Abstract and Introduction
Abstract
Study Question: What is the reason for insufficient contraceptive efficacy of levonorgestrel (LNG) delivered by intravaginal ring (IVR) releasing comparable amounts of LNG as approved progestogen-only pills (POPs)?
Summary Answer: The pharmacokinetic (PK) evaluation in a subpopulation indicated that the steady-state concentration of plasma LNG was markedly lower in the participants in the USA compared to those in Japan suggesting non-compliance in the US participants which may explain a clearly higher Pearl Index (PI) in USA (8.2, unadjusted PI) compared to Japan (1.4, unadjusted PI).
What is Known Already: Contraceptive efficacy of LNG in POPs has been demonstrated following different routes of administration (e.g. orally, implants, intrauterine systems), and the PK is well-characterized including a target exposure needed for contraception. Exposure above this target concentration was reached in Phase 1 studies using IVR delivering 40 μg LNG per day.
Study Design, Size, Duration: The primary objective of this multicenter, open-label, single-arm study conducted in the USA and in Japan was to assess the contraceptive efficacy of an LNG-containing IVR during a planned treatment period of 1 year in healthy women 18–35 years of age. The study was planned to be conducted in 1600 participants (1300 in the USA, 300 in Japan). The study was prematurely terminated after approximately one-third of the planned exposure was reached due to a high number of pregnancies (28) in the US study population.
Participants/Materials, Setting, Methods: In total, 1471 participants were treated (1166 participants in the USA and 305 participants in Japan). The PI as a measure of contraceptive efficacy was calculated from the frequency of unintended pregnancies during treatment. LNG exposure in the systemic circulation was assessed during treatment in 136 participants (PK subgroups: 106 in the USA and 30 in Japan).
Main Results and the Role of Chance: The PK evaluation in the PK subgroups indicated that the steady-state concentration of plasma LNG after 6 months was markedly lower in the participants in the USA (geometric mean 91.2 ng/l) compared to those in Japan (263.8 ng/l). This PK finding cannot be explained by the regional differences in body weight observed between the PK subgroups, thus suggesting non-compliance in the US participants. In 15.7% of the samples collected in the USA and 3.5% samples in Japan, the LNG concentration at steady state was below the lower limit of quantification (10 ng/l), which is not expected with the required continuous use of the IVR documented in most of the eDiaries.
Limitations, Reasons for Caution: The planned duration of treatment was 12 months, but due to the premature termination of the study none of the participants completed the 12-month treatment. All data collected until the study termination were considered, but it is to be noted that the amount of missing data limits the conclusions that can be drawn from the data.
Wider Implications of the Findings: The results of this study triggered the termination of the project, because the objective to show sufficient contraceptive efficacy of the LNG IVR was not met. The choice of a user-dependent contraceptive method with an LNG dose that is not inhibiting ovulation is not advisable for women who may have compliance issues.
Study Funding/Competing Interest(S): The study was funded by Bayer AG and all authors are employees of Bayer AG.
Trial Registration Number: NCT02403401
Introduction
This Pearl Index (PI) study is part of a program aiming to develop a fixed combination of anastrozole (ATZ) and levonorgestrel (LNG) delivered by an intravaginal ring (IVR) for the treatment of endometriosis-associated pelvic pain. While ATZ is thought to inhibit autonomous estradiol production from endometriotic lesions (Bulun et al., 2000) thereby inhibit proliferation of endometriotic lesions, the role of LNG is to provide contraceptive efficacy in this combination. This is deemed necessary due to the embryotoxic effects of ATZ during treatment of patients of childbearing potential (Arimidex® Prescribing Information). Low-dose LNG, resembling exposures of approved contraceptive (Jadelle® Prescribing information; Norgeston® Prescribing Information) not inhibiting ovulation, was chosen to not completely block the pituitary–ovarian axis and to avoid the risk of bone loss in combination with ATZ. The route of continuous vaginal administration was chosen to simplify compliance, i.e. the IVR was to be worn continuously with exchange to a new one every 28 days without wearing breaks. Results from a precedent Phase 1 study suggested that a release rate of 40 μg LNG/day yielded systemic exposures (average concentrations, Cav) similar to those reported for approved low-dose LNG contraceptives (progestogen-only pills (POPs), before the start of the study and before implementation of the amendment respectively. All participants gave their written informed consent. Trial registration number is NCT02403401.
IVR Characteristics, Treatment Instructions and Monitoring of Treatment Compliance
The IVRs were made of silicone elastomer with an outer diameter of 54 mm and a cross-sectional diameter of 5 mm (Nave et al., 2018a). The intended wearing period of an IVR was 28 days (±7 days), after which it was to be replaced by a new IVR without a break. The nominal in vitro release rate of LNG at the end of each wearing period was 40 μg/day. The release rate of LNG was chosen so that the resulting LNG exposure in steady state would correspond to that of a POP, a contraceptive that does not aim to inhibit ovulation (for more details with regard to dose selection see (Schultze-Mosgau et al., 2016)). The intended treatment period in the study was 1 year.
The participant received instructions on how to insert the IVR. She then inserted the first IVR at the study site, and the date and time of insertion were recorded as the start of treatment. Participants were trained on the correct application of the IVR and on the procedure to be performed in case of the loss of the IVR. The IVR was to be worn continuously. If the IVR had been removed, it had to be re-inserted or replaced with a new one as soon as possible. If the wearing was occasionally interrupted, the time without wearing was not to exceed 3 hours. If the interruption exceeded 3 h, the contraceptive protection could have been jeopardized. In that case, although the full contraceptive protection would have been reached within 2 days of uninterrupted IVR use, an additional barrier contraception had to be used during intercourse for the following 7 days of IVR use.
To monitor treatment compliance, the participants were required to report every day throughout the study in the eDiary when the IVR had been removed and inserted again with the reason for removal. In addition, the participant was to report whether the same or a new IVR had been inserted. The investigator reviewed these eDiary entries on a regular basis and during the study participant's site visits. This data were taken into account for the assessment of treatment compliance. Study participants who presented with unintended pregnancy during the study period were interviewed, and their eDiary data were assessed with regard to the correct use of the IVR.
Hum Reprod. 2020;35(11):2515-2523. © 2020 Oxford University Press
