长效可逆避孕药,包括激素左炔诺孕酮宫内释放系统,是最有效的可逆避孕方法。然而,不利的出血,特别是在使用的最初几个月,是停止或避免的最重要原因之一。尽可能早地最小化这一点将是非常有益的。已知抑制前列腺素合成的非甾体抗炎药可减少月经时的出血和疼痛。已开发出一种释放左炔诺孕酮的宫内节育器,其中包含吲哚美辛,设计为在最初的安置期释放。
这项概念验证研究旨在确定在目前可用的左炔诺孕酮宫内释放系统中添加吲哚美辛(在使用的第一年中平均体内左炔诺孕酮释放速率为8μg/24小时)是否减少了出血和斑点的数量。与未修饰的系统相比,在使用的前90天。剂量发现分析包括3剂吲哚美辛低剂量(6.5mg),中(12.5毫克),和高(15.4mg)-确定吲哚美辛的理想剂量,以减少出血和斑点天数,副作用最小。
这是一个多中心,单盲,随机化,2018年6月至2019年6月在欧洲6个中心进行的II期对照试验.三个吲哚美辛剂量范围治疗组(低,middle-,和高剂量吲哚美辛/左炔诺孕酮宫内缓释系统)与未改良的左炔诺孕酮宫内缓释系统组进行比较,参与者以1:1:1:1的比例随机分组。主要结果是90天参考(治疗)期内子宫出血和斑点天数。次要结局是显示宫内应用左炔诺孕酮预期子宫内膜组织学的女性人数和治疗引起的不良事件的频率。计算点估计值和双侧90%可信间隔,以计算治疗组与无吲哚美辛的左炔诺孕酮释放宫内节育器系统之间的平均和中位数差异。使用贝叶斯分析确定点和区间估计值。
总共174人健康,绝经前妇女,18至45岁,是随机的,有160名女性符合符合方案分析集。在90天的参考期内,3个吲哚美辛/左炔诺孕酮宫内释放系统剂量组的出血和斑点天数少于无吲哚美辛的左炔诺孕酮宫内释放系统组。使用低剂量吲哚美辛/左炔诺孕酮宫内节育系统可以最大程度地减少出血和斑点天数,这表明点估计差异为-32%(90%可信区间,-45%至-19%)与无吲哚美辛的左炔诺孕酮宫内释放系统相比。高剂量和中剂量吲哚美辛/左炔诺孕酮宫内缓释系统组相对于不含吲哚美辛的左炔诺孕酮宫内缓释系统组的差异分别为-19%和-16%,分别。总的来说,97名女性(58.1%)经历了与研究药物相关的治疗紧急不良事件,所有治疗组的发病率相似,包括未改良的左炔诺孕酮宫内节育系统。这些都是轻度或中度的,6导致停药。子宫内膜活检结果与左炔诺孕酮宫内释放系统的预期效果一致。
在放置左炔诺孕酮宫内节育器后的前90天,所有3种剂量的吲哚美辛都大大减少了出血和斑点的天数,从而提供概念证明。在左炔诺孕酮宫内缓释系统中加入吲哚美辛可以减少放置后最初90天的出血和斑点天数,在不影响安全性的情况下,并有可能提高患者的可接受性和满意度。
Long-acting reversible contraceptives, including hormonal levonorgestrel-releasing intrauterine systems, are the most effective methods of reversible contraception. However, unfavorable bleeding, particularly during the first months of use, is one of the most important reasons for discontinuation or avoidance. Minimizing this as early as possible would be highly beneficial. Nonsteroidal anti-inflammatory drugs inhibiting prostaglandin synthesis are known to reduce bleeding and pain at time of menses. A levonorgestrel-releasing intrauterine system has been developed with an additional reservoir containing indomethacin, designed to be released during the initial postplacement period.
This proof-of-concept
study aimed to establish whether the addition of indomethacin to the currently available levonorgestrel-releasing intrauterine system (average in vivo levonorgestrel release rate of 8 μg/24 h during the first year of use) reduces the number of bleeding and spotting days during the first 90 days of use compared with the unmodified system. The dose-finding analysis included 3 doses of indomethacin-low (6.5 mg), middle (12.5 mg), and high (15.4 mg)-to determine the ideal dose of indomethacin to reduce bleeding and spotting days with minimal side-effects.
This was a multicenter, single-blinded, randomized, controlled phase II
trial conducted between June 2018 and June 2019 at 6 centers in Europe. Three indomethacin dose-ranging treatment groups (low-, middle-, and high-dose indomethacin/levonorgestrel-releasing intrauterine system) were compared with the unmodified levonorgestrel-releasing intrauterine system group, with participants randomized in a 1:1:1:1 ratio. The primary outcome was the number of uterine bleeding and spotting days over a 90-day reference (treatment) period. Secondary outcomes were the number of women showing endometrial histology expected for intrauterine levonorgestrel application and the frequency of treatment-emergent adverse events. Point estimates and 2-sided 90% credible intervals were calculated for mean and median differences between treatment groups and the levonorgestrel-releasing intrauterine system without indomethacin. Point and interval estimates were determined using a Bayesian analysis.
A total of 174 healthy, premenopausal women, aged 18 to 45 years, were randomized, with 160 women eligible for the per-protocol analysis set. Fewer bleeding and spotting days were observed in the 90-day reference period for the 3 indomethacin/levonorgestrel-releasing intrauterine system dose groups than for the levonorgestrel-releasing intrauterine system without indomethacin group. The largest reduction in bleeding and spotting days was achieved with low-dose indomethacin/levonorgestrel-releasing intrauterine system, which demonstrated a point estimate difference of -32% (90% credible interval, -45% to -19%) compared with levonorgestrel-releasing intrauterine system without indomethacin. Differences for high- and middle-dose indomethacin/levonorgestrel-releasing intrauterine system groups relative to levonorgestrel-releasing intrauterine system without indomethacin were -19% and -16%, respectively. Overall, 97 women (58.1%) experienced a treatment-emergent adverse event considered related to the
study drug, with similar incidence across all treatment groups including the unmodified levonorgestrel-releasing intrauterine system. These were all mild or moderate in intensity, with 6 leading to discontinuation. Endometrial biopsy findings were consistent with effects expected for the levonorgestrel-releasing intrauterine system.
All 3 doses of indomethacin substantially reduced the number of bleeding and spotting days in the first 90 days after placement of the levonorgestrel-releasing intrauterine system, thus providing proof of concept. Adding indomethacin to the levonorgestrel-releasing intrauterine system can reduce the number of bleeding and spotting days in the initial 90 days postplacement, without affecting the safety profile, and potentially improving patient acceptability and satisfaction.