@article{1151194330ef4daa98cf6cd99555c103,
title = "Dose-finding study of a 90-day contraceptive vaginal ring releasing estradiol and segesterone acetate",
abstract = "Objective: To evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200 mcg/day and segesterone acetate (SA) 200 mcg/day to identify a dose that avoids hypoestrogenism. Study design: We conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40 pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information. Results: Sixty-five participants enrolled in E2 75 (n = 22), 100 (n = 21), and 200 (n = 22) mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100 mcg/day groups were <40 pg/mL. In the 200 mcg/day group, median E2 concentrations peaked on days 4–5 of CVR use at 194 pg/mL (range 114–312 pg/mL) and remained >40 pg/mL throughout 30 days; E2 concentrations were 37 pg/mL (range 28–62 pg/mL) on days 88–90 (n = 11). Among the E2 200 mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0–16) and three (range 0–19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days. Conclusions: Estradiol concentrations with rings releasing E2 200 mcg/day and SA 200 mcg/day avoid hypoestrogenism over 30-day use. Implications: A 90-day contraceptive vaginal ring releasing estradiol 200 mcg/day and segesterone acetate 200 mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation.",
keywords = "Clinical trial, Contraception, Estradiol, Nestorone{\textregistered}, Segesterone acetate, Vaginal ring",
author = "Chen, {Melissa J.} and Creinin, {Mitchell D.} and Turok, {David K.} and Archer, {David F.} and Barnhart, {Kurt T.} and Westhoff, {Carolyn L.} and Thomas, {Michael A.} and Jensen, {Jeffrey T.} and Bruce Variano and Regine Sitruk-Ware and Anita Shanker and Jill Long and Blithe, {Diana L.}",
note = "Funding Information: Disclosures: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Chen and Dr. Barnhart have no financial conflicts of interest to disclose. Dr. Creinin serves on an Advisory Board for Lupin and Merck and is a consultant for Danco, Estetra SPRL, Exeltis, and Medicines360. The Department of Obstetrics and Gynecology, University of California, Davis, receives research funding for contraceptive research from Dar{\'e}, HRA Pharma, Medicines360, and Sebela Pharmaceuticals.The Department of Obstetrics and Gynecology, Division of Family Planning at the University of Utah receives research funding from Bayer, Cooper Surgical, Medicines360, Merck, and Sebela Pharmaceuticals. Dr. Turok is a consultant for Sebela Pharmaceuticals.Dr. Archer has received consulting fees from AbbVie, Agile Therapeutics, Exeltis, Endoceutics,ObsEva, Radius and Therapeutics MD. Eastern Virginia Medical School has received research support from Abbvie, Bayer Healthcare, Exeltis, Endoceutics, Myovant, ObsEva, Radius, and TherapeuticsMD.Dr. Westhoff serves as a consultant for Merck and Bayer as a DSMB member for several phase 4 studies, consults for AbbVie, and receives research funding from Medicines360 and Sebela Pharmaceuticals.The Department of Obstetrics and Gynecology at the University of Cincinnati College of Medicine accepts research monies from Medicines360, Bayer Healthcare, and Sebela Pharmaceuticals. Dr. Jensen has received payments for consulting from Abbvie, Cooper Surgical, Bayer Healthcare, Merck, Sebela Pharmaceuticals, and the Population Council. OHSU has received research support from Abbie, Bayer Healthcare, Dar{\'e}, Estetra SPRL, Medicines360, Merck, and Sebela Pharmaceuticals. 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.Dr. Sitruk-Ware and Dr. Variano are employees of the Population Council, a not for profit organization, IND holder for Nestorone formulations, and developer of the vaginal ring described in this paper.Dr. Blithe and Dr. Long are employees of the NIH. Funding Information: The Endocrine Technologies Core (ETC) at the Oregon National Primate Research Center (ONPRC) is supported by NIH Grant P51 OD011092 awarded to ONPRC. Funding Information: Funding: The study was supported by NICHD Contraception Clinical Trial Network: HHSN275201300010I/HHSN27500003 (Columbia University), HHSN275201300021I/HHSN27500002 (UC Davis), HHSN275201300014I/HHSN27500003 (University of Cincinnati), HHSN275201300020I/HHSN27500003 (University of Pennsylvania), HHSN275201300016I/HHSN27500002 (University of Utah), HHSN275201300019I/HHSN27500003 (Eastern Virginia Medical School), HHSN275201300008I/HHSN27500005 (Oregon Health and Science University). MJC was additionally supported by NICHD K23 HD090323. The content of this publication is the sole responsibility of the authors and does not necessarily represent the official views of the NIH.The authors would like to acknowledge Sarah Godfrey and Clint Dart at Health Decisions, Drs. Alicia Christy and Mark Payson at the National Institutes of Health, and Dr. Ruth Merkatz at Population Council. The vaginal rings were engineered under a proprietary method and manufactured in the GMP laboratory of the Population Council, New York, holder of the IND 114,380. The Endocrine Technologies Core (ETC) at the Oregon National Primate Research Center (ONPRC) is supported by NIH Grant P51 OD011092 awarded to ONPRC. Funding Information: Funding: The study was supported by NICHD Contraception Clinical Trial Network: HHSN275201300010I / HHSN27500003 ( Columbia University ), HHSN275201300021I / HHSN27500002 ( UC Davis ), HHSN275201300014I / HHSN27500003 ( University of Cincinnati ), HHSN275201300020I / HHSN27500003 ( University of Pennsylvania ), HHSN275201300016I / HHSN27500002 ( University of Utah ), HHSN275201300019I / HHSN27500003 ( Eastern Virginia Medical School ), HHSN275201300008I / HHSN27500005 ( Oregon Health and Science University ). MJC was additionally supported by NICHD K23 HD090323 . The content of this publication is the sole responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = sep,
doi = "10.1016/j.contraception.2020.05.004",
language = "English (US)",
volume = "102",
pages = "168--173",
journal = "Contraception",
issn = "0010-7824",
publisher = "Elsevier USA",
number = "3",
}