TY - JOUR
T1 - Evaluation of ovulation and safety outcomes in a multi-center randomized trial of three 84 day ulipristal acetate regimens
AU - Westhoff, Carolyn L.
AU - Archer, David F.
AU - Barnhart, Kurt
AU - Darney, Philip
AU - Gilliam, Melissa
AU - Jensen, Jeffrey
AU - Nelson, Anita
AU - Teal, Stephanie
AU - Thomas, Michael
AU - Hu, Jack
AU - Brown, Jill
AU - Blithe, Diana L.
N1 - Funding Information:
Conflicts of Interest: CW – Consultant to Merck, Bayer, AbbVie, Therapeutics MD, HRAPharma. Research support from Estetra SPRL, Sebela, Chemoresearch Exeltis, and Medicines360, all managed through Columbia University. DA- Consultant to Agile Therapeutics, Mayne, Mithra, TherapeuticsMD. Grants from Bayer Healthcare, Mithra, Myovant, ObsEva, TherapeuticsMD. Investments in Agile Therapeutics, InnovaGyn, Inc. KB- Consultant to Bayer Health Care. PD – no conflicts. MG- no conflicts. JJ – Consultant to Bayer Healthcare, Evofem, Mayne Pharma, Merck, Sebela, and TherapeuticsMD. OHSU has received research support from Abbvie, Bayer Healthcare, Daré, Mayne, Medicines360, Merck, and Sebela. 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. ST – Consultant to Merck and Bayer Healthcare. Research support at University of Colorado from Sebela, Medicines 360, Merck & Co, Bayer Health care, and Chemo Research S.L. AN- Consultant/Advisory Board: Agile Therapeutics, Bayer HealthCare, Mayne Pharma, Pfizer, TherapeuticsMD. Honoraria/Speakers Bureau: Agile Therapeutics, Bayer HealthCare, Mayne Pharma, Myovant Sciences, Organon/Merck & Co., TherapeuticsMD. Grants/Research: Mylan Pharmaceuticals, Myovant Sciences, Organon/Merck & Co., Sagami Rubber Industries, Sebela Pharmaceuticals. MT-Dr. Thomas is the Vice President for ASRM and serves on the Board of Directors for ABOG. DB-NICHD has two Cooperative Research and Development Agreements (CRADAs) with industry, HRA Pharma and Daré, in which Dr. Blithe has served as Principal Investigator. Joint inventions resulting from the CRADA with HRA Pharma have generated royalty payments to NICHD and to Dr. Blithe as a co-inventor of therapeutic indications for Ulipristal Acetate. JB- no conflicts of interest.
Funding Information:
Funding: The National Institute of Child Health and Human Development sponsored this study. HRA Pharma supplied the investigational product; HRA Pharma had no involvement with the protocol, study execution, analysis or preparation of this manuscript. ☆ Conflicts of Interest: CW – Consultant to Merck, Bayer, AbbVie, Therapeutics MD, HRAPharma. Research support from Estetra SPRL, Sebela, Chemoresearch Exeltis, and Medicines360, all managed through Columbia University. DA- Consultant to Agile Therapeutics, Mayne, Mithra, TherapeuticsMD. Grants from Bayer Healthcare, Mithra, Myovant, ObsEva, TherapeuticsMD. Investments in Agile Therapeutics, InnovaGyn, Inc. KB- Consultant to Bayer Health Care. PD – no conflicts. MG- no conflicts. JJ – Consultant to Bayer Healthcare, Evofem, Mayne Pharma, Merck, Sebela, and TherapeuticsMD. OHSU has received research support from Abbvie, Bayer Healthcare, Daré, Mayne, Medicines360, Merck, and Sebela. 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. ST – Consultant to Merck and Bayer Healthcare. Research support at University of Colorado from Sebela, Medicines 360, Merck & Co, Bayer Health care, and Chemo Research S.L. AN- Consultant/Advisory Board: Agile Therapeutics, Bayer HealthCare, Mayne Pharma, Pfizer, TherapeuticsMD. Honoraria/Speakers Bureau: Agile Therapeutics, Bayer HealthCare, Mayne Pharma, Myovant Sciences, Organon/Merck & Co., TherapeuticsMD. Grants/Research: Mylan Pharmaceuticals, Myovant Sciences, Organon/Merck & Co., Sagami Rubber Industries, Sebela Pharmaceuticals. MT-Dr. Thomas is the Vice President for ASRM and serves on the Board of Directors for ABOG. DB-NICHD has two Cooperative Research and Development Agreements (CRADAs) with industry, HRA Pharma and Daré, in which Dr. Blithe has served as Principal Investigator. Joint inventions resulting from the CRADA with HRA Pharma have generated royalty payments to NICHD and to Dr. Blithe as a co-inventor of therapeutic indications for Ulipristal Acetate. JB- no conflicts of interest.
