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Randomized Controlled Trial
. 2014 Dec;90(6):565-74.
doi: 10.1016/j.contraception.2014.08.006. Epub 2014 Aug 12.

A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception

YongMei Huang  1 , Jeffrey T Jensen  2 , Vivian Brache  3 , Leila Cochon  3 , Alistair Williams  4 , Maria-José Miranda  5 , Horacio Croxatto  6 , Narender Kumar  1 , Heather Sussman  1 , Elena Hoskin  1 , Marlena Plagianos  1 , Kevin Roberts  1 , Ruth Merkatz  1 , Diana Blithe  7 , Regine Sitruk-Ware  8
Affiliations
Randomized Controlled Trial

A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception

YongMei Huang et al. Contraception. 2014 Dec.

Abstract

Objective: To determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles.

Study design: This was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 μg/day) or a high-dose (2500 μg/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns.

Results: All subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding.

Conclusion: The 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-μg/day ring.

Implications: The 3-month CVR delivering UPA 2500 μg/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment.

Keywords: Contraception; Endometrium; Pharmacodynamics; Ulipristal acetate; Vaginal ring.

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Conflict of interest statement

Disclosure summary:

Dr. Jensen has received payments for consulting from HRA Pharma and the Population Council, a not-for-profit organization. He has also received research funding from the Population Council. These companies and organizations may have a commercial or financial interest in the results of this research and technology. These potential conflicts of interest have been reviewed and managed by OHSU.

Vivian Brache has received payments for consulting from the Population Council, FHI360, CONRAD and HRA Pharma. She has also received research funding from the Population Council, FHI360, and HRA Pharma. These companies and organizations may have a commercial or financial interest in the results of this research and technology.

Alistair Williams currently consults for and has received consultancy payments from HRA Pharma, PregLem SA, Gedeon Richter and Bayer.

Regine Sitruk-Ware received a grant from the National Institute of Child and Health Development (NICHD) to conduct the research project described in this manuscript. She is co-inventor of the UPA vaginal ring in a patent owned by the Population Council and HRA Pharma. She is employed by The Population Council a not-for-profit organization developing the UPA vaginal ring in a joint development agreement with HRA Pharma, a company producing UPA that may have a commercial interest in the results of this study.

Dr. Diana Blithe is a principal investigator on the Collaborative Research and Development Agreement (CRADA) of the NICHD with HRA Pharma for the development of ulipristal acetate for therapeutic indications. Inventions under research in the CRADA are joint property of NICHD and HRA Pharma. Funds from the CRADA were not used in the conduct of this research; however, the company supplied the drug for the studies.

Other authors have nothing to declare and their disclosures are also reported separately on appropriate forms.

Figures

Figure 1
Figure 1. Rate of ovulation (number of ovulatory cycles/total number of cycles) during the study
Control cycle was the baseline cycle. 1st and 2nd ring correspond to cycles assessed during Treatment Periods 1 and 2. The overall rate combines all cycles during both treatment periods. The post treatment cycle reflects the first 4 weeks after discontinuation of the ring.
Figure 2
Figure 2
Mean (± SD) serum levels of UPA during treatment with a 2500 μg (high dose) (panel A) and 1500 μg (low dose) (panel B) vaginal ring. Correlation between serum levels of UPA measured with RIA and LCMS (panel C).
Figure 3
Figure 3
Mean (± SD) values of endometrial thickness change over 6 months use of a 2500 μg (high dose) and 1500 μg (low dose) CVR in subjects who received (panel B) and did not receive (panel A) levonorgestrel (LNG) 1.5 mg at the time of removal of the first and second ring.
See this image and copyright information in PMC

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