International Journal of Gynecology and Obstetrics 125 (2014) 270–274

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CLINICAL ARTICLE

Estradiol valerate plus dienogest versus ethinylestradiol plus levonorgestrel for the treatment of primary dysmenorrhea Felice Petraglia a, Susanne Parke b, Marco Serrani c,⁎, Uwe Mellinger d, Thomas Römer e a

Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Siena, Italy Global Clinical Development Women’s HealthCare, Bayer HealthCare, Berlin, Germany Global Medical Affairs Women’s HealthCare, Bayer HealthCare, Berlin, Germany d Global Clinical Statistics, Bayer HealthCare, Berlin, Germany e Department of Gynecology and Obstetrics, Evangelist Hospital Cologne-Weyertal, Cologne, Germany b c

a r t i c l e

i n f o

Article history: Received 19 July 2013 Received in revised form 27 November 2013 Accepted 3 March 2014 Keywords: Combined oral contraceptive Estradiol valerate plus dienogest Pelvic pain Primary dysmenorrhea

a b s t r a c t Objective: To demonstrate the superiority of estradiol valerate plus dienogest (E2V/DNG) over ethinylestradiol plus levonorgestrel (EE/LNG) in reducing the number of days with dysmenorrheic pain among women with primary dysmenorrhea. Methods: In a phase IIIb trial conducted at 44 centers worldwide between April 2009 and November 2010, otherwise healthy women aged 14 − 50 years requesting contraception were randomized to daily oral administration of E2V/DNG (n = 253) or EE/LNG (n = 254) for three 28-day cycles. The primary efficacy variable was number of days with dysmenorrheic pain, the category of which (none, mild, moderate, severe) was self-assessed on a daily basis (irrespective of menstrual bleeding status) and recorded on diary cards. Notably, the women documented their pain as they experienced it before taking any (permitted) rescue medication. Results: Overall, 217 and 209 women receiving E2V/DNG and EE/LNG, respectively, completed the study. The mean ± SD change from baseline in number of days with dysmenorrheic pain was –4.6 ± 4.6 days and –4.2 ± 4.2 days for the E2V/DNG and EE/LNG groups, respectively (P = 0.34). Conclusion: Both E2V/DNG and EE/LNG led to considerable relief of dysmenorrheic complaints among women with primary dysmenorrhea, decreasing the number of days with dysmenorrheic pain from baseline to a similar extent. ClinicalTrials.gov: NCT00909857 © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Primary dysmenorrhea has been defined as recurrent cramping pain in the lower abdomen and/or pelvis that occurs immediately prior to or during menstruation in the absence of any identifiable pelvic pathology [1,2]. The incidence of primary dysmenorrhea varies considerably by geographic location, but it is nonetheless widespread and considered a highly prevalent condition, affecting an estimated 30%–50% of young women [1–3]. At its most severe, primary dysmenorrhea results in work or school absenteeism for 15% of young women [1]. Primary dysmenorrhea is considered to be associated with increased prostanoid secretion from the endometrium during menstruation, which in turn induces abnormal uterine contractility [1]. Therefore, currently available treatments, typically non-steroidal anti-inflammatory drugs (NSAIDs), target prostaglandin synthesis to relieve dysmenorrheic complaints, and are recommended as a first-line medical treatment to relieve pain and to improve daily activity among women suffering ⁎ Corresponding author at: Bayer HealthCare, Müllerstraβe 178, 13353 Berlin, Germany. Tel.: +49 30 468 194276; fax: +49 30 468 14768. E-mail address: [email protected] (M. Serrani).

