OBJECTIVE

目的

To determine the efficacy, pharmacodynamic (PD) effects and safety of a range of dosing regimens (60-120 mg daily) of oral leuprolide tablets (Ovarest®) over 3 months in women with pelvic pain from endometriosis and to identify regimens with PD effects at least comparable to historical data for marketed Lupron Depot® formulations and GnRH antagonists.

确定口服3个月以上不同剂量OVAREST（每日60 ~ 120mg)治疗子宫内膜异位引起的盆腔疼痛患者的效果、药代动力学作用以及安全性，并确定至少与已经上市的醋酸亮丙瑞林和GnRH拮抗剂历史数据相当的药效学效果的给药方案。

MATERIALS AND METHODS

材料和方法

We conducted a non-randomized, open-label, crossover dose-finding study in women with endometriosis and pelvic pain, administering 3 of 5 possible dose regimens of Ovarest, each for one of three treatment cycles: 120 mg QD, 80 mg QD, 60 mg QD, 60 mg BID, and 40 mg BID. All subjects started with the highest dose (120 mg QD) in the first 28-day cycle and were subsequently allocated for cycles 2 and 3 to other treatment arms based on whether they achieved the primary endpoint of estradiol (E2) suppression below 20 pg/mL by the end of the cycle. Determination of E2, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and leuprolide levels were performed weekly. All subjects completed the Composite Pelvic Signs and Symptoms Score (CPSSS) questionnaire at screening and at the end of each treatment cycle. An interactive video-enabled software platform (AiCure) was employed to document subject treatment compliance. Subjects also maintained diary cards to track menstrual bleeding.

我们在患有子宫内膜异位症和盆腔疼痛的妇女中进行了一项非随机、开放标签、交叉剂量探索研究，给予OVAREST5种可能剂量的方案中的3种，每一种为3个治疗周期：120 mg QD、80 mg QD、60 mg QD、60 mg BID 40 mg BID。所有受试者在第一个28天月经周期口服最大剂量(120mg QD)，随后根据月经周期结束时雌二醇抑制是否低于20 pg/mL分到不同的组进行第2和第3周期的治疗。每周检测雌二醇、孕酮、黄体生成素、卵泡刺激素和亮丙瑞林水平。所有受试者在筛选时和每个治疗周期结束时完成复合盆腔体征和症状评分(CPSSS)问卷。采用一个互动式视频软件平台(AiCure)记录受试者的治疗依从性。受试者还保存日记卡以追踪其月经出血。

RESULTS

结果

A total of 23 subjects were screened at 6 investigative sites. Of these, 11 subjects were enrolled and took one or more doses of Ovarest. Due to early study termination by the Sponsor, only four subjects completed all three cycles. Two subjects discontinued the study due to Adverse Events (dizziness, dyspepsia). In all, 7 participants completed a total of 17 treatment cycles. Both 120 mg (n = 7 cycles) and 80 mg (n = 4 cycles) QD regimens produced 100% suppression of E2 into the menopausal range; median E2 levels on day 29, the primary endpoint, were 9.9 and 12.5 pg/mL, respectively. The response rates in other arms could not be accurately assessed due to the small number of treatment cycles (n = 1 - 3 per group). Across all remaining regimens, median E2 levels were uniformly <20 pg/mL. Changes in the CPSSS from pre-treatment baseline to the last assessment were consistent with suppression of estradiol levels. Despite the small sample size, the changes were statistically significant for all composite metrics (Total CPSS Score, Total Pelvic Pain Score, and Total Physical Sign Score).

在6个研究中心共筛查了23名受试者，共纳入11例受试者，均服用1剂或1剂以上的OVAREST。由于资助方提前终止了研究，只有4名受试者完成了全部三个周期研究。2名受试者因头晕，消化不良等不良事件终止研究。7例受试者共完成17个治疗周期。120 mg QD (n =7个周期)和80 mg QD (n =4个周期)方案均能100%抑制雌二醇水平至绝经期范围；第29天的E2水平中位数值(主要终点)分别为9.9和12.5 pg/mL。由于其他组治疗周期数较少(每组n =1-3)，其缓解率不能准确评估。在所有剩余的方案中，E2水平中位数均小于20 pg/mL。CPSSS从治疗前基线到最后一次评估的变化与雌二醇抑制水平一致。尽管样本量小，但所有复合指标(总CPSS评分、总骨盆疼痛评分和总物理体征评分)的变化均具有统计学意义。

CONCLUSIONS

结论

At least two dosing regimens of Ovarest demonstrate profound suppression of gonadal steroids at least comparable to that achieved historically by approved GnRH agonists and antagonists, with improvement in pelvic pain symptoms. This is the first time that a GnRH agonist has been successfully administered via the oral route in patients with pelvic pain, eliminating the need for its potentially painful parenteral administration.

至少有两种Ovarest给药方案显示出对性腺醇激素的深度抑制，至少与既往已批准的GnRH激动剂和拮抗剂达到的效果相当，并改善了盆腔疼痛症状。这是GnRH激动剂首次通过口服途径成功用于盆腔疼痛患者， 消除了胃肠外给药的潜在痛苦。

IMPACT STATEMENT

影响说明

Multiple dosing regimens of Ovarest appear to be viable candidates for Phase 2b/3 clinical trials in therapeutic indications for which currently marketed GnRH agonists and antagonists are approved.

Ovarest的多剂量给药方案作为目前上市的GnRH激动剂和拮抗剂已获批准2b/3期临床试验的治疗适应证的替代是可行的。

参考文献：

ORAL LEUPROLIDE (Ovarest®) ACHIEVES PROFOUND SUPPRESSION OF ESTRADIOL AND PAIN RELIEF COMPARABLE TO THAT OF APPROVED INJECTABLE LEUPROLIDE FORMULATIONS IN WOMEN WITH ENDOMETRIOSIS AND PELVIC PAIN Shangold, Gary A. et al.Fertility and Sterility, Volume 120, Issue 4, e227 - e228