Herman Weiss

Efficacy and safety of an ascending-dose, extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive

OBJECTIVE To evaluate the efficacy and safety of an ascending-dose, extended-regimen (ADER) combined oral contraceptive consisting of levonorgestrel (LNG) 150 mcg/ethinyl estradiol (EE) 20 mcg for 42 days, LNG 150 mcg/EE 25 mcg for 21 days, LNG 150 mcg/EE 30 mcg for 21 days and EE 10 mcg for 7 days. STUDY DESIGN This was a multicenter, open-label, phase 3, single-arm study. Sexually active women aged 18-40 years were enrolled and received ADER for up to 1 year (4 consecutive 91-day cycles). Participants kept diaries to record adherence, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index and the life-table method; safety and tolerability were assessed through reported adverse events (AEs). RESULTS A total of 3701 women were enrolled and 2144 completed the study. The Pearl Index was 3.19 [95% confidence interval (CI), 2.49-4.03], based on 70 pregnancies that occurred after ADER initiation and ≤ 7 days after the last LNG/EE or EE-only pill in women aged 18-35 years, excluding cycles in which another contraceptive method was used. Life-table pregnancy rate was 2.82% (95% CI, 2.23%-3.57%) for all users aged 18-35 years. Unscheduled bleeding/spotting decreased with increasing EE doses within each cycle and decreased after cycle 1. No unexpected AEs or changes in laboratory parameters were reported. CONCLUSION This study demonstrated that ADER effectively prevented pregnancy with a favorable safety and tolerability profile.

A phase 1, multicentre, open-label study to evaluate ovarian follicular activity and hormone levels with an extended-regimen combined oral contraceptive with low-dose ethinyl estradiol supplementation

Abstract Objectives To evaluate the effect on ovarian follicular activity of the 91-day extended-regimen combined oral contraceptive (COC), consisting of 84 days of levonorgestrel (LNG)/ethinylestradiol (EE) 150 μg/30 μg tablets plus seven days of EE 10 μg tablets in place of placebo. Methods This was a phase 1, open-label study. Ovarian follicular activity was classified via the Hoogland and Skouby method. Safety and tolerability as well as return to ovulation were assessed. Results Of the 35 subjects included in the efficacy analysis, luteinized, unruptured follicles, or ovulation were detected in 0 of 35 cycles during the first 28-day interval; 1 of 35 cycles (2.9%) in the second 28-day interval; and 2 of 35 cycles (5.7%) in the final 35-day interval. The ovarian activity rate over the entire 91-day treatment period was 2.9%. There was a low incidence of treatment-emergent adverse events. Ovulation returned in most subjects (77.1%, 27/35) within 32 days following the last dose of COC. Conclusions The 91-day extended-regimen COC with low-dose EE supplementation was found to be effective in suppressing ovarian activity and inhibiting ovulation and was well tolerated. Return to ovulation was rapid, occurring within approximately one month after discontinuation of COC. Chinese Abstract 摘要： 目的：评估91天扩展方案的复方口服避孕药对卵巢卵泡活性的影响，包括84天的左炔诺孕酮/炔雌醇（剂量分别为150ug/30ug）,剩余7天使用炔雌醇10ug代替安慰剂。 方法：这是一项1期的开放式研究。卵巢卵泡活性分类采用Hoogland 及Skouby方法。并评估药物的安全性、耐受性及恢复排卵的情况。 结果：有效性分析纳入35名研究对象，卵巢卵泡活性包括未破裂卵泡黄素化或排卵发生。在第一个28天内，其发生率为0/35，在第二个28天内，监测的未破裂的黄素化卵泡或排卵发生率为1/35（2.9%），在最后的35天内，监测的未破裂的黄素化卵泡或排卵发生率为2/35（5.7%）。 在91天的整个治疗期内，卵巢的活动率为2.9%。治疗中出现的不良事件发生率低。停止服用复方口服避孕药后32天内大部分人恢复排卵（77.1%，27/35）。 结论：补充小剂量炔雌醇的91天扩展方案的复方口服避孕药能有效抑制卵巢活力，抑制排卵，耐受性好。停用复方口服避孕药后排卵恢复快，几乎在一个月内恢复排卵。

Ovulatory effects of three oral contraceptive regimens: a randomized, open-label, descriptive trial.

