implant (total content, 68 mg; Implanon, Merck Sharp & Dohme) (10), is preloaded into a novel applicator to facilitate insertion (10). The ENG implant is a highly effective contraceptive method with a favorable 3-year safety profile in women aged 18–40 years (9). This phase III trial was conducted to compare the use of LNG-IUS 8 with the ENG implant in nulliparous and parous Q5 women.
MATERIALS AND METHODS Study Design This multicenter, randomized, open-label study (ClinicalTrials.gov: NCT01397097) was conducted between September 2011 and June 2013 at 38 centers in Australia, Finland, France, Norway, Sweden, and the United Kingdom. The protocol and its amendment were reviewed and approved by each study site's Independent Ethics Committee or Institutional Review Board. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all subjects before study entry.
Inclusion and Exclusion Criteria Healthy nulliparous and parous women aged 18–35 years (inclusive) requesting contraception were recruited. Women were required to have a normal or clinically insignificant cervical smear (i.e., not requiring further follow-up) within 6 months before screening and to have regular menstrual cycles (21–35 days). Women were excluded if they had had a vaginal delivery, cesarean section, or abortion within 6 weeks before screening. For further exclusion criteria, see Supplemental Material (available online).
Treatment Groups and Randomization Treatment allocation was performed with a computergenerated randomization list provided by the sponsor's randomization management. Each randomization number was assigned to either the LNG-IUS 8 or the ENG implant and randomization numbers were distributed in sets in a 1:1 format to each group. Randomization envelopes were prepared for each study site, consisting of complete randomization sets. Eligible women were assigned to envelopes in ascending order to ensure the randomization as planned.
After 12 months, women had the option to continue using their study treatment for an additional 2 years (total, 3 years). However, only women using LNG-IUS 8 were followed beyond 12 months. The data reported here are from the 12month randomized study only.
Study Treatment The LNG-IUS 8 and the ENG implant were evaluated. Up to two placement attempts were permitted per woman; if both attempts failed, the woman was withdrawn from the study. Use of local anesthesia or oral analgesics was permitted at the investigators' discretion. Women were allowed to use barrier methods for protection against sexually transmitted infections and were required to record this form of back-up contraception.
Study Visits and Evaluations Scheduled study visits took place at screening, randomization (for LNG-IUS 8 placement or ENG implant insertion), and months 1, 6, and 12 (end of study [EOS]). Pregnancy tests were performed at screening, randomization, and Month 12/EOS. For premature discontinuations, all examinations were to be performed within 4 weeks of the premature discontinuation date. During this visit, reasons for premature discontinuation were assessed by the investigator using a case report form. Investigators cited the reason ‘‘lost to follow-up’’ only in cases when there was no possibility of contacting the woman anymore. Overall satisfaction with study treatment was assessed at Months 6 and 12/EOS by the subject and entered into a case report form by the investigator. User satisfaction with study treatment was assessed by subjects using a five-point Likert item questionnaire, with the options of ‘‘very satisfied,’’ ‘‘satisfied,’’ ‘‘neither satisfied nor dissatisfied,’’ ‘‘dissatisfied,’’ and ‘‘very dissatisfied.’’ The questionnaire was completed by subjects at Months 6 and 12/EOS in a quiet, private environment. Overall satisfaction rate was defined as the percentage of women in each treatment group reporting they were ‘‘very satisfied’’ or ‘‘satisfied’’ with treatment. Women recorded daily bleeding in diaries as ‘‘none,’’ ‘‘spotting’’ (need for panty liners only), ‘‘light’’ (need for sanitary protection but less than normal menstruation), ‘‘normal’’ (relative to the woman's own experience), or ‘‘heavy’’ (more than normal menstruation in the woman's own experience). Adverse events, including those of special interest (pelvic inflammatory disease, uterine perforation, ectopic pregnancy [EP], expulsion, and ovarian cysts [>3 cm in diameter on ultrasound or abnormal, nonfunctional cysts]), were also recorded. Vaginal ultrasound examinations were not routinely scheduled but may have been performed by the investigator if thought to be necessary to evaluate symptoms of ovarian cyst or other pelvic pathology.
