Safety and acceptability of intravaginal rings releasing estradiol and progesterone

Abstract

Objective

This study aimed to evaluate the safety and acceptability of two fixed-dose 28-day vaginal ring formulations of 17β-estradiol (E2) and progesterone (P4) to treat vasomotor symptoms (VMS) and the genitourinary syndrome of menopause.

Design

DARE HRT1-001 was the first-in-woman study of 28-day exposure to two 28-day intravaginal rings (IVRs) designed to release 80 µg/day E2 + 4 mg/day P4 (IVR1) or 160 µg/day E2 + 8 mg/day P4 (IVR2) compared with oral E2 1 mg/day + oral P4 100 mg/day. To assess safety, participants completed a daily diary to record treatment emergent adverse events (TEAEs). To determine acceptability, at the end of treatment IVR users completed a questionnaire assessing tolerability and usability.

Results

Enrolled women (n = 34) were randomized to use IVR1 (n = 10), IVR2 (n = 12) or oral (n = 12). Thirty-one participants (IVR1 = 10, IVR2 = 10, oral = 11) completed the study. The TEAE profile of those in the IVR groups were similar to the referent oral regimen. TEAEs related to the study product were more common with IVR2 use. Endometrial biopsies were not performed unless endometrial thickness was >4 mm or for clinically significant postmenopausal bleeding. One IVR1 participant had an endometrial stripe increase from 4 mm at screening to 8 mm at the end of treatment. The biopsy indicated no evidence of plasma cells or endometritis and no evidence of atypia, hyperplasia or malignancy. Two other endometrial biopsies were performed for postmenopausal bleeding with similar findings. There were no clinically meaningful laboratory or vital sign abnormalities or trends identified in observed values or changes from baseline. Pelvic speculum examination identified no clinically significant abnormalities in any participant at any visit. Tolerability and usability data demonstrated that both IVRs were generally highly acceptable.

Conclusions

Both IVR1 and IVR2 were safe and well tolerated in healthy postmenopausal women. TEAE profiles were comparable to the referent oral regimen.

摘要

目的: 本研究旨在评价释放17 β-雌二醇(E2)和孕酮(P4)阴道环28天阴道给药治疗血管舒缩症状(VMS)和绝经期泌尿生殖系统综合征的安全性和可接受性。

设计: DARE HRT 1 -001是首次在女性中进行的研究, 该研究旨在释放80 mg/天E2 + 4 mg/天P4(IVR 1)或160 mg/天E2 + 8 mg/天P4(IVR 2), 与口服E2 1 mg/天+口服P4 100 mg/天相比。为了评估安全性, 参与者完成每日日记以记录治疗后出现的不良事件(TEAE)。为了确定可接受性, 在治疗结束时, IVR用户完成了评估耐受性和可用性的问卷调查。

结果: 入组的女性(n = 34)被随机分配使用IVR 1(n = 10)、IVR 2(n = 12)或口服(n = 12)。31名参与者(IVRl = 10、IVR 2 = 10、口服= 11)完成研究。IVR组的TEAE特征与参考口服方案相似。使用IVR 2时, 与研究药物相关的TEAE更常见。除非子宫内膜厚度> 4 mm或有临床意义的绝经后出血, 否则不进行子宫内膜活检。1例IVR 1受试者的子宫内膜厚度从筛选时的4 mm增加至治疗结束时的8 mm。活检显示无浆细胞或子宫内膜炎的证据, 也无异型性、增生或恶性肿瘤的证据。另外两个绝经后出血进行子宫内膜活检结果类似。未发现有临床意义的实验室或生命体征异常或观察值或较基线变化的趋势。在所有访视中, 盆腔超声检查均未发现任何受试者的临床显著异常。耐受性和可用性数据表明, 两种IVR通常都是高度可接受的。

结论: IVR 1和IVR 2在健康绝经后女性治疗安全且耐受性良好, TEAE特征与口服方案相当。

Keywords:

• Estradiol
• progesterone
• vaginal ring
• safety
• acceptability

Potential conflict of interest

There are no other conflicts of interest.

Additional information

Funding

D. R. Friend and A. Thurman are employees of Daré Bioscience. Both receive salary and stock options from the company. N. Zack holds stock in Daré Bioscience. K. Hartman was a paid consultant to Daré Bioscience during the performance the clinical study reported. The study was funded by Daré Bioscience.