Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist.

BACKGROUND: Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies. METHODS: We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. RESULTS: A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings. CONCLUSIONS: Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).

Effects of low-dose norethindrone acetate plus ethinyl estradiol (0.5 mg/2.5 microg) in women with postmenopausal symptoms: updated analysis of three randomized, controlled trials.

BACKGROUND: Based on the potential risks of post-menopausal hormone therapy (HT) found by the Women's Health Initiative, guidelines for HT now recommend use of the lowest effective dose and shortest treatment duration consistent with individual treatment goals. Current (2003) guidance established by the US Food and Drug Administration (FDA) recommends that clinical assessments of HT include women with more frequent and more intense vasomotor symptoms than previously studied. Therefore, this analysis was conducted to further assess the efficacy of a low-dose combination of norethindrone acetate and ethinyl estradiol (NA/EE) previously assessed in dose-ranging studies, while meeting conservative FDA trial design and analysis criteria. OBJECTIVES: The aim of this post hoc analysis and overview was to present data on the efficacy and tolerability of a low-dose combination-NA/EE 0.5 mg/2.5 microg-in the treatment of postmenopausal symptoms, based on data from previously published studies of NA/EE. In addition, the effects of low-dose NA/EE on bone and endometrium are briefly reviewed. METHODS: Data from 3 previously published randomized, placebo-controlled trials were analyzed using current FDA guidance for the assessment of HT in postmenopausal women. Studies 1 and 2 assessed the efficacy of NA/EE at various doses, including 0.5 mg/2.5 microg, in vasomotor symptom (hot-flush [HF]) relief over 16 and 12 weeks, respectively, using self-reporting of symptom frequency and intensity (scores: 0=none; 1=mild; 2=moderate; and 3=severe) in daily diaries. Study 3 assessed the effects of NA/EE at various doses, including 0.5 mg/2.5 microg, on bone and endometrium, using quantitative computed tomography of the lumbar spine at 12 and 24 months and endometrial biopsy at 6, 12, 18, and 24 months of treatment. In all 3 studies, women were asked to record vaginal bleeding and spotting in diaries. Any adverse events were recorded in diaries and/or at clinic visits. Physical and gynecologic examinations and standard clinical laboratory testing were conducted at baseline and at appropriate follow-up visits in all 3 studies. RESULTS: Studies 1, 2, and 3 enrolled 219, 266, and 1265 women, respectively. Overall, in studies 1 and 2, 91% of women were white, the mean age was approximately 52 years, and mean time since last menstrual period was approximately 24 months. In study 1, NA/EE 0.5 mg/2.5 microg was associated with significant reductions from baseline in mean weekly total HF frequency from week 4 (63.6%) through week 16 (73.7%) (all, P<0.05). In study 2, the frequency of moderate or severe HFs was decreased by 61.1% at week 4 (P<0.05) and by 82.2% at week 12 (P<0.001) with NA/EE 0.5 mg/2.5 microg, and the mean intensity score was significantly lower than that with placebo at weeks 8 and 12 (both, P=0.001). In study 3, cumulative amenorrhea rates were approximately 90% in the NA/EE 0.5-mg/2.5-microg and placebo groups at 12 months. Lumbar spine bone mineral density (BMD) was maintained at 24 months with NA/EE 0.5 mg/2.5 microg but was significantly decreased from baseline, by 7.4%, in the placebo group (P<0.001). Endometrial hyperplasia was not observed in the group receiving NA/EE 0.5 mg/2.5 microg over 24 months. The tolerability of NA/EE was similar to that of placebo. The most common adverse events experienced with NA/EE were headache (15.2%), abdominal pain (10.2%), and breast pain (9.0%). CONCLUSIONS: The results from this post hoc analysis and overview of 3 previously published studies suggest that NA/EE 0.5 mg/2.5 microg was associated with decreased frequency and intensity of vasomotor symptoms. This dose of NA/EE was also associated with maintenance of BMD over 24 months, a significant positive effect on BMD compared with placebo. Low-dose NA/EE was also associated with cumulative amenorrhea rates comparable to those of placebo and was not associated with endometrial hyperplasia. This dose was well tolerated, with rates of adverse events generally similar to those of placebo.