Study Outcomes The primary outcome was discontinuation rate, by treatment group, at Month 12. Secondary outcomes included discontinuations by reason at Month 12, Pearl index (PI), overall user satisfaction, user satisfaction and bleeding questionnaire VOL. - NO. - / - 2016
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Fertility and Sterility® 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295
results, bleeding profile, and safety profile in the LNG-IUS 8 and ENG implant groups.
Statistical Analyses and Determination of Sample Size Based on data from previous studies, 12-month discontinuation rates of approximately 14% for LNG-IUS 8 (7, 11) and 19.8% for the ENG implant (12) were assumed. A sample size of 760 women was determined to provide 90% power to demonstrate noninferiority for LNG-IUS 8 compared with the ENG implant in discontinuation rates (primary objective; with a 3% noninferiority margin) at a one-sided a-level of 2.5%. The overall 12-month discontinuation rate in each treatment group was determined using Kaplan-Meier analysis. The 12-month discontinuation rates were compared for noninferiority and superiority of LNG-IUS 8 versus the ENG implant. These tests were performed by comparing the upper limit of the 95% confidence interval (CI) for the difference in proportions (i.e., the 12-month discontinuation rate of LNGIUS 8 minus the 12-month discontinuation rate of the ENG implant) with 3% (the noninferiority margin) and 0 (the superiority margin). For noninferiority, the upper limit of the 95% CI for the difference in proportions had to be >3%. For superiority, the upper limit of the 95% CI for the difference in proportions had to be >0. Superiority testing was only performed if noninferiority could be established. Twelve-month discontinuation rates, by reason for discontinuation, were also assessed. Women in each treatment group selected a reason for discontinuation from a predetermined list. The PR was expressed as the PI (number of pregnancies per 100 woman-years); 95% CI calculations assumed that the number of pregnancies followed a Poisson distribution. The cumulative failure rate was calculated for each treatment group using Kaplan-Meier analysis. Times during which women used concomitant contraception were subtracted from exposure times used for the calculations. Overall user satisfaction with study treatment was analyzed by the last observation carried forward method, which accounted for women who prematurely discontinued. Satisfaction ratings reported at premature discontinuation were assigned to the closest missing visit (for Months 6 and 12) and subsequently carried forward. Bleeding patterns during 12 months were evaluated using 90-day and 28-day reference intervals (RIs). The modified intention-to-treat set comprised all women for whom at least one placement attempt with LNG-IUS 8 or insertion attempt with the ENG implant was made. The full analysis set comprised all women for whom an LNG-IUS 8 or ENG implant was successfully placed or inserted.
RESULTS Study Subjects Of 952 subjects screened for inclusion, 766 were randomized; 385 to LNG-IUS 8 and 381 to the ENG implant (Supplemental Fig. 1, available online). The LNG-IUS 8 placement was attempted in 382 of 385 women (modified intention-to-treat) and was successful at the first attempt in 375 women
(98.2%). Four women had a second placement attempt, which was successful in three women (378/385 women [98.2%] in total) (full analysis set). The ENG implant insertion was successful in all 381 women. Therefore, all were included in the full analysis set and modified intention-to-treat. Local anesthesia was administered to 14.9% of LNG-IUS 8 users and 99.5% of ENG implant users. However, data were missing for 160 LNG-IUS 8 users and two ENG implant users. Baseline characteristics are summarized in Table 1.
Study Discontinuations The 12-month discontinuation rates in the LNG-IUS 8 and ENG implant groups were 19.6% and 26.8%, respectively, and noninferiority was demonstrated. The upper 95% CI of -1.2% for the difference in proportions was <3% (the noninferiority margin; P¼ .0004) (Table 2). In additional superiority analyses, the 12-month discontinuation rate was significantly lower with LNG-IUS 8 than with the ENG implant. The upper 95% CI for the difference in proportions was <0 (P¼ .0092) (Table 2). The most common reason for discontinuation at Month 12 was bleeding pattern alteration, mainly attributable to ‘‘increased bleeding’’ (11.3% in the ENG implant group, 3.2% in the LNG-IUS 8 group; Table 2).
Contraceptive Efficacy Three pregnancies (one intrauterine [IUP], one EP, and one biochemical [transient serum b-hCG increase]) were reported—all within the LNG-IUS 8 group. In all three cases the LNG-IUS 8 was still in situ, and estimated conception dates were 88, 310, and 349 days after LNG-IUS 8 placement.
