Contraception 91 (2015) 113 – 120
Original research article
Bleeding pattern and cycle control of a low-dose transdermal contraceptive patch compared with a combined oral contraceptive: a randomized study☆,☆☆,★ M. Merz a,⁎, R. Kroll b , R. Lynen c , K. Bangerter a a Bayer Pharma AG, 13353 Berlin, Germany Women's Clinical Research Center, Seattle, WA, USA c Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ, USA Received 17 March 2014; revised 25 September 2014; accepted 4 October 2014 b
Abstract Objective(s): The aim of this study was to investigate the bleeding pattern and cycle control of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a combined oral contraceptive (COC) containing 0.02 mg EE and 0.1 mg levonorgestrel (LNG). Study design: In this phase III, randomized, controlled, double-blind, double-dummy, multicenter trial, healthy women aged 18–45 years (smokers aged 18–35 years) received either the EE/GSD patch and a placebo tablet (n= 171), or a placebo patch and the COC (n= 175) for seven 28-day cycles. Bleeding control was assessed in two 90-day reference periods. Results: Mean number of bleeding/spotting days was comparable across treatment groups in both reference periods (pN.05). Mean number of bleeding/spotting episodes was also comparable in reference period 1; however, there were fewer bleeding/spotting episodes for COC in reference period 2 (3.4 versus 3.1; p=.01). Mean length of bleeding/spotting episodes was comparable across treatment groups for both reference periods (pN.05). Withdrawal bleeding occurred consistently in both groups over the entire treatment period, but its absence was more common in the COC group in cycles 4 and 6 of reference period 2 (pb.01). Intracyclic bleeding was comparable between groups. Conclusion(s): Bleeding pattern and cycle control with the EE/GSD patch was comparable to an EE/LNG-containing COC. Implications statement: The findings suggest that bleeding patterns with the EE/GSD patch are similar to an EE/LNG-containing COC, except for absence of withdrawal bleeding, which was less common in patch users. The EE/GSD patch may constitute an additional contraceptive option for women. © 2015 Elsevier Inc. All rights reserved. Keywords: Transdermal; Female contraception; Contraceptive patch; Bleeding pattern; Cycle control
1. Introduction ☆
Registration no. NCT00920985. Acknowledgement of funding. This study was funded by Bayer Pharma AG, Berlin, Germany. Editorial assistance for the manuscript was provided by Ogilvy 4D, Oxford, UK, and also funded by Bayer Pharma AG. ★ Financial disclosures. Martin Merz and Keith Bangerter are salaried employees of Bayer Pharma AG, Berlin, Germany. Robin Kroll has received research grants and/or consulting fees for Bayer Pharma AG, Teva, Watson, Agile, Merck, Noven, GSK, Alder, Amgen, Warner Chilcott, Abbott, Trimel, Ferring, Palatin, Targacept and Salix. Richard Lynen is a full-time employee of Bayer HealthCare Pharmaceuticals Inc. and owns stock in the company. ⁎ Corresponding author at: Bayer Pharma AG, Müllerstr. 178, 13353 Berlin, Germany. Tel.: + 49 30 468 11453; fax: + 49 30 468 91453. E-mail address: [email protected] (M. Merz). ☆☆
http://dx.doi.org/10.1016/j.contraception.2014.10.004 0010-7824/© 2015 Elsevier Inc. All rights reserved.
Daily use of oral contraceptives is the most common means of female contraception in the developed world [1]; however, poor compliance has been reported due to the daily dosing schedule [2]. Further issues with this method of contraception include low bioavailability of ethinyl estradiol (EE; 38–48%) [3], the tendency for serum concentrations of estrogens and progestins to fluctuate widely [4], and large intra- and interindividual pharmacokinetic variations of serum hormone levels due to oral administration [5]. In comparison with oral contraceptives, data from transdermal contraceptive patch technology suggest effective drug
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absorption and delivery of relatively constant serum hormone concentrations [4,6]. The need to apply three transdermal patches (rather than taking 21 tablets) per cycle may be beneficial in terms of perceived convenience and compliance [7]. Both EE and gestodene (GSD) are effectively absorbed into the systemic circulation through the skin and are therefore suitable hormones for use in transdermal contraceptives [4,8]. The use of both hormones in combined oral contraceptives (COCs) is well documented, with EE being the most potent estrogen agonist currently available [9] and GSD being a well-researched progestin with an established safety and efficacy profile, and more than two decades of use in Europe [10–12]. An additional advantage of GSD is the low absolute dose required for contraceptive efficacy [13], which allows for a small patch size. A problem associated with hormonal contraceptives is unscheduled and prolonged uterine bleeding – one of the often-cited reasons that women stop using these agents [14]; thus, studies evaluating their effect on bleeding patterns and cycle control can provide clinically useful data for any new hormonal contraceptive. An additional transdermal option – a once-a-week contraceptive patch – has been developed with transparent, transdermal technology delivering low doses of EE and GSD. This patch provides the same systemic exposure as observed after oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD, based on an analysis of relative bioavailability [15]. The primary objective of the present study was to investigate, and reliably describe, the bleeding pattern and cycle control parameters of the EE/GSD patch in comparison with a COC containing EE and levonorgestrel (LNG).
2. Materials and methods 2.1. Study design This was a phase IIIa, double-blind, double-dummy, randomized, controlled, parallel-group, multicenter trial conducted at 28 centers in the United States. The main objective was to investigate the bleeding pattern and cycle control parameters of a patch containing 0.55 mg EE and 2.1 mg GSD in comparison with a COC containing 0.02 mg EE and 0.1 mg LNG. Additional objectives of the study were to investigate the contraceptive efficacy and safety profile of the EE/GSD patch. Compliance and subjective user assessments were also evaluated. The conduct of this clinical study met all local legal and regulatory requirements in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization Guideline E6: Good Clinical Practice. The protocol was reviewed and approved by each study site's internal ethics committee or review board, and written informed consent was obtained from each participant before the start of the study.