from primary dysmenorrhea [2]. Concerns about the gastrointestinal safety of NSAIDs [4] or the cardiovascular safety of COX-2 inhibitors [5], however, indicate the need for a treatment for dysmenorrhea with an improved risk–benefit profile. Although NSAIDs are specifically suited for the treatment of acute dysmenorrheic pain, combined oral contraceptives (COCs) are often used off-label to prevent the development of primary dysmenorrhea symptoms. Their efficacy, however, has not been adequately demonstrated in clinical trials [6], and symptoms sometimes reoccur during the hormone-free interval (HFI), which is 7 days for most COC regimens. The 26/2-day dynamic dosing regimen of a COC containing estradiol valerate and dienogest (E2V/DNG) administered via an estrogen stepdown and progestogen step-up approach (E2V 3 mg on days 1–2, E2V 2 mg/DNG 2 mg on days 3–7, E2V 2 mg/DNG 3 mg on days 8–24, E2V 1 mg on days 25–26, and placebo on days 27–28) includes a shortened HFI compared with conventional 21/7-day regimen COCs. This ensures that stable levels of estradiol are maintained throughout the 28-day cycle, including during the HFI [7]. Furthermore, the short serum half-life of DNG (approximately 10 hours) [8] results in only a limited accumulation of DNG during the 28-day E2V/DNG regimen and, as such, its rapid systemic clearance from the circulation during

http://dx.doi.org/10.1016/j.ijgo.2013.11.017 0020-7292/© 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

F. Petraglia et al. / International Journal of Gynecology and Obstetrics 125 (2014) 270–274

the HFI does not seem to have a negative impact on symptoms associated with hormonal withdrawal, such as headache and pelvic pain. As a result, it was hypothesized that E2V/DNG might have a more favorable effect on primary dysmenorrhea compared with established 21/7-day monophasic regimen COCs. Therefore, the primary objective of the present study, CALM, was to demonstrate superiority of E2 V/DNG over an established COC (ethinylestradiol 0.02 mg, levonorgestrel 0.1 mg; EE/LNG) with respect to the number of days with dysmenorrheic pain (defined as pelvic pain during the menstrual or withdrawal bleeding episode and the 2 days before this episode) in a defined period (i.e. 2 treatment and 2 baseline cycles). 2. Materials and methods In a phase IIIb, double-blind, double-dummy, parallel-group study conducted at 44 centers across Canada, Chile, Germany, Italy, the Philippines, and the United States, women suffering from primary dysmenorrhea were recruited between April 15, 2009, and November 18, 2010. The study was performed in keeping with the ethical principles of the International Conference on Harmonization–Good Clinical Practice guidelines, which have their origin in the Declaration of Helsinki. The study was approved by local ethics committees and institutional review boards, and written informed consent was obtained from all women before study enrollment. Otherwise healthy women aged 14 − 50 years (smokers ≤35 years) requesting contraception and suffering from primary dysmenorrhea were eligible for inclusion in the study. At the screening visit, the gynecologic, menstrual, and surgical history of patients was recorded, and a gynecologic examination of every patient was performed. Pregnant or breastfeeding women, women with a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) of more than 32, and women with pelvic pathology were excluded from the study. Regarding sample size, it was calculated that 164 evaluable subjects per treatment group would be required to detect a standardized effect size of 0.36 between the 2 treatment groups with 90% power assuming a 2-sided t test at an α level of 0.05. Experience in similar studies among patients with primary dysmenorrhea suggested that there might be a dropout rate of 40%–50% over the treatment period. Assuming a 45% dropout rate, it was determined that 290 women per treatment group (i.e. 580 women in total) would be required for the study. Eligible women underwent 2 observation baseline cycles to confirm the occurrence of dysmenorrhea. The women rated their pelvic pain on a daily basis on diary cards using the following 4-point scale: 0, none (no pain); 1, mild (mild dysmenorrheic pain with no need for the intake of painkiller); 2, moderate (moderate dysmenorrheic pain with need for the intake of painkiller); and 3, severe (severe dysmenorrheic pain with need for the intake of painkiller). Dysmenorrhea was defined as a total score of 8 or more points per cycle for pelvic or lower abdominal pain that started up to 2 days before the onset of the menses or during menstrual flow, and ended before or at cessation of menstrual flow. Women who met the inclusion criteria were randomized to daily oral administration of E2V/DNG (Qlaira; Bayer HealthCare, Berlin, Germany) plus placebo, or placebo plus EE/LNG (Miranova; Bayer HealthCare, Berlin, Germany) for 3 cycles of 28 days each. The investigational and reference product were packed for a double-dummy design that included the study product plus matching placebo in 1 wallet containing 2 blisters of 28 tablets each. Women were randomly assigned to the 2 treatments in a 1:1 ratio via a centralized computer-generated randomization list provided by the sponsor. Study medication was assigned in blocks via an interactive voice response system according to the randomization list; randomization numbers were allocated in ascending order based on the sequence of arrival of patients to the study center. Both patients and investigators remained blind to the medication assigned. Women were permitted to use rescue medication