TABLE 1 Baseline characteristics (modified intention-to-treat seta). Variable
LNG-IUS 8 (n [ 382)
Mean age, y (range) 24.8 (18–35) 23.6 (15.3–46.0) Mean BMI, kg/m2 (range) Nulliparous, n (%) 291 (76.2) Mean duration of menses (d) 5.0 Mean cycle length (d) 28.5 Mean uterine depth (cm) 7.2 Contraceptive method used at screening, n (%) Oral hormonal 169 (44.2) contraception Barrier methods 131 (34.3) Vaginal hormonal 27 (7.1) contraception LNG-IUS 11 (2.9) Implants 6 (1.6) Transdermal hormonal 5 (1.3) contraception IUD 5 (1.3) Other 0 None 28 (7.3)
ENG implant (n [ 381) 25.0 (18–35) 24.3 (16.4–44.0) 275 (72.2) 5.0 28.7 Not relevant 175 (45.9) 127 (33.3) 23 (6.0) 10 (2.6) 11 (2.9) 7 (1.8) 4 (1.0) 1 (0.3) 23 (6.0)
Note: BMI ¼ body mass index; ENG ¼ etonogestrel; IUD ¼ intrauterine device; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year). a Modified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
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ORIGINAL ARTICLE: CONTRACEPTION 355 TABLE 2 356 357 Discontinuations at 12 months and by selected reasons of interest 358 (full analysis seta). 359 LNG-IUS 8 ENG implant 360 Reason for discontinuation (n [ 378) (n [ 381) 361 Premature discontinuation 74 (19.6) 102 (26.8) 362 (any reason), n (%) 363 Difference in the proportions 7.2%b (95% CI 13.2%, 1.2%) Non-AE-related reason, n (%) 20 (5.3) 19 (5.0) 364 Wish for pregnancy 3 (0.8) 4 (1.0) 365 AE-related reason, n (%) 54 (14.3) 83 (21.8) 366 LNG-IUS 8 expulsion 3 (0.8) Not relevant ENG implant site infection Not relevant 0 367 or expulsion 368 Bleeding pattern alterations 16 (4.2) 44 (11.5) 369 12 (3.2) 43 (11.3) Increased bleedingc 370 1 (0.3) 0 Decreased bleedingc 3 (0.8) 1 (0.3) Unspecified or irregular 371 c bleeding 372 Note: AE ¼ adverse event; CI ¼ confidence interval; ENG ¼ etonogestrel; LNG-IUS 8 ¼ levo373 norgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year); MedDRA ¼ Medical Dictionary for Regulatory Activities. 374 a Full analysis set: all women who had a successful placement/insertion. b 375 P¼ .0004 for noninferiority; P¼ .0092 for superiority. c MedDRA preferred term. 376 Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016. 377 378 379 The IUP resulted in elective abortion, and the EP was medi380 cally managed. The PIs for LNG-IUS 8 and the ENG implant 381 were 0.9 (95% CI 0.2–2.6) and 0.0 (95% CI 0.0–1.2), respec382 tively. The relevant exposure duration was 333.6 woman383 years in the LNG-IUS 8 group and 312.7 woman-years in 384 the ENG implant group. Kaplan-Meier estimates for the 12385 month cumulative failure rates when using LNG-IUS 8 and 386 the ENG implant were 1.0% and 0, respectively. 387 388 389 Overall User Satisfaction 390 Q6 At all time points (Months 6, 12, and 12/EOS), overall treat391 ment satisfaction was significantly higher with LNG-IUS 8 392 than with the ENG implant (95% CIs for the two treatments 393 do not overlap at any time point; Table 3). At Month 12, 394 395 396 TABLE 3 397 398 Overall satisfaction with study treatment (last observation carried 399 forward analysis; full analysis seta). 400 LNG-IUS 8 ENG implant 401 Satisfaction rate, % Satisfaction 402 n (95% CI)c n rate, % (95% CI)c Visitb 403 Month 6 365 82.7 (78.5, 86.5) 369 71.3 (66.4, 75.8) 404 Month 12 327 86.5 (82.4, 90.1) 319 75.9 (70.8, 80.5) 405 Month 12/EOS 369 80.2 (75.8, 84.2) 372 66.1 (61.1, 70.9) 406 Note: CI ¼ confidence interval; ENG ¼ etonogestrel; EOS ¼ end of study; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first 407 year). a 408 Full analysis set: all women who had a successful placement/insertion. b For women who discontinued prematurely, assessments of the premature discontinuation 409 visit were assigned to the closest missing visit for Months 6 and 12. For Month 12/EOS, assessments were carried forward from the previous visit. 410 c Satisfaction rate: combined percentages of women reporting that they were ‘‘satisfied’’ or 411 ‘‘very satisfied’’ in response to the following question ‘‘How satisfied are you with the birth control method used during the study?’’ 412 Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016. 413
among the 327 and 319 women in the LNG-IUS 8 and ENG implant groups, respectively, who completed the overall satisfaction questionnaire, 53.8% and 49.5% were ‘‘very satisfied,’’ 32.7% and 26.3% were ‘‘satisfied,’’ 6.7% and 10.3% were ‘‘neither satisfied nor dissatisfied,’’ 5.8% and 11.9% were ‘‘dissatisfied,’’ and 0.9% and 1.9% were ‘‘very dissatisfied,’’ respectively.