2.2. Study population Participants were healthy women, 18–45 years of age (18–35 years, if smokers), who were seeking contraception. When asked about contraceptive use in the 28 days prior to screening, 50.0% of women (n= 173) reported having used hormonal contraception, 36.1% (n= 125) had used barrier methods, 12.7% (n= 44) had not used contraception, and 1.2% (n= 4) had used ‘other’ methods, for example, vasectomy. Percentages were similar in both groups. Key exclusion criteria included pregnancy and lactation (fewer than three menstrual cycles since delivery or abortion, or cessation of lactation); any disease or condition that could affect the pharmacokinetics of the study drug or worsen during hormonal treatment; undiagnosed abnormal genital bleeding; abuse of alcohol, drugs, or medicines; and medical contraindications to hormonal contraception. Women with a presence or history of venous or arterial thrombotic/thromboembolic events (e.g., deep venous thrombosis, pulmonary embolism, myocardial infarction), or conditions that could increase their risk (e.g., hereditary predisposition), were also excluded. No participant was excluded on the basis of body mass index (BMI). At the suggestion of the FDA, at least a third of the women should not have been using hormonal contraceptives within 3 months before their study start date to eliminate any carryover effect. 2.3. Study treatment Women were randomized (1:1) to one of two parallel groups, receiving either the EE/GSD patch and a placebo tablet, or the COC tablet and a placebo patch. For each of the seven 28-day cycles, all women applied one patch (either the EE/GSD patch or a placebo) on days 1, 8, and 15 to the outer upper arm, abdomen, or buttocks. The third patch was removed on day 22, and no patch was worn on days 23–28. In parallel, all women also took one tablet daily (either the placebo tablet or the COC tablet) for 21 days at the same time of the day (± 2 h), followed by a 7-day, tablet-free interval. The application of the patch and ingestion of the tablet were to occur at the same time. If a patch was detached for less than 24 h, the patch was to be reapplied; if no longer adhesive, a replacement patch was to be applied. In either case, the patch was to be worn until the next scheduled change. If a patch became detached for 24 h or more, or the participant was unsure about how long the patch was detached, they were to restart the current cycle by applying a new patch. Restarting meant the application of three patches during the subsequent 3 consecutive weeks followed by a 7-day, patch-free interval. The study included a screening visit, admission visit, treatment visits and final visit. Study visits took place during treatment cycles 3 and 7, with the final examination after cycle 7. Self-reported outcome measures, assessed using diary cards, were the primary method of evaluating bleeding pattern, cycle control, and compliance.
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2.4. Study assessments 2.4.1. Efficacy assessments Bleeding pattern was described in terms of number of bleeding/spotting days and episodes in each of two 90-day reference periods. Cycle control was evaluated according to classifications of bleeding as either withdrawal (scheduled) bleeding (i.e., a bleeding or spotting episode that began during the hormone-free period or started not more than 4 days before the progestin withdrawal), or intracyclic (unscheduled) bleeding [16]. Bleeding intensity was categorized as none, spotting, light, normal, or heavy [16]. Additional efficacy variables of interest included the number of unintended pregnancies while receiving treatment up to 7 days after removal of the last patch, that is, upon completing the 7-day, patch-free interval of cycle 7. 2.4.2. Safety and compliance assessments Safety was assessed by means of adverse event monitoring, general physical and gynecologic examination (including breast examination by palpation), clinical laboratory tests, vital signs, body weight and height, and cervical smear testing. Laboratory evaluations included hematology, general serum chemistry, liver enzymes, carbohydrate metabolism, and lipids. Treatment compliance and patch adhesion were evaluated based on information recorded by the participants in their diaries. Compliance was calculated as a percentage of actual versus planned treatment days per cycle.
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withdrawal bleeding were analyzed using the two-sample t test. These post hoc tests were unrelated to any power analysis. No statistical analyses were undertaken to analyze between-treatment differences in the occurrence of adverse events.
3. Results 3.1. Study population Of the 593 women screened, 397 were randomized to one of the two contraceptive regimens. Unless otherwise indicated, data in the results section relate to the FAS, which included 346 women (171 in the EE/GSD patch group and 175 in the COC group) (Fig. 1). A total of 178 women were included in the PPS (89 in each group). Baseline demographics are shown in Table 1. Major protocol deviations resulting in exclusion from the PPS (participants could have more than one) for the EE/GSD patch and COC were as follows: treatment deviations in 78 women (45.6%) and 84 women (48.0%), respectively; improper diary documentation in 14 women (8.2%) and 10 women (5.7%), respectively; and treatment despite not meeting inclusion/exclusion criteria in 1 woman (0.6%) in the COC group. Withdrawal by subject was 12.3% in the EE/GSD patch group and 8.0% in the COC group. Subjects were not required to provide a reason for choosing to withdraw and, in most cases, did not.
