Phase II dose-finding study on ovulation inhibition and cycle control associated with the use of contraceptive vaginal rings containing 17β-estradiol and the progestagens etonogestrel or nomegestrol acetate compared to NuvaRing

Abstract

Purpose: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing^® (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%.

Methods: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18–35 years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 µg 17β-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 µg/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 µg/day), or the active control NuvaRing^® (ENG/ethinylestradiol 120/15 µg), for three 28-day cycles.

Results: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16 nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 µg/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing^® with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups.

Conclusions: Contraceptive rings releasing 300 µg E2 and 75–125 µg/day of ENG or 500–900 µg/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing^® was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control.

摘要

目的：确定至少一种阴道避孕环在抑制排卵和月经周期中意外出血的效果不劣于NuvaRing VR（Merck Sharp & Dohme B.V., The Netherlands）, 非劣效率为10%。

方法：采用随机、对照、平行、多中心、单盲的研究, 试验对象为18-35岁的健康女性。受试者接受六种避孕阴道环中的一种, 避孕环平均每日释放量为300毫克17β-雌二醇, 依托孕酮（75, 100或125ug/天）或醋酸诺美孕酮（500, 700或900ug/天）, 或对照组受试者使用NuvaRing （依托孕酮/炔雌醇120/15 ug）, 28天一个周期, 共用3个周期。

结果：所有组均观察到排卵抑制, 与排卵后黄体酮（>16nmol/L）相比, 这些患者黄体酮的缺乏以及无超声排卵的表现均证实了这一点。所有的阴道避孕环都提供了良好的周期控制, 其中依托孕酮/17β-雌二醇 125/300ug /天组周期意外出血的概率最低, 周期控制最好。与NuvaRing组相比, 其他各组在周期意外出血的控制方面尚未达到非劣效的水平。药物的安全性方面与已知的雌激素/黄体酮联合避孕药的安全性资料一致的, 而且各组的安全性相似。

结论：每天释放300ug的17β-雌二醇和75-125ug的依托孕酮或500-900ug的醋酸诺美孕酮均达到提供很好的排卵抑制和周期控制的效果。与NuvaRing相比, 虽然尚未满足非劣效性, 但是依托孕酮/17β-雌二醇 125/300ug /天的避孕环的周期控制效果最好。

Keywords:

• Contraceptive vaginal ring
• 17β-estradiol
• etonogestrel
• nomegestrol acetate
• ovulation inhibition
• cycle control

Acknowledgements

The authors thank Michelle C. Fox and Alan Meehan (Merck & Co., Inc., Kenilworth, NJ, USA) for editorial assistance and Jennifer Rotonda (Merck & Co., Inc., Kenilworth, NJ, USA) for her assistance in preparing this paper for publication.

Disclosure statement

Ghassan N. Fayad, Tara L. Frenkl and Sandra M. Cruz report that they are current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may hold stock or stock options in the company. Tjeerd Korver is a former employee of Merck & Co., Inc., Kenilworth, NJ, USA and reports that he has received personal fees from the company during the conduct and reporting of the study. Ingrid Duijkers, Christine Klipping and Doris Heger-Mahn report that they served as investigators on the study and received study funding from Merck & Co., Inc., Kenilworth, NJ, USA. All authors are responsible for the work described in this manuscript. All authors were involved in at least one of the following: [conception, design, acquisition, analysis, statistical analysis, or interpretation of data] and [drafting the manuscript and/or revising it for important intellectual content]. All authors provided final approval of the version to be published.

Data Availability

Merck & Co., Inc.’s data sharing policy, including restrictions, is available at http://engagezone.merck.com/ds_documentation.php. Requests for access to the study data can be submitted through the EngageZone site or via email to [email protected].

Additional information

Funding

Financial support for the conduct of the research and the preparation of this article was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.