Further User Satisfaction and Bleeding Questionnaire Outcomes At 12 months, in response to the question ‘‘If given a choice, after completion of the study, you would: continue with the study treatment; use a different hormonal contraceptive; use a different contraceptive method; discontinue use of all types of contraceptives; no need for contraceptive at this time; don't know,’’ 70.1% of LNG-IUS 8 users and 58.5% of ENG implant users stated that they would continue their study treatment beyond study completion, and 2.2% of LNG-IUS 8 users and 3.3% of ENG implant users stated they had no need for contraception at that time. In response to the question ‘‘Since your last study visit, when you had menstrual bleeding, how satisfied were you with your menstrual bleeding pattern?,’’ at 12 months, 60.9% of LNG-IUS 8 users were ‘‘very satisfied’’ or ‘‘somewhat satisfied’’ with their bleeding pattern compared with 33.6% of ENG implant users. Among women who were amenorrheic, in response to the question ‘‘How satisfied were you with the absence of menstrual bleeding?,’’ 78.7% of LNG-IUS 8 users and 77.7% of ENG implant users reported being ‘‘very satisfied’’ with bleeding absence at Month 12.
Bleeding Profiles In both treatment groups, the mean and median number of bleeding days decreased over time during use (Supplemental Fig. 2, available online). The mean number of combined bleeding and spotting days was higher in the LNG-IUS 8 group than in the ENG implant group in the first 90-day RI. However, during the second 90-day RI, the number of bleeding and spotting days in the LNG-IUS 8 group reduced to a similar number to that of the ENG implant group. For the fourth 90-day RI, the mean number of bleeding days (excluding spotting) was 8.8 days in the ENG implant group and 6.5 days in the LNG-IUS 8 group. Furthermore, the median length of bleeding and spotting episodes by 28-day RI decreased more substantially with LNG-IUS 8 than with the ENG implant over time during use (17 days and 6 days [RI 1]; 5 days and 2 days [RI 12], for LNG-IUS 8 and the ENG implant, respectively). For the fourth 90-day RI, the incidence of amenorrhea was 28.5% in the ENG implant group compared with 9.3% in the LNG-IUS 8 group, and the incidence of prolonged bleeding was 15.9% in the ENG implant group and 4.8% in the LNGIUS 8 group (Table 4). In addition, the incidence of ‘‘normal bleeding’’ (bleeding that does not meet the World Health Organization criteria for amenorrhea, prolonged bleeding, frequent bleeding, infrequent bleeding, or irregular bleeding) in the LNG-IUS 8 group increased from 10.8% in RI 1 to >30% in VOL. - NO. - / - 2016
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Fertility and Sterility® 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531
TABLE 4 Bleeding patterns according to World Health Organization criteria for menstrual bleeding patterns and 90-day RIs (modified intention-to-treat seta). LNG-IUS 8
b
Amenorrhea (%) Infrequent bleeding (%)c Frequent bleeding (%)d Prolonged bleeding (%)e Irregular bleeding (%)f Normal (none of the above) (%)g
ENG implant
First 90-d RI
Second 90-d RI
Fourth 90-d RI
First 90-d RI
Second 90-d RI
Fourth 90-d RI
0.00 20.5 19.9 38.6 48.6 10.8
3.9 16.6 13.3 15.1 29.9 35.3
9.3 24.8 9.7 4.8 24.5 31.4
3.8 37.3 8.7 36.1 34.1 15.3
20.1 33.2 9.1 23.8 31.0 6.0
28.5 28.9 10.0 15.9 27.8 4.8
Note: ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year); RI ¼ reference interval. a Modified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. b Amenorrhea was defined as no bleeding/spotting throughout the 90-day RI. c Infrequent bleeding was defined as one or two bleeding/spotting episodes per 90-day RI. d Frequent bleeding was defined as more than five bleeding/spotting episodes per 90-day RI. e Prolonged bleeding was defined as bleeding/spotting episodes lasting >14 days. Women with prolonged bleeding may also be included in one of the other categories (excluding amenorrhea). f Irregular bleeding was defined as three to five bleeding/spotting episodes and fewer than three bleeding/spotting-free intervals of R14 days. g Normal bleeding was defined as none of the above categories. Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