2.5. Statistical analysis The analyses in this study were purely descriptive in nature, and the study was not designed to show equivalence or noninferiority. Thus, no formal sample size calculation was undertaken, but a study with 400 participants was expected to provide sufficient data to describe the menstrual bleeding pattern reliably based on results from previous studies [16]. All variables were analyzed according to their type using descriptive statistics (e.g., frequencies for categorical data and arithmetic mean, standard deviation [SD], minimum, quartiles, median and maximum for metric data). Statistical analyses were performed using SAS® software (release 9.1 or higher; SAS Institute Inc., Cary, NC, USA). Analyses were based on the full analysis set (FAS), defined as all women who were randomized, had applied at least one patch, and for whom at least one observation after admission to treatment was available. A per-protocol set (PPS) was also defined, including all women from the FAS who had no major protocol deviations considered to affect the main efficacy variables. Post hoc statistical analyses were conducted in order to test for treatment differences in bleeding pattern and cycle control outcomes. Data related to the number of women with withdrawal bleeding and intracyclic bleeding, and the maximum intensity of these two measures, were analyzed using the Fisher's exact test or the chi-square test. Data related to bleeding pattern outcomes and the length of
3.2. Treatment compliance Mean compliance was good in both treatment groups. Mean percentages for treatment compliance were 97.9% for the EE/GSD patch group and 99.8% for the COC group. 3.3. Bleeding pattern During treatment, the overall bleeding profile was similar between treatment groups. The mean number of bleeding/ spotting days was comparable for the EE/GSD patch and COC in reference period 1 (20.9 versus 21.3, respectively; pN.05) and reference period 2 (17.0 versus 16.2, respectively; pN.05). Similar results were found for the mean number of bleeding-only days, spotting-only days and extend to the PPS population. The mean numbers of bleeding/spotting episodes for the EE/GSD patch and COC were comparable in reference period 1 (3.2 versus 3.3, respectively; pN.05); however, there were fewer bleeding/spotting episodes in the COC group as compared to the EE/GSD patch group in reference period 2 (3.1 versus 3.4, respectively; p=.01). The same finding was observed in the PPS population, that is, fewer bleeding/ spotting episodes in the COC group as compared to the EE/GSD patch in reference period 2 (3.1 versus 3.5, respectively; p=.01), corresponding to more women in the COC group with absence of scheduled withdrawal bleeding in cycles 4 and 6.
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Fig. 1. Disposition of study participants. *A subject was considered to have completed the treatment if at least one patch was applied after day 14 of cycle 7 according to the subject's diary or a completion date was available that was at least 182 days after start of treatment. †A subject was considered to have completed the study when she had completed the treatment period and the follow-up visit. The percentages are based on the number of subjects randomized. EE/GSD patch, 0.55 mg EE and 2.1 mg GSD; COC, 0.02 mg EE and 0.1 mg LNG. COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel.
Mean length of bleeding/spotting episodes was comparable for the EE/GSD patch group and the COC group in reference period 1 (5.46 days versus 5.80 days, respectively; pN.05) and reference period 2 (5.10 days versus 5.21 days, respectively; pN.05). Similar findings were observed for the PPS. Results for bleeding pattern indices are summarized in Table 2. 3.4. Cycle control
groups. For withdrawal bleeding intensity for the FAS and PPS populations, the percentage of spotting or light bleeding was generally higher in the COC group than in the EE/GSD patch group (Fig. 2b), whereas the percentage of women with normal or heavy bleeding was higher in the patch group during cycles 1 to 3 (pb.05) and, additionally, in cycle 5 of the PPS (pb.05). There were no notable treatment differences in cycles 4–7 (pN.05) of the FAS and cycles 4, 6, and 7 of the PPS analysis.
3.4.1. Withdrawal bleeding For both the FAS and PPS populations, scheduled withdrawal bleeding episodes occurred very reliably in both treatment groups over the entire treatment period (pN.05) (Fig. 2a). However, in the FAS population, absence of scheduled withdrawal bleeding was more often observed in women using COC in treatment cycles 4 (10.3% versus 1.7%; pb.01) and 6 (12.6% versus 0.9%; pb.01), corresponding to the second reference period. The median length of these episodes was 5 days for all cycles in both treatment
3.4.2. Intracyclic bleeding In the FAS and PPS, a similar number of subjects in both treatment groups experienced episodes of intracyclic bleeding/ spotting (pN.05) (Fig. 3a). Maximum intensity of intracyclic bleeding/spotting episodes was generally comparable between groups for the FAS and PPS, except in cycle 1 where the percentage of light but also heavy bleeding was higher in the COC group, and the percentage of normal bleeding was higher in the EE/GSD group (pb.01) (Fig. 3b).
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Table 1 Demographics and baseline characteristics of participants at screening (FAS)
Age, height, body weight, BMI c mean±SD (range) Age (years) Height (cm) Body weight (kg) BMI (kg/m 2) Race, n (%) Asian Black/African American Multiple Native Hawaiian/other Pacific Islander Not reported White Ethnicity, n (%) Not Hispanic/Latino Hispanic/Latino Not reported Smoking history, n (%) Never Former Current Alcohol consumption, n (%) Abstinent Light Moderate
EE/GSD patch a n= 171
COC b n=175
29.1±7.3 (18–45) 164.6±6.9 (147–183) 70.7±16.5 (44–138) 26.1±5.9 (16–46)
27.2±6.8 (18–45) 164.5±7.9 (150–198) 73.9±18.8 (46–159) 27.3±6.5 (19–64)
5 (2.9) 29 (17.0) 2 (1.2) 1 (0.6) 2 (1.2) 132 (77.2)
4 (2.3) 35 (20.0) 2 (1.1) 1 (0.6) 0 (0.0) 133 (76.0)
154 (90.1) 14 (8.2) 3 (1.8)
158 (90.3) 17 (9.7) 0 (0.0)
117 (68.4) 27 (15.8) 27 (15.8)
125 (71.4) 28 (16.0) 22 (12.6)
49 (28.7) 113 (66.1) 9 (5.3)
47 (26.9) 113 (64.6) 15 (8.6)
a 0.55 mg EE and 2.1 mg GSD. b 0.02 mg EE and 0.1 mg LNG. c Weight and height were not reported by one subject each, and, therefore, BMI could not be calculated for two subjects. BMI, body mass index; COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel; SD, standard deviation.
