Pooled eﬃcacy results of estetrol/drospirenone combined oral contraception phase 3 trials ✩ , ✩✩

Objective: To evaluate overall and subgroup eﬃcacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen. Study design: We pooled eﬃcacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP con- ducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (conﬁrmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors. Results: Analyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥ 30 kg/m 2 . The pooled PI was 1.52 (95% conﬁdence interval 1.04 - 2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%– 1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94–2.57) and 1.43 (0.78–2.40), respectively; in new starters and switchers of 1.88 (1.09–3.00) and 1.24 (0.68–2.08), respectively; and by BMI < 25 kg/m 2 , 25 to 29.9 kg/m 2 , and ≥ 30 kg/m 2 of 1.14 (0.64–1.88), 2.19 (1.05–4.03), and 2.27 (0.83–4.94), respectively. In multivariable analysis, we found associations of prior pregnancy (hazard ratio [HR] two demonstrate the estetrol-drospirenone contraceptive. non–modiﬁable associated higher pregnancy Additional understand

Two recent phase 3 clinical trials using E4 15 mg/DRSP 3 mg (E4/DRSP), one trial conducted in the US/Canada and one in Europe/Russia, demonstrated high contraceptive efficacy, a predictable bleeding pattern, and a good safety and tolerability profile in daily users [ 13 , 14 ]. In the current analyses, we have pooled results of these two phase 3 trials to analyze the contraceptive efficacy of the entire cohort of participants and to assess if contraceptive efficacy is modified by participant characteristics including age, prior contraceptive use, and body mass index (BMI). Pooled bleeding and safety results from the Phase 3 studies are presented in separate publications.

Materials and methods
We performed pooled analyses of data from two multicenter, open-label phase 3 trials to evaluate the contraceptive efficacy of E4/DRSP for up to 13 cycles. These trials enrolled participants from 70 centers in the US and 7 centers in Canada between August 2016 and November 2018, and from 59 centers in Europe and 10 centers in Russia between June 2016 and April 2018. Independent ethics committees or institutional review boards from each center reviewed and approved the study protocols. Investigators conducted the trials in accordance with Good Clinical Practice guidelines and  [ 13 , 14 ], which included an upper BMI limit of 35 kg/m 2 . Participants agreed to use E4/DRSP for up to thirteen 28-day cycles (12 months) as their only method of contraception. After providing informed consent and completing screening evaluations, participants received treatment with E4/DRSP (Haupt Pharma, Münster, Germany) packaged in a blister pack of 24 tablets containing E4 15 mg (as monohydrate, equivalent to 14.2 mg anhydrous)/DRSP 3 mg and 4 placebo tablets with instructions to take one tablet daily for up to thirteen 28-day cycles. Investigators instructed participants not currently using hormonal contraception to begin treatment on the first day of their next menses. Investigators instructed those that switched from another combined hormonal contraceptive or progestin-only pill to start treatment on the day that they would have initiated their next pill pack, patch, or ring. Participants performed a urine pregnancy test prior to starting the study drug.
Investigators conducted study follow-up visits at Cycles 2, 4, 7, 10, and at end of treatment (Cycle 13 or discontinuation). Participants completed a daily paper diary to record medication intake, use of other contraceptives (hormonal or barrier methods), and sexual intercourse. During each study visit, a study coordinator reviewed the diary and collected empty study drug packets to check treatment compliance. We considered any day without a diary entry as a day with no pill intake. Participants completed a urine pregnancy test before first pill intake, following any treatment cycle without withdrawal bleeding, and at the end of treatment.
We included all participants who used at least one E4/DRSP pill and had at least one follow-up contact in the analyses. We defined the primary efficacy endpoint as the Pearl Index (PI) in participants 16 to 35 years (at screening) in accordance with regulatory agency age criteria, calculated as the number of pregnancies per 100 woman-years of exposure during at-risk 28-day cycles. We defined any reported/confirmed pregnancy as "on-treatment pregnancy" if the investigator estimated the conception date ≤7 days after the last intake of study drug (with E4/DRSP or placebo pill), based on the FDA definition. We considered cycles at-risk if the participant self-reported study drug use in the diary, having intercourse ≥1 time in that cycle, and no use of other contraceptive methods. We also evaluated the overall PI using the EMA definition (conception date ≤2 days after the last intake of study drug), method-failure PI (pregnancy occurred with self-reported correct E4/DRSP intake and no use of excluded medications known to interact with oral contraceptives), life-table pregnancy rates, and PIs according to subcategories.
We calculated PIs by age group (16-25 years, 26-35 years, 36-50 years), along with further subcategorization by contraceptive history (starters, switchers), BMI class ( < 25 kg/m 2 , ≥25-29.9 kg/m 2 , ≥30 kg/m 2 ), race (Asian, Black, Other, White) and smoking status (former smokers, current smokers, nonsmokers) for age groups 16 to 25 years and 26 to 35 years. Starters included persons who had not used hormonal contraception within three months prior to E4/DRSP initiation (including those who had never used hormonal contraception [referred to as true new users]), while all others were defined as switchers.
For the primary efficacy group 16 to 35 years, we further evaluated PIs by subgroups of age (16-25 years vs 26-35 years), BMI ( ≥30 kg/m 2 vs < 30 kg/m 2 ), contraceptive history (starters vs switchers), gravidity (at least one pregnancy before study vs no pregnancies), smoking status (current or former smoker vs never smoker), race (Asian or Black or Other vs White), region (US/Canada vs Europe/Russia) and compliance (low compliance vs high compliance). Treatment compliance was defined as the reported number of pills taken divided by the expected number of pills taken based on the duration of participation, with ≥99% of expected pills defined as high compliance. We also evaluated compliance by subgroups. We calculated PIs with a 95% confidence interval (CI) assuming an underlying Poisson distribution. We used life-table analysis (Kaplan-Meier estimates and 95% CIs) to calculate the cumulative pregnancy rate of on-treatment and method-failure pregnancies through 13 cycles. To adjust for the effects of confounding on these multiple efficacy comparisons in the primary efficacy group, we performed multivariable analysis using a Cox regression model with hazard ratios (HR) and 95% Wald Confidence Limits to assess confounding by age, BMI, past hormonal contraceptive use, gravidity, smoking status, race, region, and compliance. We used nonparametric tests (Wilcoxon for 2 levels and Kruskal Wallis for more than 2 levels) for subgroup comparisons for self-reported compliance. We performed all statistical analyses using SAS software (version 9.4) for Windows.