subsequent RIs, whereas in the ENG implant group, the incidence decreased from 15.3% in RI 1 to 4.8% in RI 4.
Safety Both LNG-IUS 8 and the ENG implant were associated with a favorable safety profile. The incidence of treatment-emergent adverse events (TEAEs) was 84.3% and 79.5% in the LNG-IUS 8 and the ENG implant groups, respectively. Among LNG-IUS 8 users, the most frequently reported TEAEs were dysmenorrhea (33.5%), uterine spasms (16.2%), procedural pain (13.6%), headache (11.3%), and acne (9.9%), whereas among ENG implant users, they were acne (15.5%), headache (12.3.%), dysmenorrhea (12.3%), nasopharyngitis (9.2%), and cervical dysplasia (8.9%). Serious TEAEs were reported by 2.4% of women in each treatment group (9 events in each treatment group); two of these events (one EP and one pregnancy of unknown location [biochemical pregnancy]) were considered by the investigator to be study drug-related in the LNG-IUS 8 group and one of these events (cerebral infarction) was considered by the investigator to be study drug-related in the ENG implant group. The discontinuation rate owing to TEAEs was 15.4% and 21.8% in the LNG-IUS 8 and ENG implant groups, respectively. Study drug-related TEAEs leading to discontinuation are shown in Supplemental Table 1, available online. Adverse events of special interest are summarized in Supplemental Table 2, available online. Ovarian cysts were reported in 10 women in the LNG-IUS 8 group and 3 women in the ENG implant group. These were considered study drug-related in eight women in the LNG-IUS 8 group and in all three women in the ENG implant group.
DISCUSSION During 12 months of use, significantly fewer women discontinued LNG-IUS 8 than discontinued with the ENG implant. The higher discontinuation rate with the ENG implant was mainly attributable to bleeding pattern alterations (11.5% of ENG implant users discontinued for this reason compared
with 4.2% of LNG-IUS 8 users). Almost all discontinuations were associated with increased bleeding. This is consistent with the properties of the ENG implant, which are known to alter bleeding in an unpredictable manner (13, 14). The lower discontinuation rate with LNG-IUS 8 reflects increased user satisfaction compared with ENG implant users at all study visits. Overall user satisfaction at Month 12/EOS was 80.2% in the LNG-IUS 8 group and 66.1% in the ENG implant group. User satisfaction with LNG-IUS 8 in this study was similarly high to that reported for LNG-IUS 20 in the US-based contraceptive CHOICE study. Of the LNG- Q7 IUS 20 users, 85.7% reported that they were ‘‘very satisfied’’ or ‘‘somewhat satisfied’’ with treatment after 12 months of use (15). Furthermore, a prospective analysis examining use of LNG-IUS 20 and the ENG implant in women aged 20–35 years demonstrated a significantly higher 12-month continuation rate with LNG-IUS 20 than with the ENG implant (93% vs. 86%, respectively) (16). User satisfaction, assessed as the number of women reporting that they ‘‘definitely agree’’ or ‘‘somewhat agree’’ with the statement ‘‘I am satisfied with my contraceptive method,’’ was also higher with LNG-IUS 20 than with the ENG implant after 12 months (80% using LNG-IUS 20 vs. 65% using the ENG implant) (16). Although discontinuation rates were higher in the present study than with LNG-IUS 20 and the ENG implant in the study by Short et al. (16), overall satisfaction for both types of contraception was similar in both studies. This may be due to the higher proportion of young and nulliparous women in the present study who may more readily discontinue their contraceptive method than older, parous women, despite a similar level of user satisfaction. In addition, a numerically higher proportion of LNG-IUS 8 users than ENG implant users stated a preference to continue treatment after study completion, and the percentage of women who were satisfied with their bleeding pattern at Month 12 was greater in the LNG-IUS 8 group than in the ENG implant group. These results suggest that LNG-IUS is an appealing contraceptive option.