3.5. Unintended pregnancies No pregnancies occurred during study treatment up to 7 and 14 days after the last day of using study contraception. 3.6. Safety The percentage of women experiencing at least one treatment-emergent adverse event (TEAE) was similar between the patch and COC groups (49.1% versus 50.9%, respectively). The most common drug-related TEAEs are listed in Supplementary Table 1. The overall rate of drugrelated discontinuations due to TEAEs was 8.2% for the patch compared with 4.6% for the COC. In both treatment groups, most discontinuations were due to skin reactions at the application site. 1 No clinically significant trends or safety signals were observed in the other safety parameters monitored. Most laboratory values were within normal limits at baseline and during the study. Heart rate and body weight remained stable over the course of the study. 4. Discussion The results of this study demonstrate that the EE/GSD patch is similar to the comparator COC in regard to bleeding 1
COC users were required to wear a placebo patch.
profile. The cycle control results are largely consistent with those of other methods of hormonal contraception. In a direct comparison with a patch containing 0.6 mg EE and 6 mg norelgestromin, the EE/GSD patch was largely comparable in terms of bleeding pattern and cycle control [17]. Furthermore, in a historical comparison with a 3 mg drospirenone/0.02 mg EE pill and a 0.015 mg desogestrel/ 0.02 mg EE pill, the EE/GSD patch displayed similar bleeding pattern and cycle control [18]. Overall, contraceptive efficacy in this study was good, with no pregnancies reported in the EE/GSD patch group. In both treatment groups, compliance was very high and the patch was generally well tolerated. Safety analyses revealed similar results for both study groups. The TEAEs that occurred during the study were in line with events expected in a young female population using a transdermal contraceptive. In terms of study limitations, the small sample size restricts the extent to which the data can be used to evaluate pregnancy and safety outcomes; however, data from a previous phase III study (n= 1,631) of the EE/GSD patch suggest good contraceptive efficacy, with an adjusted Pearl Index score of 0.81 [19]. Despite this, the risk of rare but pertinent events such as venous thromboembolism cannot reasonably be assessed here. Additional considerations include the descriptive nature of the analyses (which should not be overinterpreted to imply benefit), the relatively small number of cycles, the pragmatic use of participant diaries rather than direct, objective evaluation, and the use of paper
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Table 2 Mean number of bleeding/spotting days, mean number of bleeding/spotting episodes, and mean length of bleeding/spotting episodes, shown by treatment group and reference period (FAS). Length of each reference period was 90 days and p values for differences between treatment groups were pN.05, unless otherwise indicated EE/GSD patch a
COC b
Reference period 1 n= 127 Reference period 2 n= 111 Reference period 1 n=152 Reference period 2 n= 131 Number of bleeding/spotting days Mean±SD Median (range) Number of bleeding/spotting episodes (days) Mean±SD Median (range) Length of bleeding/spotting episodes (days) d Mean±SD Median (range)
20.9±7.8 20.0 (3–47)
17.0±5.7 16.0 (1–35)
21.3±9.7 20.5 (0–88)
16.2±5.8 16.0 (0–36)
3.2±0.9 3.0 (1–7)
3.4±1.0 c 3.0 (1–9)
3.3±1.0 3.0 (0–8)
3.1±0.8 c 3.0 (0–7)
5.46±2.0 5.0 (2–17)
5.10±1.6 5.0 (1–11)
5.80±6.9 5.0 (2–86)
5.21±1.6 5.0 (1–11)
a
0.55 mg EE and 2.1 mg GSD. b 0.02 mg EE and 0.1 mg LNG. c p=.01 for the comparison of EE/GSD patch versus COC. d n= 151 in reference period 1 and n= 130 in reference period 2. COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel.
diaries for the assessment of bleeding, rather than real-time electronic variants. Furthermore, as an exploratory study, it was not formally powered for comparisons. Future analyses
of bleeding data could benefit from the use of more standardized terminology, thus allowing for more direct comparison of data between studies [20].
a) EE/GSD patch COC
Percentage of women with withdrawal bleeding
100 90 80 70 60 50 40 30 20 10 0 1
2
3
4
5
6
7
Cycle
Percentage of women
b)
Heavy
Normal
Light
Spotting
100 80 60 40 20 0 1
2
3
4
5
Cycle EE/GSD patch
6
7
1
2
3
4
5
6
7
Cycle COC
Fig. 2. (a) Percentage of women with withdrawal bleeding, by treatment and cycle (FAS); (b) Percentage of women with withdrawal bleeding, by maximum intensity, treatment, and cycle (FAS). EE/GSD patch, 0.55 mg EE and 2.1 mg GSD; COC, 0.02 mg EE and 0.1 mg LNG. COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel.
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a) Percentage of women with intracyclic bleeding and/or spotting
25
EE/GSD patch COC
20
15
10
5
0
1
2
3
4 Cycle
b)
5
6
7
Heavy
Normal
Light
Spotting
100 Percentage of women
90 80 70 60 50 40 30 20 10 0 1
2
3
4
5
6
7
1
2
Cycle EE/GSD patch
3
4
5
6
7
Cycle COC
Fig. 3. (a) Percentage of women with intracyclic bleeding/spotting episodes, by treatment and cycle (FAS); (b) percentage of women with intracyclic bleeding/ spotting episodes, by maximum intensity, treatment, and cycle (FAS). EE/GSD patch, 0.55 mg EE and 2.1 mg GSD; COC, 0.02 mg EE and 0.1 mg LNG. COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel.
Strengths of this investigation include the randomized, double-blind, double-dummy design, and the lack of any restriction on inclusion based on BMI, which is in line with current recommendations on the inclusion of women in combined hormonal contraceptive studies without restrictions on body weight [20]. Where possible, this study was conducted in concordance with World Health Organization terminology and definitions [16] and complied with the recommendation of the FDA that at least a third of the women should not have been using hormonal contraceptives within 3 months before their study start date to eliminate any carryover effect. In conclusion, the findings of this exploratory study are indicative of comparable bleeding pattern and cycle control for the EE/GSD patch when compared with a COC containing EE/LNG. These preliminary results suggest a potential role for the EE/GSD patch as an additional contraceptive option for women. Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.contraception.2014.10.004. Acknowledgment The authors would like to acknowledge Keith Falconer of inVentiv Health Clinical for conducting the post-hoc
statistical analyses. Editorial assistance was provided by Ogilvy 4D, Oxford, UK, and funded by Bayer Pharma AG, Berlin, Germany.