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(ibuprofen, maximum 1200 mg on any single day) to relieve, but not to prevent, menstruation-related pelvic pain. To assess treatment compliance, the women were required to complete a diary card on a daily basis to determine their intake of study and rescue medication. Missed tablets and use of back-up contraception (excluding natural methods, as documented in the diary cards) were also included in the compliance assessment. Compliance to study treatment was calculated as the actual number of tablets taken divided by the scheduled number of tablets for the respective duration of treatment. The primary efficacy variable was the number of days with dysmenorrheic pain (defined as pelvic pain during the menstrual/withdrawal bleeding episode and the 2 days before this episode) in a defined period (i.e. 2 treatment and 2 baseline cycles). Dysmenorrheic pain represented any spasmodic pelvic or lower abdominal pain with possible radiation toward the back or thighs. Pain severity (none, mild, moderate, severe) was self-assessed by the women on a daily basis (irrespective of menstrual bleeding status) throughout the study and recorded on diary cards. Notably, the women had to document their pain as they experienced it before taking any permitted rescue medication. Secondary efficacy variables included the total points score for dysmenorrheic pain, number of days with pelvic pain independent of the occurrence of vaginal bleeding, rescue medication consumption (standardized intake of ibuprofen), interference of dysmenorrheic pain with work or school and social or other activity, bleeding pattern and cycle control parameters, and sick leave taken, as noted in the absenteeism questionnaire (data not shown) [9,10]. In addition, the following questionnaires were used: the Resource Use Questionnaire, the General Health and Well-Being Questionnaire Short Form 36 version 1 (SF-36v1) [11], and Global Clinical Impression [12]. The Resource Use Questionnaire was completed at screening before the start of the first baseline cycle. The SF-36v1 and absenteeism questionnaires were completed at screening, during days 12–19 of the second baseline cycle and the second treatment cycle, and during days 12–19 after the end of treatment or at end of the study for those who discontinued prematurely. The Global Clinical Impression scale assessment was completed during days 12–19 of the second treatment cycle or on premature discontinuation. Safety assessments included physical and gynecologic examinations (cervical smear), monitoring vital signs (heart rate and blood pressure), body weight and BMI, and reporting of adverse events (AEs). The primary efficacy variable was assessed on the basis of the full analysis set, defined as all women who took at least 1 dose of study medication and who had at least 1 observation recorded after starting the study treatment. Statistical analyses were done via SAS for Windows version 9 (SAS Institute, Cary, NC, USA). The 2-sample t test was used to determine the superiority of E2V/DNG over EE/LNG. A P value of less than 0.05 was considered statistically significant. 3. Results During the study period, 507 women were randomized to treatment: 253 women to E2 V/DNG, and 254 to EE/LNG. In total, 464 women received study medication and were included in the full analysis set: 234 in the E2 V/DNG group, and 230 in the EE/LNG group (Fig. 1). Overall, 217 women receiving E2V/DNG and 209 women receiving EE/LNG completed the treatment; 38 women prematurely discontinued study medication across the 2 treatment groups. The women’s demographic and baseline characteristics were similar in the 2 groups (Table 1). Overall, 231 of 234 (98.7%) women in the E2V/DNG group and 227 of 230 (98.7%) women in the EE/LNG group showed at least 75% compliance with the allocated study treatments. For the primary efficacy variable, the change from baseline in the number of days with dysmenorrheic pain was similar in both treatment groups: the mean ± SD change from baseline was –4.6 ± 4.6 days in the