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ORIGINAL ARTICLE: CONTRACEPTION 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649
During the 12-month study, the mean number of bleeding and spotting days per 90-day RI and the median length of bleeding and spotting episodes per 28-day RI decreased over time during use. The overall reduction was more substantial with LNG-IUS 8 than with the ENG implant in both cases. Bleeding patterns according to World Health Organization criteria (17) demonstrated that amenorrhea increased over time during use. However, in all RIs, more women experienced amenorrhea in the ENG implant group than in the LNG-IUS 8 group. The frequency of prolonged bleeding decreased over time with both study treatments, but more substantially with LNG-IUS 8. The increase in amenorrhea and decrease in prolonged bleeding over time were consistent with the expected bleeding profile for LNG-IUS 8 (6, 11). In addition, the proportion of women experiencing ‘‘normal bleeding’’ increased over time with LNG-IUS 8 use and decreased over time with the ENG implant. Three pregnancies occurred during the 12-month study, all within the LNG-IUS 8 group, resulting in a PI of 0.9 compared with 0.0 for the ENG implant. However, this study was not powered to determine the PI accurately for either treatment, and the short relevant exposure times mean no definite conclusions regarding comparative efficacy of the two contraceptive methods can be made. Both LNG-IUS 8 and the ENG implant were well tolerated, with no new or unexpected safety events observed. However, the number of study drug-related TEAEs that led to study discontinuation was higher in the ENG implant group (LNGIUS 8, 14.7% vs. ENG implant, 21.0%). Ovarian cysts were reported in 10 women in the LNG-IUS 8 group and 3 women in the ENG implant group. Because reporting of ovarian cysts included women with complaints as well as those in whom cysts were detected without complaints on routine ultrasound at each study visit, the results may overstate the clinical importance of this event. Transvaginal ultrasound follow-up of 1,432 women during a 3-year phase III trial indicated that ovarian cysts associated with LNG-IUS 8 use are uncommon (18). The high spontaneous resolution rate for ovarian cysts reflects their physiologic/functional nature. More women in the ENG implant group than in the LNG-IUS 8 group reported acne as a TEAE (15.5% vs. 9.9%). The difference may be explained by the higher systematic activity of the progestin with the ENG implant compared with the LNG-IUS 8. Although this was a large, randomized phase III study, some additional limitations to those outlined exist. The study was open-label and, because 75% of women were nulliparous, this precludes subgroup analysis according to parity. Women compared their bleeding intensity satisfaction with their own previous menstrual experience, meaning that results were subjective, and bleeding data at baseline were not captured. Therefore, it was difficult to fully interpret data in the first RI. Furthermore, women's perceptions of bleeding patterns in the first 90 days after placement may have been affected because approximately 45% of women in each treatment group switched from using oral contraception, and thus may have experienced lighter bleeding patterns before entering in the study. In addition, the number of bleeding and spotting days was not adjusted for women who prematurely discontinued.
