Abstract
Objectives
To determine the incidence of out-of-range segesterone acetate (NES) concentrations
in participants of a pharmacokinetic/pharmacodynamic trial of a continuous use contraceptive
vaginal ring (CVR) releasing NES and estradiol (E2). We hypothesized that out-of-range
concentrations reflect nonadherent ring use and predict ovulation risk.
Study Design
We conducted a secondary analysis of data from a prospective, multi-centered, randomized,
Phase IIa dose-finding trial for a CVR releasing NES and E2. Our primary outcome was
the risk of ovulation associated with out-of-range NES events. We calculated the 5th
and 95th percentile NES concentrations of subjects at steady state to determine high
and low cutoffs. We used a Fisher's exact test to determine group differences, and
calculated the relative risk of ovulation for each group.
Results
We analyzed available serum NES data from cycles 2 (n = 172), 3 (n = 156) and 7 (n = 115)
to determine the 5th and 95th percentile of all NES concentrations (64, 296 pg/mL).
In the 443 cycles of observation, no ovulations occurred in participants with NES
concentrations within the expected range. In contrast, we found ovulatory elevations
of progesterone in 21 cycles with out-of-range values. Of these, 15 (71%) cycles had
evidence of one or more nonadherent low and 6 (29%) one or more unexpected peak. The
relative risk of ovulation increased with evidence of multiple non-adherent levels.
Conclusions
We found out-of-range NES concentrations, suggestive of improper use of a CVR associated
with an increased risk of ovulation, with a direct relationship between the number
of out-of-range events and the relative risk.
Implications
The results of this study support the use of out-of-range serum NES values as a marker
of adherence in contraceptive clinical trials of continuous vaginal rings, and suggest
that nonadherence occurs even in early phase clinical trials with close monitoring.
Keywords
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Article info
Publication history
Published online: December 27, 2021
Accepted:
December 8,
2021
Received in revised form:
November 23,
2021
Received:
August 6,
2021
Footnotes
Declaration of Competing Interest: Dr. Jensen has received payments for consulting from Bayer Healthcare, Evofem, Hope Medicine, Foundation Consumer Healthcare, Mayne Pharma, ViiV Healthcare, and TherapeuticsMD. OHSU has received research support from Abbvie, Bayer Healthcare, Daré, Estetra SPRL, Hope Medicine, Medicines360, Merck, Myovent, 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. The other authors have no potential conflicts.
Funding: The study was supported by NICHD Contraception Clinical Trial Network: HHSN275201300008I/HHSN27500005 (Oregon Health and Science University).
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