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Original research article
Bleeding pattern and cycle control of a low-dose transdermal contraceptive patch compared with a combined oral contraceptive: a randomized study☆,☆☆,★ M. Merz a,⁎, R. Kroll b , R. Lynen c , K. Bangerter a a Bayer Pharma AG, 13353 Berlin, Germany Women's Clinical Research Center, Seattle, WA, USA c Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ, USA Received 17 March 2014; revised 25 September 2014; accepted 4 October 2014 b
Abstract Objective(s): The aim of this study was to investigate the bleeding pattern and cycle control of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a combined oral contraceptive (COC) containing 0.02 mg EE and 0.1 mg levonorgestrel (LNG). Study design: In this phase III, randomized, controlled, double-blind, double-dummy, multicenter trial, healthy women aged 18–45 years (smokers aged 18–35 years) received either the EE/GSD patch and a placebo tablet (n= 171), or a placebo patch and the COC (n= 175) for seven 28-day cycles. Bleeding control was assessed in two 90-day reference periods. Results: Mean number of bleeding/spotting days was comparable across treatment groups in both reference periods (pN.05). Mean number of bleeding/spotting episodes was also comparable in reference period 1; however, there were fewer bleeding/spotting episodes for COC in reference period 2 (3.4 versus 3.1; p=.01). Mean length of bleeding/spotting episodes was comparable across treatment groups for both reference periods (pN.05). Withdrawal bleeding occurred consistently in both groups over the entire treatment period, but its absence was more common in the COC group in cycles 4 and 6 of reference period 2 (pb.01). Intracyclic bleeding was comparable between groups. Conclusion(s): Bleeding pattern and cycle control with the EE/GSD patch was comparable to an EE/LNG-containing COC. Implications statement: The findings suggest that bleeding patterns with the EE/GSD patch are similar to an EE/LNG-containing COC, except for absence of withdrawal bleeding, which was less common in patch users. The EE/GSD patch may constitute an additional contraceptive option for women. © 2015 Elsevier Inc. All rights reserved. Keywords: Transdermal; Female contraception; Contraceptive patch; Bleeding pattern; Cycle control
1. Introduction ☆
Registration no. NCT00920985. Acknowledgement of funding. This study was funded by Bayer Pharma AG, Berlin, Germany. Editorial assistance for the manuscript was provided by Ogilvy 4D, Oxford, UK, and also funded by Bayer Pharma AG. ★ Financial disclosures. Martin Merz and Keith Bangerter are salaried employees of Bayer Pharma AG, Berlin, Germany. Robin Kroll has received research grants and/or consulting fees for Bayer Pharma AG, Teva, Watson, Agile, Merck, Noven, GSK, Alder, Amgen, Warner Chilcott, Abbott, Trimel, Ferring, Palatin, Targacept and Salix. Richard Lynen is a full-time employee of Bayer HealthCare Pharmaceuticals Inc. and owns stock in the company. ⁎ Corresponding author at: Bayer Pharma AG, Müllerstr. 178, 13353 Berlin, Germany. Tel.: + 49 30 468 11453; fax: + 49 30 468 91453. E-mail address: [email protected] (M. Merz). ☆☆
http://dx.doi.org/10.1016/j.contraception.2014.10.004 0010-7824/© 2015 Elsevier Inc. All rights reserved.
Daily use of oral contraceptives is the most common means of female contraception in the developed world [1]; however, poor compliance has been reported due to the daily dosing schedule [2]. Further issues with this method of contraception include low bioavailability of ethinyl estradiol (EE; 38–48%) [3], the tendency for serum concentrations of estrogens and progestins to fluctuate widely [4], and large intra- and interindividual pharmacokinetic variations of serum hormone levels due to oral administration [5]. In comparison with oral contraceptives, data from transdermal contraceptive patch technology suggest effective drug
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absorption and delivery of relatively constant serum hormone concentrations [4,6]. The need to apply three transdermal patches (rather than taking 21 tablets) per cycle may be beneficial in terms of perceived convenience and compliance [7]. Both EE and gestodene (GSD) are effectively absorbed into the systemic circulation through the skin and are therefore suitable hormones for use in transdermal contraceptives [4,8]. The use of both hormones in combined oral contraceptives (COCs) is well documented, with EE being the most potent estrogen agonist currently available [9] and GSD being a well-researched progestin with an established safety and efficacy profile, and more than two decades of use in Europe [10–12]. An additional advantage of GSD is the low absolute dose required for contraceptive efficacy [13], which allows for a small patch size. A problem associated with hormonal contraceptives is unscheduled and prolonged uterine bleeding – one of the often-cited reasons that women stop using these agents [14]; thus, studies evaluating their effect on bleeding patterns and cycle control can provide clinically useful data for any new hormonal contraceptive. An additional transdermal option – a once-a-week contraceptive patch – has been developed with transparent, transdermal technology delivering low doses of EE and GSD. This patch provides the same systemic exposure as observed after oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD, based on an analysis of relative bioavailability [15]. The primary objective of the present study was to investigate, and reliably describe, the bleeding pattern and cycle control parameters of the EE/GSD patch in comparison with a COC containing EE and levonorgestrel (LNG).
2. Materials and methods 2.1. Study design This was a phase IIIa, double-blind, double-dummy, randomized, controlled, parallel-group, multicenter trial conducted at 28 centers in the United States. The main objective was to investigate the bleeding pattern and cycle control parameters of a patch containing 0.55 mg EE and 2.1 mg GSD in comparison with a COC containing 0.02 mg EE and 0.1 mg LNG. Additional objectives of the study were to investigate the contraceptive efficacy and safety profile of the EE/GSD patch. Compliance and subjective user assessments were also evaluated. The conduct of this clinical study met all local legal and regulatory requirements in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization Guideline E6: Good Clinical Practice. The protocol was reviewed and approved by each study site's internal ethics committee or review board, and written informed consent was obtained from each participant before the start of the study.