In conclusion, during 12 months of use, discontinuation rates were significantly lower with LNG-IUS 8 compared with the ENG implant. The higher discontinuation rate with the ENG implant was mainly due to increased bleeding. Accordingly, almost twice as many women in the LNG-IUS 8 group than in the ENG implant group reported being ‘‘very/somewhat satisfied’’ with their bleeding pattern, which may have contributed to more women in the LNG-IUS 8 group than the ENG implant group reporting a preference to use their study treatment after the study. Both LNG-IUS 8 and the ENG implant were highly effective and neither method was associated with any new or unexpected safety events. This study demonstrates that LARC methods are a suitable contraceptive option for nulliparous and parous women, and it provides further evidence that could be used by healthcare providers in contraceptive counseling. Increased use of LARC in the general population could substantially reduce unintended PRs. Acknowledgments: The authors thank the participating investigators and coordinators at the 38 study centers and Liisa Lindstr€ om and Heidi Wikstr€ om for management of the study. In the development of the manuscript, medical writing support was provided by Laura Miller, Claire Jessop, and Helen Attisha of Chameleon Communications, with financial support from Bayer Pharma AG.
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Fertility and Sterility® 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767
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Croxatto HB, Urbancsek J, Massai R, Coelingh Bennink H, van Beek A, Implanon Study Group. A multicentre efficacy and safety study of the single contraceptive implant Implanon. Hum Reprod 1999;14:976–81. Merck Sharp & Dohme. Nexplanon (etonogestrel) Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/ 23824/SPC/Nexplanonþ68þmgþimplantþforþsubdermalþuse/; 2014. Accessed February 16, 2016. Mansour D, Korver T, Marintcheva-Petrova M, Fraser IS. The effects of Implanon on menstrual bleeding patterns. Eur J Contracept Reprod Health Care 2008;13(Suppl 1):13–28. Peipert JF, Zhao Q, Allsworth JE, Petrosky E, Madden T, Eisenberg D, et al. Continuation and satisfaction of reversible contraception. Obstet Gynecol 2011;117:1105–13.
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Short M, Dallay D, Omokanye S, Hanisch JU, Inki P. Acceptability of the levonorgestrel releasing-intrauterine system and etonogestrel implant: oneyear results of an observational study. Eur J Contracept Reprod Health Care 2012;17:79–88. Belsey EM, Machin D, d'Arcangues C. The analysis of vaginal bleeding patterns induced by fertility regulating methods. World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction. Contraception 1986; 34:253–60. Nahum GG, Kaunitz AM, Rosen K, Schmelter T, Lynen R. Ovarian cysts: presence and persistence with use of a 13.5 mg levonorgestrel-releasing intrauterine system. Contraception 2015;91: 412–7.
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ORIGINAL ARTICLE: CONTRACEPTION 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885
SUPPLEMENTAL MATERIAL Exclusion Criteria Further exclusion criteria were known or suspected pregnancy; current lactation; infected abortion or postpartum endometritis within 3 months before screening; distortion of the uterine cavity, which may, at the investigator's discretion, cause problems with placement, retention, or removal of levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year) (LNG-IUS 8); acute, or a history of recurrent, pelvic inflammatory disease; abnormal genital bleeding of unknown origin; any acute lower genital infection (until successfully treated); or use of any long-acting injectable hormonal contraceptive within 10 months before randomization.
Study Treatment For women not switching from another hormonal contraceptive, placement of LNG-IUS 8 or insertion of the etonogestrel (ENG) implant was performed during the first 5 days of the woman's menstrual cycle. For women switching from other hormonal contraceptives, the timing of placement of LNG-
IUS 8 and insertion of the ENG implant was according to the local Summary of Product Characteristics for the reference drug (the ENG implant) (13).
Study Visits and Evaluation Women answered two further questions at Month 6 and Month 12/EOS. The first of these questions was ‘‘If given a choice, after completion of the study, you would .’’. The response options were ‘‘continue with the study treatment,’’ ‘‘use a different hormonal contraceptive,’’ ‘‘use a different contraceptive method,’’ ‘‘discontinue use of all types of contraceptives,’’ ‘‘no need for contraceptive at this time,’’ or ‘‘don't know.’’ For the second question, ‘‘Since your last study visit, when you had menstrual bleeding, how satisfied were you with your menstrual bleeding pattern?,’’ the response options were ‘‘very satisfied,’’ ‘‘somewhat satisfied,’’ ‘‘neither satisfied nor dissatisfied,’’ ‘‘dissatisfied,’’ ‘‘very dissatisfied,’’ or ‘‘no menstrual bleeding during study treatment.’’ The subset of women with absence of menstrual bleeding answered a further question, ‘‘How satisfied were you with the absence of menstrual bleeding?,’’ using the response options ‘‘very satisfied,’’ ‘‘somewhat satisfied,’’ ‘‘neither satisfied nor dissatisfied,’’ and ‘‘dissatisfied.’’
