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Jörg Elliesen, Dietmar Trummer Bayer Pharma AG, Berlin, Germany Background: The Clyk™ digital pill dispenser helps ensure correct and consistent administration of a flexible extended regimen of the combined oral contraceptive, ethinylestradiol (EE) 20 µg/drospirenone 3 mg (EE/drospirenoneFlex; YAZ® Flex), guiding users through the intake cycle and 4-day pill break and providing visible and acoustic daily reminders when pill intake is due. A study showed that the audible alarm function of the dispenser could help reduce the number of missed pills, but it lacked an appropriate “non-dispenser” group for a meaningful assessment of the impact of the dispenser on adherence. This study indirectly assessed the overall effect of the digital dispenser on adherence by comparing data from a treatment with standard blister packaging.Materials and methods: One-year adherence data were compared from two similarly designed, Phase III, open-label, randomized trials of EE/drospirenoneFlex. In study 1, women used diary cards to record adherence with EE/drospirenoneFlex dispensed in blister packs (n=640), and in study 2 the dispenser was used with the alarm activated (n=250) or deactivated (n=248) in addition to using diary cards.Results: A mean (±SD) of 4.3 (±4.24) missed pills over 1 year were recorded in diary cards among women who dispensed their pills from the blister packages (study 1) compared with 1.0 (±2.4) recorded by the alarm-activated dispenser (study 2). In study 2, a mean of 1.9 (±4.2) missed pills were reported in the diaries over 1 year compared with 4.4 (±9.1) from automatic recording by the dispenser (both arms of study 2), indicating underreporting of missed pills in diary cards vs the digital dispenser. Adjusting for this rate of underreporting, an estimated mean of ten pills were missed over 1 year by women using EE/drospirenoneFlex in blister packs, or ten times more than with the digital dispenser with activated acoustic alarm.Conclusion: The digital dispenser helps reduce the number of missed pills and increases adherence. Keywords: compliance, contraception, drospirenone, ethinylestradiol, flexible extended regimen, efficacy, pill dispenser

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. [ABSTRACT FROM AUTHOR]