2.2. Study population Participants were healthy women, 18–45 years of age (18–35 years, if smokers), who were seeking contraception. When asked about contraceptive use in the 28 days prior to screening, 50.0% of women (n= 173) reported having used hormonal contraception, 36.1% (n= 125) had used barrier methods, 12.7% (n= 44) had not used contraception, and 1.2% (n= 4) had used ‘other’ methods, for example, vasectomy. Percentages were similar in both groups. Key exclusion criteria included pregnancy and lactation (fewer than three menstrual cycles since delivery or abortion, or cessation of lactation); any disease or condition that could affect the pharmacokinetics of the study drug or worsen during hormonal treatment; undiagnosed abnormal genital bleeding; abuse of alcohol, drugs, or medicines; and medical contraindications to hormonal contraception. Women with a presence or history of venous or arterial thrombotic/thromboembolic events (e.g., deep venous thrombosis, pulmonary embolism, myocardial infarction), or conditions that could increase their risk (e.g., hereditary predisposition), were also excluded. No participant was excluded on the basis of body mass index (BMI). At the suggestion of the FDA, at least a third of the women should not have been using hormonal contraceptives within 3 months before their study start date to eliminate any carryover effect. 2.3. Study treatment Women were randomized (1:1) to one of two parallel groups, receiving either the EE/GSD patch and a placebo tablet, or the COC tablet and a placebo patch. For each of the seven 28-day cycles, all women applied one patch (either the EE/GSD patch or a placebo) on days 1, 8, and 15 to the outer upper arm, abdomen, or buttocks. The third patch was removed on day 22, and no patch was worn on days 23–28. In parallel, all women also took one tablet daily (either the placebo tablet or the COC tablet) for 21 days at the same time of the day (± 2 h), followed by a 7-day, tablet-free interval. The application of the patch and ingestion of the tablet were to occur at the same time. If a patch was detached for less than 24 h, the patch was to be reapplied; if no longer adhesive, a replacement patch was to be applied. In either case, the patch was to be worn until the next scheduled change. If a patch became detached for 24 h or more, or the participant was unsure about how long the patch was detached, they were to restart the current cycle by applying a new patch. Restarting meant the application of three patches during the subsequent 3 consecutive weeks followed by a 7-day, patch-free interval. The study included a screening visit, admission visit, treatment visits and final visit. Study visits took place during treatment cycles 3 and 7, with the final examination after cycle 7. Self-reported outcome measures, assessed using diary cards, were the primary method of evaluating bleeding pattern, cycle control, and compliance.
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2.4. Study assessments 2.4.1. Efficacy assessments Bleeding pattern was described in terms of number of bleeding/spotting days and episodes in each of two 90-day reference periods. Cycle control was evaluated according to classifications of bleeding as either withdrawal (scheduled) bleeding (i.e., a bleeding or spotting episode that began during the hormone-free period or started not more than 4 days before the progestin withdrawal), or intracyclic (unscheduled) bleeding [16]. Bleeding intensity was categorized as none, spotting, light, normal, or heavy [16]. Additional efficacy variables of interest included the number of unintended pregnancies while receiving treatment up to 7 days after removal of the last patch, that is, upon completing the 7-day, patch-free interval of cycle 7. 2.4.2. Safety and compliance assessments Safety was assessed by means of adverse event monitoring, general physical and gynecologic examination (including breast examination by palpation), clinical laboratory tests, vital signs, body weight and height, and cervical smear testing. Laboratory evaluations included hematology, general serum chemistry, liver enzymes, carbohydrate metabolism, and lipids. Treatment compliance and patch adhesion were evaluated based on information recorded by the participants in their diaries. Compliance was calculated as a percentage of actual versus planned treatment days per cycle.
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withdrawal bleeding were analyzed using the two-sample t test. These post hoc tests were unrelated to any power analysis. No statistical analyses were undertaken to analyze between-treatment differences in the occurrence of adverse events.
3. Results 3.1. Study population Of the 593 women screened, 397 were randomized to one of the two contraceptive regimens. Unless otherwise indicated, data in the results section relate to the FAS, which included 346 women (171 in the EE/GSD patch group and 175 in the COC group) (Fig. 1). A total of 178 women were included in the PPS (89 in each group). Baseline demographics are shown in Table 1. Major protocol deviations resulting in exclusion from the PPS (participants could have more than one) for the EE/GSD patch and COC were as follows: treatment deviations in 78 women (45.6%) and 84 women (48.0%), respectively; improper diary documentation in 14 women (8.2%) and 10 women (5.7%), respectively; and treatment despite not meeting inclusion/exclusion criteria in 1 woman (0.6%) in the COC group. Withdrawal by subject was 12.3% in the EE/GSD patch group and 8.0% in the COC group. Subjects were not required to provide a reason for choosing to withdraw and, in most cases, did not.
