Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone only pill.

Abstract Introduction Approximately 100 million women currently use combined oral contraceptives. Combined oral contraceptives use is associated with increased risk of venous thromboembolic events and cardiovascular disease. Progestin‐only pills do not increase the risk of venous thromboembolic events, stroke and myocardial infarction but are associated with a poor cycle control. A novel estrogen‐free pill containing only drospirenone (DRSP) was developed to improve bleeding pattern, tolerability and acceptance without increasing venous thromboembolic events risks in contraception. Material and methods Two prospective, multicenter Phase III studies in healthy women aged 18‐45 years were performed to demonstrate the efficacy and safety of a drospirenone‐only pill in a regimen of 24 days of 4 mg of drospirenone tablets followed by 4 days of placebo. A total of 1571 women (14 329 exposure cycles) were analyzed: 713 patients in the 13‐cycle study 1 with 7638 exposure cycles and 858 patients in the 9‐cycle study 2 with 6691 exposure cycles. The primary endpoint was the overall Pearl index, calculated for each study separately, and for both pooled. As main secondary efficacy endpoint, the “method failure Pearl index” including all pregnancies during “perfect medication cycles” was evaluated. EudraCT registration numbers: 2010‐021787‐15 & 2011‐002396‐42. Results Calculations on pooled studies 1 and 2 with 1571 patients gave an overall Pearl index (based on 14 329 cycles) of 0.7258 (95% CI 0.3133 to 1.4301). No single case of deep vein thrombosis or pulmonary embolism and only one case of hyperkalemia were reported. Additional information such as laboratory parameters, body mass index, bodyweight, heart rate and blood pressure showed no statistically significant changes due to the treatment. Conclusions This is the first report of a new drospirenone‐only oral contraceptive providing clinical efficacy similar to combined oral contraceptives, with a good safety profile, and favorable cycle control.


| INTRODUC TI ON
Various effects of progestogens, in addition to inhibition of ovulation, have been identified, such as protection against endometrial and ovarian cancer, relief of dysmenorrhea and endometriosis symptoms, and decreased menstrual flow. 1 4 The most frequent side effect of the continuous use of progestogens is irregular bleeding. 6 The progestogen-only pill (POP) containing 75 μg desogestrel daily is taken continuously without a 7-day break. Desogestrel inhibits ovulation and is as effective as combined hormonal contraceptives. No major health risks are known, and it has a Pearl index (PI) like COCs. It also alleviates menstrual migraine, pain in patients with endometriosis, and hypermenorrhea and dysmenorrhea. [7][8][9] Irregular bleeding together with a stringent daily timing and missed pill rules may affect contraceptive reliability. For these reasons, despite their safe and efficacious profile, POPs are still not widely used and there is a need for new estrogen-free products.
A new estrogen-free contraceptive containing 4 mg drospirenone (DRSP) has been developed to address this need.
Drospirenone is a unique progestogen derived from spirolactone that closely matches the properties of progesterone. It has antimineralocorticoid and antiandrogenic properties. 10 A 4-mg dose of DRSP was selected after completion of pharmacokinetic and pharmacodynamic studies. 11 Multiple exposure to DRSP 4 mg demonstrated a lower systemic exposure of DRSP compared with 20 mg ethinylestradiol/3 mg DRSP. Additional testing with 4 mg DRSP demonstrated inhibition of ovulation similar to desogestrel 75 μg for two 28-day cycles. 10,12 Although the dosage of the new formulation is higher than the dosage of other POP when compared to their dosage in COC, no safety concerns are expected, as ethinylestradiol is known to be a potent inhibitor of CYP3A4 and of SULT1A1, resulting in a significantly higher serum level of DRSP in combined formulations. 13,14 The aim of the presented studies was to assess the contraceptive efficacy of the DRSP-only pill and to provide safety information.
Tolerability regarding a bleeding pattern in comparison with the existing POP was a secondary aim of these trials.

| Study medication
The study medication was one tablet containing 4 mg non-micronized DRSP per day, via oral route, with consecutive administration of 24 active tablets and four placebo tablets, and no tablet-free interval between two consecutive cycles.
Desogestrel 0.075 mg (in a regimen of 28 active pills) was the comparator for safety in study 2. Randomization to DRSP or desogestrel in a 5:2 ratio was performed by a contract research organization (Scope International AG, Mannheim, Germany) using a validated system that automates the random assignment of treatment groups to randomization numbers. During the study, the subjects and all personnel involved in the conduct and interpretation of the trial, were blinded to the medication codes. Compliance was measured using an electronic diary.

| Duration of studies
The duration of treatment intake in study 1 was 13 cycles of 28 days, with a follow-up visit without treatment 10-28 days after the last study medication. The duration of treatment intake in study 2 was 9 cycles of 28 days, with a follow-up visit without treatment performed 7-10 days after the last study medication.

| Study populations
Inclusion criteria for these studies were: women of child-bearing potential, at risk of pregnancy, agreeing to use only the study medication for contraception for the duration of the study treatment, aged 18-45, with a systolic blood pressure <140 mmHg and a diastolic blood pressure <90 mmHg.