OBJECTIVE This study describes ovarian activity suppression of a 21/7-active low-dose combined oral contraceptive (COC) regimen that included only ethinyl estradiol (EE) during the traditional hormone-free interval (HFI) and two commercially available 28-day regimens, a 24/4 and a 21/7 regimen. STUDY DESIGN The randomized, open-label, parallel-group descriptive study was conducted at two US sites. Healthy, reproductive-aged women (n=146) were randomized to one of three groups for three consecutive 28-day cycles, as follows: treatment 1 (n=39 completed): 21/7-active COC [21 days of 150 mcg desogestrel (DSG)/20 mcg EE, followed by 7 days of 10 mcg EE (DSG/EE+7 days EE)], treatment 2 (n=39 completed): 24 days of 3mg drospirenone (DRSP)/20 mcg EE, followed by 4 placebo (PBO)-pill days (DRSP/EE+4 days PBO) and treatment 3 (n=42 completed): 21 days of 100 mcg levonorgestrel (LNG)/20 mcg EE, followed by 7 PBO-pill days (LNG/EE+7 days PBO). The primary outcome was ovarian activity suppression assessed by transvaginal ultrasound and serum hormone concentrations and classified using the Hoogland and Skouby (H/S) method. RESULTS Ovarian activity rate (H/S grade 4 or 5) was low for all three treatments: 0% [95% confidence interval (CI) 0-2.8] for DSG/EE+7 days EE, 1% (95% CI 0.2-5.2) for DRSP/EE+4days PBO and 1% (95% CI 0-3.9) for LNG/EE+7 days PBO. All three treatments showed similar suppression of serum progesterone, 17β-estradiol, follicle-stimulating hormone and luteinizing hormone levels. CONCLUSIONS The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) showed ovarian activity suppression that was similar to the 24/4 (DRSP/EE+4 days PBO) and 21/7 (LNG/EE+7days PBO) regimens. IMPLICATIONS The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) that included only EE during the traditional HFI showed suppression of ovarian follicular activity that was similar to the 24/4 (DRSP/EE+4days PBO) and the 21/7 (LNG/EE+7 days PBO) comparator regimens.

Multinational, multicentre, randomised, open-label study evaluating the impact of a 91-day extended regimen combined oral contraceptive, compared with two 28-day traditional combined oral contraceptives, on haemostatic parameters in healthy women

Abstract Objectives To evaluate the impact of a 91-day extended regimen combined oral contraceptive (150 μg levonorgestrel [LNG]/30 μg ethinylestradiol [EE] for 84 days, followed by 10 μg EE for seven days [Treatment 1]) compared with two traditional 21/7 regimens (21 days 150 μg LNG/30 μg EE [Treatment 2] or 150 μg desogestrel [DSG]/30 μg EE [Treatment 3], both with seven days’ hormone free), on several coagulation factors and thrombin formation markers. Methods Randomised, open-label, parallel-group comparative study involving healthy women (18–40 years). The primary endpoint was change from baseline in prothrombin fragment 1 + 2 (F1 + 2) levels over six months. Results A total of 187 subjects were included in the primary analysis. In all groups, mean F1 + 2 values were elevated after six months of treatment. Changes were comparable between Treatments 1 and 2 (least squares mean change: 170 pmol/L and 158 pmol/L, respectively) but noticeably larger after Treatment 3 (least squares mean change: 592 pmol/L). The haemostatic effects of Treatment 1 were comparable to those of Treatment 2 and noninferior to those of Treatment 3 (lower limit of 95% confidence interval [− 18.3 pmol/L] > − 130 pmol/L). Conclusions The LNG/EE regimens had similar effects on F1 + 2. Noninferiority was demonstrated between extended regimen LNG/EE and DSG/EE. Chinese Abstract 摘 要 目的 评估口服避孕药91天长周期疗法（150μg左炔诺孕酮[levonorgestrel，LNG]/30μg炔雌醇[ethinylestradiol，EE]84天，10μg EE 7天[治疗1]）与两种21/7常规方案（21天150μg LNG/30μg EE [治疗2]或150μg去氧孕烯[desogestrel，DSG]/30μg EE [治疗3]，两种治疗均有7天的间歇期）对凝血因子和凝血酶形成标记物的影响。 方法 关于18-40岁健康女性的随机、开放、平行组对照研究。主要研究终点为治疗6个月后凝血酶原片段F1+2与基线水平的变化。 结果 初步分析了187名受试者，治疗6个月后整个人群的F1+2平均水平上升。治疗1与治疗2的变化类似：最小二乘均数变化分别为170 pmol/L和158 pmol/L，但治疗3的变化明显大：最小二乘均数变化为592 pmol/L。治疗1的止血效果与治疗2的相似，但不比治疗3差（95%置信区间下限[ -18.3 pmol/L] ＞ -130 pmol/L）。 结论 LNG/EE两种治疗方案对F1+2的影响相似，LNG/EE长周期方案与DSG/EE常规方案相比无差别。

Efficacy and safety of a 21/7-active combined oral contraceptive with continuous low-dose ethinyl estradiol