2.5. Statistical analysis The analyses in this study were purely descriptive in nature, and the study was not designed to show equivalence or noninferiority. Thus, no formal sample size calculation was undertaken, but a study with 400 participants was expected to provide sufficient data to describe the menstrual bleeding pattern reliably based on results from previous studies [16]. All variables were analyzed according to their type using descriptive statistics (e.g., frequencies for categorical data and arithmetic mean, standard deviation [SD], minimum, quartiles, median and maximum for metric data). Statistical analyses were performed using SAS® software (release 9.1 or higher; SAS Institute Inc., Cary, NC, USA). Analyses were based on the full analysis set (FAS), defined as all women who were randomized, had applied at least one patch, and for whom at least one observation after admission to treatment was available. A per-protocol set (PPS) was also defined, including all women from the FAS who had no major protocol deviations considered to affect the main efficacy variables. Post hoc statistical analyses were conducted in order to test for treatment differences in bleeding pattern and cycle control outcomes. Data related to the number of women with withdrawal bleeding and intracyclic bleeding, and the maximum intensity of these two measures, were analyzed using the Fisher's exact test or the chi-square test. Data related to bleeding pattern outcomes and the length of
3.2. Treatment compliance Mean compliance was good in both treatment groups. Mean percentages for treatment compliance were 97.9% for the EE/GSD patch group and 99.8% for the COC group. 3.3. Bleeding pattern During treatment, the overall bleeding profile was similar between treatment groups. The mean number of bleeding/ spotting days was comparable for the EE/GSD patch and COC in reference period 1 (20.9 versus 21.3, respectively; pN.05) and reference period 2 (17.0 versus 16.2, respectively; pN.05). Similar results were found for the mean number of bleeding-only days, spotting-only days and extend to the PPS population. The mean numbers of bleeding/spotting episodes for the EE/GSD patch and COC were comparable in reference period 1 (3.2 versus 3.3, respectively; pN.05); however, there were fewer bleeding/spotting episodes in the COC group as compared to the EE/GSD patch group in reference period 2 (3.1 versus 3.4, respectively; p=.01). The same finding was observed in the PPS population, that is, fewer bleeding/ spotting episodes in the COC group as compared to the EE/GSD patch in reference period 2 (3.1 versus 3.5, respectively; p=.01), corresponding to more women in the COC group with absence of scheduled withdrawal bleeding in cycles 4 and 6.
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Fig. 1. Disposition of study participants. *A subject was considered to have completed the treatment if at least one patch was applied after day 14 of cycle 7 according to the subject's diary or a completion date was available that was at least 182 days after start of treatment. †A subject was considered to have completed the study when she had completed the treatment period and the follow-up visit. The percentages are based on the number of subjects randomized. EE/GSD patch, 0.55 mg EE and 2.1 mg GSD; COC, 0.02 mg EE and 0.1 mg LNG. COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel.
Mean length of bleeding/spotting episodes was comparable for the EE/GSD patch group and the COC group in reference period 1 (5.46 days versus 5.80 days, respectively; pN.05) and reference period 2 (5.10 days versus 5.21 days, respectively; pN.05). Similar findings were observed for the PPS. Results for bleeding pattern indices are summarized in Table 2. 3.4. Cycle control
groups. For withdrawal bleeding intensity for the FAS and PPS populations, the percentage of spotting or light bleeding was generally higher in the COC group than in the EE/GSD patch group (Fig. 2b), whereas the percentage of women with normal or heavy bleeding was higher in the patch group during cycles 1 to 3 (pb.05) and, additionally, in cycle 5 of the PPS (pb.05). There were no notable treatment differences in cycles 4–7 (pN.05) of the FAS and cycles 4, 6, and 7 of the PPS analysis.
3.4.1. Withdrawal bleeding For both the FAS and PPS populations, scheduled withdrawal bleeding episodes occurred very reliably in both treatment groups over the entire treatment period (pN.05) (Fig. 2a). However, in the FAS population, absence of scheduled withdrawal bleeding was more often observed in women using COC in treatment cycles 4 (10.3% versus 1.7%; pb.01) and 6 (12.6% versus 0.9%; pb.01), corresponding to the second reference period. The median length of these episodes was 5 days for all cycles in both treatment
3.4.2. Intracyclic bleeding In the FAS and PPS, a similar number of subjects in both treatment groups experienced episodes of intracyclic bleeding/ spotting (pN.05) (Fig. 3a). Maximum intensity of intracyclic bleeding/spotting episodes was generally comparable between groups for the FAS and PPS, except in cycle 1 where the percentage of light but also heavy bleeding was higher in the COC group, and the percentage of normal bleeding was higher in the EE/GSD group (pb.01) (Fig. 3b).
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Table 1 Demographics and baseline characteristics of participants at screening (FAS)
Age, height, body weight, BMI c mean±SD (range) Age (years) Height (cm) Body weight (kg) BMI (kg/m 2) Race, n (%) Asian Black/African American Multiple Native Hawaiian/other Pacific Islander Not reported White Ethnicity, n (%) Not Hispanic/Latino Hispanic/Latino Not reported Smoking history, n (%) Never Former Current Alcohol consumption, n (%) Abstinent Light Moderate
EE/GSD patch a n= 171
COC b n=175
29.1±7.3 (18–45) 164.6±6.9 (147–183) 70.7±16.5 (44–138) 26.1±5.9 (16–46)
27.2±6.8 (18–45) 164.5±7.9 (150–198) 73.9±18.8 (46–159) 27.3±6.5 (19–64)
5 (2.9) 29 (17.0) 2 (1.2) 1 (0.6) 2 (1.2) 132 (77.2)
4 (2.3) 35 (20.0) 2 (1.1) 1 (0.6) 0 (0.0) 133 (76.0)
154 (90.1) 14 (8.2) 3 (1.8)
158 (90.3) 17 (9.7) 0 (0.0)
117 (68.4) 27 (15.8) 27 (15.8)
125 (71.4) 28 (16.0) 22 (12.6)
49 (28.7) 113 (66.1) 9 (5.3)
47 (26.9) 113 (64.6) 15 (8.6)
a 0.55 mg EE and 2.1 mg GSD. b 0.02 mg EE and 0.1 mg LNG. c Weight and height were not reported by one subject each, and, therefore, BMI could not be calculated for two subjects. BMI, body mass index; COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel; SD, standard deviation.