Results
The primary efficacy population included one thousand six hundred seventy-four 16 to 35 year old participants in the US/Canada trial and one hundred three hundred fifty three 18 to 35 year old participants in the Europe/Russia trial. Participant characteristics for the primary efficacy analyses are presented in Table 1 with additional data for participants 36 to 50 years and by study location in Supplemental Tables 1 and 2 ( Fig. 1 ). Among 16 to 35-year olds, the median self-reported compliance with daily pill intake was 100% (interquartile range [IQR] 99.5%-100%) across all cycles and 100% with the lower IQR > 99% for all subgroups.
The PI was 1.61 (0.94-2.57) pregnancies per 100 women-years in participants 16 to 25 years and 1.43 (0.78-2.40) pregnancies per 100 women-years in those 26 to 35 years ( Table 2 ). Overall, we found no clinically important differences in the unadjusted PIs for the primary efficacy group age categories with further stratification by subgroups (BMI, past hormonal contraceptive use, race, and smoking status; Table 3 ). The efficacy results from the pooled analyses of participants > 35 years at screening are presented in Supplemental Table 3.
In women 16 to 35 years, the corresponding PIs for BMI classes < 25 kg/m 2 , 25 to 29.9 kg/m 2 and ≥30 kg/m 2 , were 1.14 (0.   In multivariable analysis of markers of efficacy in the primary efficacy group ( Table 4 )

Discussion
The pooled PI for E4/DRSP in 16 to 35 year olds of 1.52 (1.04-2.16) pregnancies per 100 women-years and life-table contraceptive protection of 98.7% demonstrates high contraceptive efficacy over 1 year of use. We found higher PIs in the individual primary efficacy study conducted in the US/Canada (2.65, 95% CI 1.73-3.88) [13] compared with that conducted in Europe/Russia (0.47, 95% CI 0.15-1.11) [14] , a phenomenon reported previously [15][16][17] . Fundamental differences in sexual education and health service provision between US and Europe may explain some of the differences in pregnancy rates [18] , as well as other differences in socioeconomic and education status in study participants [15] . In our pooled analysis, we found a significant difference in self-reported compliance between Europe vs US participants.
More recently approved combined hormonal contraceptives tend to have higher PIs than those approved decades earlier. Trussell and Portman [19] coined the term "Creeping Pearl" in a 2013 review of increased rates of contraceptive failures in recent versus older hormonal contraceptive trials. They identified more frequent and sensitive pregnancy testing and less adherent participants as the two most likely important contributors to the increased PI in recent trials.
Our results provide evidence of high contraceptive efficacy across a diverse group of users. Strengths of this pooled analyses include a large number of participants and a diverse population, including women with BMI ≥30 kg/m 2 . Although we identified small PI differences within subgroups, all remain in a highly effective range. We did not find an association between obesity and lower efficacy of E4/DRSP in our multivariable analysis. The inclusion of a relatively large proportion (15%) of obese partic-ipants supports contraceptive efficacy in this subgroup. Previous studies examining other hormonal contraceptives suggest an association between obesity and oral contraception failure [ 11 , 20 ]. Studies have not clarified whether these differences occur due to progestin-specific pharmacokinetic differences, adherence, or both [ 11 , 21 ].
Multivariable analysis in the primary efficacy group found prior gravidity, Black race, younger age, and low compliance as independent risk factors for pregnancy in this pooled cohort. The lower PI with increasing age likely reflects decreasing fecundity and more consistent pill taking [22] . The association between Black race and efficacy likely reflect other unmeasured variables, such as socioeconomic status and other social factors, or genetic variants affecting hormone metabolism [23][24][25] . The majority of Black race participants were from the US (98%), suggesting that race itself may not be an independent risk factor but, instead, is reflective of underlying social issues that may include systemic racism within healthcare [26] .
Limitations include the open-label noncomparator design common to phase 3 contraceptive efficacy studies. While pooling of results from two large phase 3 trials of the same contraceptive formulation with internal consistency improves confidence in the efficacy findings, direct comparison to other contraceptive formulations require caution. The compliance data comes from participant reported diaries; accordingly, we have no objective means to confirm the accuracy of this self-reported information. Most participants were white (82.9%) and from the United States (50.6%); therefore, all results may not be generalizable. The majority of nonwhite and obese participants were enrolled in US study sites; thus, associations between race and obesity may not be generalizable. The study enrolled participants with an upper BMI limit of 35 kg/m 2 , so the findings do not reflect a population with very high BMI.
The E4/DRSP formulations represents the first pharmaceutical compound formulated with the natural estrogen E4 that has been approved for clinical use. In this pooled analysis of two phase 3 clinical trials examining E4/DRSP in a 24/4-day regimen for 1 year of usage, this oral contraceptive showed high contraceptive efficacy  overall and in subgroups stratified by age, contraceptive history and BMI.