Publisher Copyright:
© 2022
PY - 2022/8
Y1 - 2022/8
N2 - Objectives:: To describe ovulation inhibition and safety of daily oral ulipristal acetate (UPA) over 84 days. Study Design:: This multi-center phase 1 and/or 2 trial randomized participants to use oral ulipristal 10 mg or 5 mg daily or a 3 cycle regimen of 5 mg for 24 days followed by four placebo days. We stratified randomization by body mass index (BMI) <32 or 32-40 kg/m2. To estimate ovulation inhibition, the primary outcome, participants underwent transvaginal ultrasound and blood sampling twice weekly; we analyzed compliant participants who completed the 84 day study. Safety endpoints included 3 endometrial biopsies and liver chemistry tests. Results:: We enrolled 180 participants and included 137 in the ovulation inhibition analyses. Progesterone values that remained below 3ng/mL throughout treatment suggested consistent ovulation inhibition in 52 of 137 (38%) participants; 25 of 47(53%), 20 of 44(45%), and 7 of 46(15%) among participants randomized to the 10 mg, 5 mg, and cyclic treatments, respectively (p < 0.01). Progesterone values consistently <3 ng/mL were more frequent in participants with a BMI > 32kg/m2 (25/50(50%) vs 27/87(31%), p = 0.01). Average ulipristal concentrations were higher among participants with low progesterone concentrations (p < 0.01). Endometrial biopsies during treatment showed progesterone-receptor-modulator-associated endometrial changes in 52 of 164 participants (32%); 22 of 49(40%), 16 of 48(29%), and 14 of 51(26%) in women randomized to the 10 mg, 5 mg, and the cyclic treatments, respectively (p = 0.07, test-for-trend); these changes resolved after treatment cessation. Liver transaminase changes were rare. Conclusions:: Oral ulipristal acetate over 12 weeks did not reliably suppress ovulation, particularly in the 5 mg cyclic-dose group. Ovulation inhibition and endometrial changes were dose dependent. Reversible endometrial changes occurred during treatment. Implications:: Progesterone-receptor modulators have been suggested for daily oral contraception. Since progesterone concentrations suggest that ovulation occurred during treatment, further studies would be necessary to assess whether these were functional ovulations and to evaluate other possible mechanisms of contraception.
AB - Objectives:: To describe ovulation inhibition and safety of daily oral ulipristal acetate (UPA) over 84 days. Study Design:: This multi-center phase 1 and/or 2 trial randomized participants to use oral ulipristal 10 mg or 5 mg daily or a 3 cycle regimen of 5 mg for 24 days followed by four placebo days. We stratified randomization by body mass index (BMI) <32 or 32-40 kg/m2. To estimate ovulation inhibition, the primary outcome, participants underwent transvaginal ultrasound and blood sampling twice weekly; we analyzed compliant participants who completed the 84 day study. Safety endpoints included 3 endometrial biopsies and liver chemistry tests. Results:: We enrolled 180 participants and included 137 in the ovulation inhibition analyses. Progesterone values that remained below 3ng/mL throughout treatment suggested consistent ovulation inhibition in 52 of 137 (38%) participants; 25 of 47(53%), 20 of 44(45%), and 7 of 46(15%) among participants randomized to the 10 mg, 5 mg, and cyclic treatments, respectively (p < 0.01). Progesterone values consistently <3 ng/mL were more frequent in participants with a BMI > 32kg/m2 (25/50(50%) vs 27/87(31%), p = 0.01). Average ulipristal concentrations were higher among participants with low progesterone concentrations (p < 0.01). Endometrial biopsies during treatment showed progesterone-receptor-modulator-associated endometrial changes in 52 of 164 participants (32%); 22 of 49(40%), 16 of 48(29%), and 14 of 51(26%) in women randomized to the 10 mg, 5 mg, and the cyclic treatments, respectively (p = 0.07, test-for-trend); these changes resolved after treatment cessation. Liver transaminase changes were rare. Conclusions:: Oral ulipristal acetate over 12 weeks did not reliably suppress ovulation, particularly in the 5 mg cyclic-dose group. Ovulation inhibition and endometrial changes were dose dependent. Reversible endometrial changes occurred during treatment. Implications:: Progesterone-receptor modulators have been suggested for daily oral contraception. Since progesterone concentrations suggest that ovulation occurred during treatment, further studies would be necessary to assess whether these were functional ovulations and to evaluate other possible mechanisms of contraception.
KW - Endometrial safety
KW - Ovulation suppression
KW - Pharmacodynamics
KW - Ulipristal acetate
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U2 - 10.1016/j.contraception.2022.04.002
DO - 10.1016/j.contraception.2022.04.002
M3 - Article
C2 - 35430238
AN - SCOPUS:85130317846
VL - 112
SP - 54
EP - 60
JO - Contraception
JF - Contraception
SN - 0010-7824
ER -