3.5. Unintended pregnancies No pregnancies occurred during study treatment up to 7 and 14 days after the last day of using study contraception. 3.6. Safety The percentage of women experiencing at least one treatment-emergent adverse event (TEAE) was similar between the patch and COC groups (49.1% versus 50.9%, respectively). The most common drug-related TEAEs are listed in Supplementary Table 1. The overall rate of drugrelated discontinuations due to TEAEs was 8.2% for the patch compared with 4.6% for the COC. In both treatment groups, most discontinuations were due to skin reactions at the application site. 1 No clinically significant trends or safety signals were observed in the other safety parameters monitored. Most laboratory values were within normal limits at baseline and during the study. Heart rate and body weight remained stable over the course of the study. 4. Discussion The results of this study demonstrate that the EE/GSD patch is similar to the comparator COC in regard to bleeding 1
COC users were required to wear a placebo patch.
profile. The cycle control results are largely consistent with those of other methods of hormonal contraception. In a direct comparison with a patch containing 0.6 mg EE and 6 mg norelgestromin, the EE/GSD patch was largely comparable in terms of bleeding pattern and cycle control [17]. Furthermore, in a historical comparison with a 3 mg drospirenone/0.02 mg EE pill and a 0.015 mg desogestrel/ 0.02 mg EE pill, the EE/GSD patch displayed similar bleeding pattern and cycle control [18]. Overall, contraceptive efficacy in this study was good, with no pregnancies reported in the EE/GSD patch group. In both treatment groups, compliance was very high and the patch was generally well tolerated. Safety analyses revealed similar results for both study groups. The TEAEs that occurred during the study were in line with events expected in a young female population using a transdermal contraceptive. In terms of study limitations, the small sample size restricts the extent to which the data can be used to evaluate pregnancy and safety outcomes; however, data from a previous phase III study (n= 1,631) of the EE/GSD patch suggest good contraceptive efficacy, with an adjusted Pearl Index score of 0.81 [19]. Despite this, the risk of rare but pertinent events such as venous thromboembolism cannot reasonably be assessed here. Additional considerations include the descriptive nature of the analyses (which should not be overinterpreted to imply benefit), the relatively small number of cycles, the pragmatic use of participant diaries rather than direct, objective evaluation, and the use of paper
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Table 2 Mean number of bleeding/spotting days, mean number of bleeding/spotting episodes, and mean length of bleeding/spotting episodes, shown by treatment group and reference period (FAS). Length of each reference period was 90 days and p values for differences between treatment groups were pN.05, unless otherwise indicated EE/GSD patch a
COC b
Reference period 1 n= 127 Reference period 2 n= 111 Reference period 1 n=152 Reference period 2 n= 131 Number of bleeding/spotting days Mean±SD Median (range) Number of bleeding/spotting episodes (days) Mean±SD Median (range) Length of bleeding/spotting episodes (days) d Mean±SD Median (range)
20.9±7.8 20.0 (3–47)
17.0±5.7 16.0 (1–35)
21.3±9.7 20.5 (0–88)
16.2±5.8 16.0 (0–36)
3.2±0.9 3.0 (1–7)
3.4±1.0 c 3.0 (1–9)
3.3±1.0 3.0 (0–8)
3.1±0.8 c 3.0 (0–7)
5.46±2.0 5.0 (2–17)
5.10±1.6 5.0 (1–11)
5.80±6.9 5.0 (2–86)
5.21±1.6 5.0 (1–11)
a
0.55 mg EE and 2.1 mg GSD. b 0.02 mg EE and 0.1 mg LNG. c p=.01 for the comparison of EE/GSD patch versus COC. d n= 151 in reference period 1 and n= 130 in reference period 2. COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel.
diaries for the assessment of bleeding, rather than real-time electronic variants. Furthermore, as an exploratory study, it was not formally powered for comparisons. Future analyses
of bleeding data could benefit from the use of more standardized terminology, thus allowing for more direct comparison of data between studies [20].
a) EE/GSD patch COC
Percentage of women with withdrawal bleeding
100 90 80 70 60 50 40 30 20 10 0 1
2
3
4
5
6
7
Cycle
Percentage of women
b)
Heavy
Normal
Light
Spotting
100 80 60 40 20 0 1
2
3
4
5
Cycle EE/GSD patch
6
7
1
2
3
4
5
6
7
Cycle COC
Fig. 2. (a) Percentage of women with withdrawal bleeding, by treatment and cycle (FAS); (b) Percentage of women with withdrawal bleeding, by maximum intensity, treatment, and cycle (FAS). EE/GSD patch, 0.55 mg EE and 2.1 mg GSD; COC, 0.02 mg EE and 0.1 mg LNG. COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel.
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a) Percentage of women with intracyclic bleeding and/or spotting
25
EE/GSD patch COC
20
15
10
5
0
1
2
3
4 Cycle
b)
5
6
7
Heavy
Normal
Light
Spotting
100 Percentage of women
90 80 70 60 50 40 30 20 10 0 1
2
3
4
5
6
7
1
2
Cycle EE/GSD patch
3
4
5
6
7
Cycle COC
Fig. 3. (a) Percentage of women with intracyclic bleeding/spotting episodes, by treatment and cycle (FAS); (b) percentage of women with intracyclic bleeding/ spotting episodes, by maximum intensity, treatment, and cycle (FAS). EE/GSD patch, 0.55 mg EE and 2.1 mg GSD; COC, 0.02 mg EE and 0.1 mg LNG. COC, combined oral contraceptive; EE, ethinyl estradiol; FAS, full analysis set; GSD, gestodene; LNG, levonorgestrel.
Strengths of this investigation include the randomized, double-blind, double-dummy design, and the lack of any restriction on inclusion based on BMI, which is in line with current recommendations on the inclusion of women in combined hormonal contraceptive studies without restrictions on body weight [20]. Where possible, this study was conducted in concordance with World Health Organization terminology and definitions [16] and complied with the recommendation of the FDA that at least a third of the women should not have been using hormonal contraceptives within 3 months before their study start date to eliminate any carryover effect. In conclusion, the findings of this exploratory study are indicative of comparable bleeding pattern and cycle control for the EE/GSD patch when compared with a COC containing EE/LNG. These preliminary results suggest a potential role for the EE/GSD patch as an additional contraceptive option for women. Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.contraception.2014.10.004. Acknowledgment The authors would like to acknowledge Keith Falconer of inVentiv Health Clinical for conducting the post-hoc
statistical analyses. Editorial assistance was provided by Ogilvy 4D, Oxford, UK, and funded by Bayer Pharma AG, Berlin, Germany.
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