OBJECTIVE Substituting low-dose ethinyl estradiol (EE) for the hormone-free interval in combined oral contraceptives (COCs) may enhance ovarian suppression and improve tolerability. This noncomparative phase 3 study evaluated the efficacy and safety of a 21/7-active COC regimen including 21days of desogestrel (DSG)/EE followed by 7days of EE. STUDY DESIGN This multicenter, open-label, phase 3, single-arm study enrolled sexually active women aged 18-40years at risk for pregnancy. Women received up to 1year, or 13 consecutive 28-day cycles, of DSG 150mcg/EE 20mcg for 21days and EE 10mcg alone for 7days. Participants kept diaries to record compliance, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index (PI) and life-table approach. Safety and tolerability were assessed primarily through reported adverse events (AEs). RESULTS A total of 2858 women enrolled and 1680 completed the study. Forty-six pregnancies in 2401 women aged 18-35years occurred after COC initiation and up to 7days after last DSG/EE or EE-only tablet was taken. When cycles in which another contraceptive method was used were excluded, the PI was 2.68 [95% confidence interval (CI), 1.96-3.57]. The cumulative pregnancy rate after 1year of treatment was 2.47% (95% CI, 1.85-3.29) for all users aged 18-35years. When only cycles during which women considered compliant were included, the PI was 2.00 (95% CI, 1.39-2.80). AEs were similar to those seen with other oral contraceptives. CONCLUSIONS This 21/7-active DSG/EE COC with 7days of low-dose EE was efficacious and well tolerated for pregnancy prevention. IMPLICATIONS STATEMENT This phase 3 open-label study demonstrated that a 21/7-active COC regimen including 21days of DSG 150mcg/EE 20mcg and 7days of EE 10mcg was efficacious and well tolerated for pregnancy prevention.

Menstrual-Related Side Effects After Intrauterine Device Insertion or Tubal Ligation [245]

INTRODUCTION: This retrospective claims database analysis compares menstrual-related side effects associated with the insertion of an intrauterine device (IUD) or tubal ligation. METHODS: The Clinformatics DataMart database from January 1, 2006, to September 30, 2012, was used. Women between ages 15 and 45 years were required to have an IUD inserted (Paragard or Mirena) or a tubal ligation (identified as index date) and have continuous insurance coverage from 1 year prior (preperiod) through 1 year postindex date (postperiod). &khgr;2 statistics assessed associations between preperiod and postperiod menstrual-related side effects. RESULTS: The sample consisted of 107,516 women (11,864 Paragard; 56,661 Mirena; 38,991 tubal ligation). The majority were age 25–34 years (46.20%) or 35–45 years (45.22%), resided in the South (49.96%), and had point of service insurance (68.46%). There were significant differences in both preperiod and postperiod rates of dysmenorrhea, heavy menstrual bleeding, menorrhagia, anemia, and amenorrhea (all P<.001) among the three groups. Women who received a tubal ligation had the highest rates of preperiod and postperiod dysmenorrhea (3.93%; 4.77%), heavy menstrual bleeding (10.19%; 15.81%), menorrhagia (0.48%; 0.72%), and anemia (3.11%; 3.49%) and the highest preperiod rate of amenorrhea (21.60%). In contrast, women who used Paragard had the lowest reported rates of preperiod dysmenorrhea (1.47%), heavy menstrual bleeding (2.43%), menorrhagia (0.15%), anemia (2.31%), and postperiod menorrhagia (0.23%), whereas those who used Mirena had the lowest preperiod rates of amenorrhea (14.23%) and postperiod dysmenorrhea (2.27%), heavy menstrual bleeding (6.54%), anemia (1.82%), and amenorrhea (3.32%). CONCLUSION: Tubal ligation, compared with IUD insertion, is generally associated with higher rates of menstrual-related side effects.

Metabolic profiles in phase 2 study of two 21/7 oral contraceptive regimens (+/-7 hormone-free days).

INTRODUCTION: Metabolic changes observed in women taking combined oral contraceptives may vary, depending on the dose and regimen of the combined oral contraceptive components. METHODS: We compared metabolic profiles (secondary endpoints) in women enrolled in a multinational, randomized, parallel-group, open-label study comparing a 21-day combined oral contraceptive regimen containing 150 micrograms desogestrel and 20 micrograms ethinyl estradiol followed by 7 days of 10 micrograms of ethinyl estradiol (Lecette; Treatment 1) compared with a traditional combined oral contraceptive with 7 no treatment (hormone-free) days (Treatment 2). Healthy women aged 18–40 years with regular menstrual cycles and no contraindications to estrogens, progestins, or both received one of the two combined oral contraceptive regimens for six consecutive 28-day cycles. Serum total cortisol, cortisol-binding globulin, thyroid-stimulating hormone, and sex hormone–binding globulin were measured at baseline and weeks 11 and 23. RESULTS: Of 293 women randomized, 246 comprised the per-protocol population (Treatment 1: n=125; Treatment 2: n=121). Mean baseline metabolic parameters were similar for both groups. Increases in mean total cortisol, cortisol-binding globulin, and sex hormone–binding globulin, evident by week 11, were similar with both combined oral contraceptives through week 23. Overall, least square mean changes±standard errors for Treatments 1 and 2 were 239.0±15.7 and 230.8±16.0 nmol/L, respectively, for total cortisol (P=.71) and 40.8±1.6 and 37.2±1.6 mg/L for cortisol-binding globulin (P=.11); overall, sex hormone–binding globulin rose by 163.4±7.3 and 149.1±7.5 nmol/L (P=.17). Neither group had clinically relevant changes in thyroid-stimulating hormone. CONCLUSIONS: Observed total cortisol, cortisol-binding globulin, and sex hormone–binding globulin increases in women taking a 21/7 combined oral contraceptive regimen followed by either 7 days of 10 micrograms ethinyl estradiol or 7 hormone-free days were similar.