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886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944
Fertility and Sterility® 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003
SUPPLEMENTAL FIGURE 1 Screened (n=952)
Not randomized (n=186) Screening failure (n=161) Withdrew consent (n=20) Lost to follow-up (n=5)
Randomized (n=766)
LNG-IUS 8 (n=385)
ENG implant (n=381)
Modified intention-to-treat seta (n=382)
Modified intention-to-treat seta (n=381)
Full analysis setb (n=378)
Full analysis setb (n=381)
Completed the 12-month study (n=304)
Completed the 12-month study (n=279)
Disposition of women in the study. aModified intention-to-treat set: all women for whom at least one placement attempt was made. bFull analysis set: all women who had a successful placement/insertion. ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year). Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
VOL. - NO. - / - 2016
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FLA 5.4.0 DTD FNS30136_proof 23 March 2016 4:23 pm ce DPH
1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062
ORIGINAL ARTICLE: CONTRACEPTION
SUPPLEMENTAL FIGURE 2 45 Bleeding days (excluding spotting)
40 Mean number of days
1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121
Spotting-only days
35 30 25 20 15 10 5 0
LNGIUS 8
ENG implant
1
LNGIUS 8
ENG implant
2
LNGIUS 8
ENG implant
3
LNGIUS 8
ENG implant
4
90-day reference interval Mean number of bleeding and spotting days by 90-day reference intervalsa (modified intention-to-treat setb) in the LNG-IUS 8 and ENG groups. a The numbers of bleeding and spotting days were not recorded at baseline. bModified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year). Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
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FLA 5.4.0 DTD FNS30136_proof 23 March 2016 4:23 pm ce DPH
1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180
Fertility and Sterility® 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239
1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298
SUPPLEMENTAL TABLE 1 Incidence (>1% in either treatment group) of study drug-related TEAEs leading to discontinuation of study treatment (modified intent to treat seta). MedDRA preferred term Any study drug-related TEAE (%) Acne Dysmenorrhea Abdominal pain, lower Menometrorrhagia Menorrhagia Metrorrhagia Vaginal hemorrhage Weight increased Mood altered Libido decreased
LNG-IUS 8 (n [ 382)
ENG implant (n [ 381)
14.7 2.9 2.1 1.6 1.0 0.8 0.8 0.8 0.3 0.3 0.0
21.0 5.2 0.0 0.0 1.8 3.7 2.6 2.9 1.8 1.6 1.3
Note: ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year); MedDRA ¼ Medical Dictionary for Regulatory Activities; TEAE ¼ treatment-emergent adverse event. a Modified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
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FLA 5.4.0 DTD FNS30136_proof 23 March 2016 4:23 pm ce DPH
ORIGINAL ARTICLE: CONTRACEPTION 1299 1300 1301 1302 1303 Q8 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357
1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416
SUPPLEMENTAL TABLE 2 Adverse events of special interest (modified intention-to-treat seta). XXX
LNG-IUS 8 (n [ 382)
ENG implant (n [ 381)
Ectopic pregnancy (n) Expulsion (n) Uterine perforation (n) Pelvic inflammatory disease (n) Deeply inserted implant (n) Implant site complications (n) Implant site pruritus Implant site pain Implant site bruising Implant site hematoma Implant site erosion Implant site irritation Ovarian cysts (n)
1 3b 0 1 Not relevant Not relevant – – – – – – 10
0 0 Not relevant 0 0 25 9 6 3 2 1 1 3
Note: ENG ¼ etonogestrel; LNG-IUS 8 ¼ levonorgestrel intrauterine system total content 13.5 mg (average, 8 mg/24 hours during the first year). a Modified intention-to-treat set: all women for whom at least one placement/insertion attempt was made. b All partial expulsions. Apter. Comparing LNG-IUS 8 and the ENG implant. Fertil Steril 2016.
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FLA 5.4.0 DTD FNS30136_proof 23 March 2016 4:23 pm ce DPH