Contraception 99 (2019) 323–328 Contents lists available at ScienceDirect Contraception journal homepage: www.elsevier.com/locate/con Original article Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal ☆ ☆☆ system safety evaluation , Kristina Gemzell-Danielsson a,⁎, Regine Sitruk-Ware b,MitchellD.Creininc, Michael Thomas d, Kurt T. Barnhart e, George Creasy b, Heather Sussman b, Mohcine Alami b,AnneE.Burkef, Edith Weisberg g, Ian Fraser h, Marie-José Miranda i, Melissa Gilliam j, James Liu k, Bruce R. Carr l, Marlena Plagianos b, Kevin Roberts b, Diana Blithe m a Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden b Center for Biomedical Research, Population Council, New York, NY, USA c Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, CA, USA d Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, OH, USA e Department of Obstetrics and Gynecology, Perelman School of medicine, University of Pennsylvania, Philadelphia, PA, USA f Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Bayview Medical Center, Baltimore, MD, USA g Family Planning NSW, and University of Sydney, Sydney, Australia h University of New South Wales; Family Planning NSW, and University of Sydney, Sydney, Australia i Instituto Chileno de Medicina Reproductiva (ICMER), Santiago, Chile j Department of Obstetrics, Gynecology and Pediatrics, University of Chicago, Chicago, IL, USA k Department of Obstetrics and Gynecology, Case Western Reserve University, Cleveland, OH, USA l UT Southwestern University, Dallas, TX, USA m Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA article info abstract Article history: Objectives: To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) re- Received 27 September 2018 leasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily. Received in revised form 20 February 2019 Study design: We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive Accepted 20 February 2019 days and removed it for 7 days of each 28-day cycle. Four studies used the final manufactured CVS, including a 1- year pharmacokinetic study, two 1-year phase 3 trials and a second-year treatment extension study. We assessed Keywords: safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety Contraceptive vaginal system Nestorone studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies. Segesterone acetate Results: The combined studies included 3052 women; 2308 women [mean age 26.7±5.1 years; mean body mass 2 Ethinyl estradiol index (BMI) 24.1±3.7 kg/m ]receivedthefinal manufactured CVS, of whom 999 (43.3%) completed 13 cycles of Adverse events use. Women using the final CVS most commonly reported adverse events of headache (n=601, 26%), nausea (n=420, 18%), vaginal discharge/vulvovaginal mycotic infection (n=242, 10%) and abdominal pain (n=225, 10%). Few (b1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboem- bolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMIN29 kg/m2 (n= 2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expul- sions in 4259 (19.5%) cycles and complete expulsions in 1509 (7%) cycles, most frequently in the initial cycle [499/2050 (24.3%) and 190/2050 (9.3%), respectively]. Safety-focused studies revealed no safety concerns. Conclusion: The 1-year SA/EE CVS has an acceptable safety profile. Additional studies are warranted in obese women at higher risk of VTE. ☆ Declaration of interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was supported by the National Institute of Child Health and Human Development of the National Institutes of Health and the United States Agency for International Development, WHO's RHRP, and the Population Council. Authors are employed by the Population Council/NICDH, are members of the International Committee for Contraceptive Research/Population Council or participated in the reported trials sponsored by these agencies. ☆☆ Funding: The National Institute of Child Health and Human Development of the National Institutes of Health (NICHD; Contract Numbers HHSN27500403366, HHSN27500403371, HHSN27500403372, HHSN27500403373, HHSN27500403374, HHSN27500403375, HHSN27500403376, HHSN27500403377, HHSN27500403378, HHSN27500403379, HHSN27500403380, HHSN27500403381, HHSN27500403382) funded and conducted the US study; the United States Agency for International Development (Grant Number GPO-A- 00-04-00019-00) funded the international study, which was conducted by the Population Council; and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP) funded two clinical sites in Europe. ⁎ Corresponding author. E-mail address: [email protected] (K. Gemzell-Danielsson). https://doi.org/10.1016/j.contraception.2019.02.001 0010-7824/© 2019 Elsevier Inc. All rights reserved. 324 K. Gemzell-Danielsson et al. / Contraception 99 (2019) 323–328 Implications: This 1-year contraceptive vaginal system represents a new long-term, user-controlled and procedure- free option with a safety profile similar to other combination hormonal contraceptives. The same precautions cur- rently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system. © 2019 Elsevier Inc. All rights reserved. 1. Introduction compared the impact of EE on hepatic proteins with oral versus vaginal delivery [7]. Finally, a 13-cycle, phase 2, dose-finding study of the pilot Segesterone acetate (SA), also known as Nestorone®, is a novel 19- SA/EE 150/13 CVS evaluated vaginal and cervical epithelium by colpos- nor-progesterone that is inactive orally but highly effective when ad- copy [8,9]. The institutional review boards (IRBs) of the Population ministered via implantable, vaginal and transdermal systems [1]. Like Council and one contracted by the National Institute of Child Health progesterone, SA binds specifically to progesterone receptors but not and Human Development's Contraceptive Clinical Trials Network Coor- to androgen or estrogen receptors, thus limiting undesired androgen, dinating Center (Advarra, Columbia, MD 21046), and each participating antiandrogen or estrogenic effects [2]. Although SA binds to the gluco- site's IRB or Ethical Committee approved the protocols. All subjects corticoid receptor, no glucocorticoid-related effects appear at therapeu- signed written informed consent prior to initiating any study tic doses [2]. SA does not transactivate the androgen receptor, and its procedures. metabolites do not interact with the GABA-A receptor [3]. This latter The two phase 3, multicenter, single arm, open-label studies, con- finding could theoretically avoid mood changes and sleepiness de- ducted from 2006 to 2009, were identically designed and provided scribed with progesterone treatment related to allopregnanolone (the most of the safety information. Participants were healthy, sexually ac- main progesterone metabolite) action on the GABA-A receptor [3]. tive, nonpregnant, nonsterilized women 18–40 years old. Subjects re- The Population Council developed an SA/ethinyl estradiol (EE) con- ported AEs, concomitant medications and CVS expulsions (partial or traceptive ring with a final formulation delivering an average of SA 150 complete) on diary cards (see definitions in Supplemental Information). mcg and EE 13 mcg daily. The US Food and Drug Administration ap- During the first 6 months of study enrollment, two venous thromboem- proved this product as a contraceptive vaginal system (CVS) in April bolic events (VTEs) occurred in women who had a baseline body mass 2018. Women used the CVS for 21 consecutive days and then removed index (BMI) N29.0 kg/m2 in the US-only study. The Data Safety Monitor- it for 7 days in each 28-day cycle for all studies. Women can use the ing Board recommended limiting further enrollment to women with same CVS for up to 13 cycles (1 year). The CVS requires minimal to no baseline BMI ≤29.0 kg/m2 and to discontinue women in the two studies daily attention and can be inserted or removed without a trained health with BMI N29.0 kg/m2. An additional open-label investigation collected provider. This report summarizes the safety data from two phase 3 stud- PK and PD data from 39 subjects during cycles 1, 3 and 13 and safety ies and seven other clinical studies that included a broad range of data from all cycles of this study (see Supplemental Information). The women at United States (US) and non-US sites. safety data of this PK/PD study were part of each pooled dataset. For the overall integrated safety summary analysis, we created three 2. Methods pooled datasets of SA/EE CVS use (Table 1). Investigators graded relat- edness of AEs to CVS use as possibly, probably or definitely/highly prob- The overall safety evaluation plan for the SA/EE 150/13 CVS program ably (Supplemental Table 1S). included phase 1 and 2 studies