Abstract
Objectives: To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily. Study design: We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive 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 safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies. Results: The combined studies included 3052 women; 2308 women [mean age 26.7±5.1 years; mean body mass index (BMI) 24.1±3.7 kg/m2] received the final manufactured CVS, of whom 999 (43.3%) completed 13 cycles of 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 (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMI>29 kg/m2 (n=2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions 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. 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 currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 323-328 |
| Number of pages | 6 |
| Journal | Contraception |
| Volume | 99 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2019 |
Keywords
- Adverse events
- Contraceptive vaginal system
- Ethinyl estradiol
- Nestorone
- Segesterone acetate
ASJC Scopus subject areas
- Reproductive Medicine
- Obstetrics and Gynecology
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In: Contraception, Vol. 99, No. 6, 06.2019, p. 323-328.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation
AU - Gemzell-Danielsson, Kristina
AU - Sitruk-Ware, Regine
AU - Creinin, Mitchell D.
AU - Thomas, Michael
AU - Barnhart, Kurt T.
AU - Creasy, George
AU - Sussman, Heather
AU - Alami, Mohcine
AU - Burke, Anne E.
AU - Weisberg, Edith
AU - Fraser, Ian
AU - Miranda, Marie José
AU - Gilliam, Melissa
AU - Liu, James
AU - Carr, Bruce R.
AU - Plagianos, Marlena
AU - Roberts, Kevin
AU - Blithe, Diana
N1 - Funding Information: 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 Information: 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.? 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. The authors acknowledge the major contribution of Dr. Daniel R Mishell Jr. (deceased), from the Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA, who invented the concept of the vaginal system to deliver contraceptive steroids and conducted several of the studies analyzed here while he was a member of the International Committee for Contraceptive Research (ICCR) of the Population Council. The authors also acknowledge the contribution of Dr. Horacio B Croxatto, from the University of Chile, who established the clinical center in Chile and participated in all pivotal clinical studies while he was a member of the ICCR. The authors acknowledge the other principal investigators in the phase 3 clinical trials: David F Archer, Eastern Virginia Medical School, Norfolk, VA (USA); Luis Bahamondes, Campinas Univ, Campinas, SP (Brazil); Carolyn Westhoff, Columbia University, NY (USA); Dan Apter, VL-Medi Clinical Research Center, Helsinki (Finland); Philip Darney, University of California, San Francisco, CA (USA); Jeffrey Jensen Oregon Health & Science University, Portland, OR (USA); Anita Nelson, University of California, Los Angeles-Harbor, CA (USA); Vivian Brache, Profamilia, Santo Domingo (Dominican Republic); George Bartfai, Albert Szent-Gy?rgy Medical University, Szeged (Hungary); Erika Banks, Albert Einstein Medical Center, NY (USA); Livia Wan, New York University, NY (USA); David Portman and Lisa Keder, Ohio State University, Columbus, OH (USA); William Schlaff, University of Colorado, Aurora, CO (USA); Ronald Burkman, Bay State Medical Center, Springfield, MA (USA); Ken Muse, University of Kentucky, Lexington, KY (USA). The authors would like to thank the women who volunteered for these studies; the participating study investigators and coordinators at the 27 clinical sites for conduct of the phase 3 clinical studies; and Kathleen Ohleth, PhD, for medical editing of the resubmitted manuscript (supported by TherapeuticsMD). The Population Council and the NICHD co-sponsored the phase 3 clinical studies and collaborated in the study design together with FDA reviewers when submitted to the Population Council IND (and NDA 209,627). Both sponsors collaborated in the collection, analysis and interpretation of data and in the writing of the report. Both conferred and agreed to submit this article for publication.? 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. Funding Information: 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. Publisher Copyright: © 2019 Elsevier Inc.
PY - 2019/6
Y1 - 2019/6
N2 - Objectives: To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily. Study design: We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive 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 safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies. Results: The combined studies included 3052 women; 2308 women [mean age 26.7±5.1 years; mean body mass index (BMI) 24.1±3.7 kg/m2] received the final manufactured CVS, of whom 999 (43.3%) completed 13 cycles of 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 (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMI>29 kg/m2 (n=2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions 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. 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 currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.
AB - Objectives: To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily. Study design: We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive 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 safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies. Results: The combined studies included 3052 women; 2308 women [mean age 26.7±5.1 years; mean body mass index (BMI) 24.1±3.7 kg/m2] received the final manufactured CVS, of whom 999 (43.3%) completed 13 cycles of 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 (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMI>29 kg/m2 (n=2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions 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. 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 currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.
KW - Adverse events
KW - Contraceptive vaginal system
KW - Ethinyl estradiol
KW - Nestorone
KW - Segesterone acetate
UR - http://www.scopus.com/inward/record.url?scp=85063444853&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063444853&partnerID=8YFLogxK
U2 - 10.1016/j.contraception.2019.02.001
DO - 10.1016/j.contraception.2019.02.001
M3 - Article
C2 - 30831102
AN - SCOPUS:85063444853
SN - 0010-7824
VL - 99
SP - 323
EP - 328
JO - Contraception
JF - Contraception
IS - 6
ER -