Key message
A new estrogen-free contraception containing 4 mg drospirenone in a 24/4 cycle regimen was shown to be a safe and effective option with a Pearl index of 0.72 improving cycle control in comparison with established estrogenfree contraceptives.

| Primary efficacy endpoint
The primary efficacy criterion was the overall Pearl Index (PI), calculated as follows: The overall PI included all pregnancies which occurred during the study. Pregnancies following premature termination of the study medication were excluded from calculations.

| Secondary efficacy endpoints
The "method failure PI" included all pregnancies during "perfect medication cycles"; defined as sexually active cycles without additional contraception where the e-diary documented regular pill intake during the scheduled active cycle period (days 1-24), excluding cycles with ≥4 days forgotten tablets/missed diary entries, ≥2 consecutive days with forgotten tablets/missed diary entries in the active cycle period or protocol deviations affecting the cycle.

| Safety
Adverse events (AEs) reported by the women or observed by the clinical investigator during the study were registered using the case report form (CRF), including duration, causality assessed by investigator, seriousness, severity, frequency, treatment, action taken and outcome.
Deep vein thrombosis or pulmonary embolism and hyperkalemia were considered AEs of special interest and led to discontinuation.

| Sample size
According to European Medicines Agency requirements, the overall PI may be evaluated from more than one study. 12 For an assumed PI <1.0, the number of cycles needed to fulfill the precision requirement with 90% power is 12.337. Thus 6169 cycles should be collected in each of the two studies, requiring 685 evaluable subjects with a treatment duration of 13 cycles in study 1 and 9 cycles in study 2.
Study 1 was performed to have at least half the evaluable cycles needed for an assumed PI <1.0 with a power of 90%. Considering a possible drop-out rate of 25%, 700 women were to be enrolled in the study to give ≥6169 evaluable cycles. The cycles were collected such that ≥400 women would have 13 cycles, as specified in European Medicines Agency Guidelines. 12 In study 2, to test non-inferiority of the bleeding pattern between the two treatment groups (assuming a 24% proportion of the control group, 9% non-inferiority margin, one-sided type I error 2.5, 80% power, and 2:1 treatment allocation rate) a sample size of 531 in the DRSP group and of 266 in the desogestrel group was required. To prove superiority under the same assumptions, a sample size of 443 in the DRSP group and of 222 in the desogestrel group was required.
Considering a possible drop-out rate of 20%, to attain a 5:2 ratio, 857 DRSP and 333 desogestrel-treated women should be enrolled.

| Statistical analyses
In each study, efficacy analyses were performed on the full-analysis set (FAS), defined as all subjects who took at least one dose of the study medication and who were not pregnant at entry.
The primary and secondary efficacy endpoints were calculated for each study separately and for both studies pooled, as well as their 95%CI.
For safety analyses, all AEs were coded according to MEDDRA version 15.0. All AEs were summarized using default summary statistics calculated from the number and percentage of subjects with AEs according to primary MEDDRA system organ class (SOC) and preferred term (PT). Summary and incidence of AEs were to be presented for each subgroup as well.
For tolerability analyses in study 2, rates of overall or unscheduled bleeding/spotting were compared between treatment groups using chi-square tests. Significance between treatment groups was documented with a P value of <0.001.

| Baseline characteristics
A total of 1571 women (14 329 exposure cycles) were treated with 4 mg DRSP: 713 patients in the 13-cycle study 1 with 7638 exposure cycles and 858 patients in the 9-cycle study 2 with 6691 exposure cycles (see Figures 1 and 2). Demographic data are presented in Table 1.  Table 2.

| Efficacy based on the primary and secondary endpoints in the whole population
The baseline characteristics of the eight pregnant women were identical to the non-pregnant women. No ectopic pregnancy was recorded.

| Efficacy based on the primary and secondary endpoints in women aged ≤35 years
During study 1, all pregnancies occurred in women aged ≤35 years. In The cumulative 13-cycle pregnancy ratio was 0.64% (95%CI 1-1.37%).
During study 2, all pregnancies occurred in women aged ≤35 years.

| Bleeding profile
In both studies, and in all treatment groups, there was a decrease over time in the overall number of patients with bleeding or spotting and in the number of unscheduled bleeding or spotting. The highest rates were observed during the first reference period, Cycle 2 to Cycle 4, in all studies and treatment groups. There was a significantly lower rate in the DRSP 4 mg group as compared with the desogestrel group in study 2 (79.9 vs 86.5% for overall bleedings, P = 0.0324; 67.9 vs 86.5% for unscheduled bleedings, P <0.001).
Early study withdrawals associated with abnormal bleeding were reported for four (2%) patients during the 13-cycle study 1 and for three (3%) DRSP 4 mg patients and six (6%) desogestrel patients in the 9-cycle study 2 (see Table 3).

| Safety
No case of deep vein thrombosis or pulmonary embolism was re- in study 1 and 19.8% in study 2. The most frequently reported reasons for early study withdrawal were adverse events (12.3% in study 1 and 9.6% in study 2). It is well established that estrogens in combined hormonal contraceptives are the primary cause of the elevated risk of thromboembolic events. 16 Epidemiological studies have also shown that the

| CON CLUS ION
This new DRSP-only pill provides clinical contraceptive efficacy similar to currently marketed COCs containing DRSP, with a good safety profile, widening the group of women able to use this contraceptive method. 23 The strengths of these trials were the large program, methodically well conducted, providing clinically meaningful information on a novel POP. The weakness is the number of cycles to assess the PI properly are still not enough, even if indicative, to draw conclusions regarding the risk of VTE.
Future research must focus on the general and widespread use of this new contraceptive method and epidemiological data must be obtained to align the promising results of these two primary studies.