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Screened (n=771) Failed screening (n=264) Randomized (n=507)

E2V/DNG (n=253)

EE/LNG (n=254)

Didn’t take medication (n=19)

Didn’t take medication (n=24) Took medication (n=234)

Took medication (n=230) Discontinued study (n=21)

Discontinued study (n=17)

Withdrawal of consent (n=7) Adverse event (n=5) Lost to follow-up (n=5) Other (n=4)

Withdrawal of consent (n=6) Adverse event (n=5) Lost to follow-up (n=2) Other (n=4)

Completed medication (n=217)

Completed medication (n=209)

Fig. 1. Flow of women through the study. Women who failed screening (n = 264), were not randomized because they did not meet the inclusion criteria (n = 155), withdrew consent (n = 49), were lost to follow-up (n = 36), were pregnant (n = 10), had a protocol deviation during the baseline observational cycles (n = 2), or had other reasons (n = 12).

E2V/DNG group and –4.2 ± 4.2 days in the EE/LNG group (Fig. 2). The difference between the 2 groups in mean change from baseline was –0.40 (95% confidence interval, –1.23 to 0.42). The 2-sample t test did not show superiority of E2V/DNG over EE/LNG (t442 = –0.96, P = 0.34). A similar pattern was observed for the mean change from baseline in the other pain-related secondary efficacy variables (mean change in total points score for dysmenorrheic pain, –10.6 ± 9.7 vs –10.0 ± 8.9; mean change in number of days with pelvic pain independent of the occurrence of vaginal bleeding, –4.0 ± 5.7 vs –3.7 ± 5.7; and mean change in number of tablets of ibuprofen consumed, –6.2 ± 14.8 vs –6.6 ± 12.3) with comparable changes between the 2 treatment groups. Changes in other efficacy variables of secondary health outcomes (interference of dysmenorrheic pain with work or school and social or other activity, bleeding pattern and cycle control parameters, absenteeism questionnaire, Resource Use Questionnaire, General Health and Table 1 Demographic and baseline characteristics of the study women by treatment groupa. Characteristic

E2V/DNG group (n = 234)

EE/LNG group (n = 230)

Age, y Body weight, kg BMI Ethnicity White Black Hispanic Asian Other Current smoker Alcohol consumptionb Never Seldom Occasionally Regularly Missing data Total score (baseline dysmenorrheic pain)

28.0 ± 7.9 61.7 ± 10.8 23.3 ± 3.6

27.6 ± 8.0 60.3 ± 11.7 22.8 ± 3.8

128 (54.7) 14 (6.0) 39 (16.7) 2 (0.9) 51 (21.8) 69 (29.5)

126 (54.8) 12 (5.2) 39 (17.0) 5 (2.2) 48 (20.9) 68 (29.6)

2 (0.9) 59 (25.2) 55 (23.5) 6 (2.6) 112 (47.9) 17.5 ± 7.5

2 (0.9) 70 (30.4) 56 (24.3) 4 (1.7) 98 (42.6) 16.9 ± 7.5

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); E2V/DNG, estradiol valerate plus dienogest; or EE/LNG, ethinylestradiol plus levonorgestrel. a Data are presented as mean ± SD or number (percentage) unless stated otherwise. b Six months before screening.

Well-being SF-36v1, and Global Clinical Impression) were also comparable between the 2 treatment groups (data not shown). The safety evaluation showed that both study drugs were well tolerated; there were no notable variations between the 2 treatment groups aside from slight numeric differences. The overall incidence of treatment-emergent AEs (TEAEs) was similar: 65.0% in the E2V/DNG group, and 64.8% in the EE/LNG group. The TEAEs (as defined by the Medical Dictionary for Regulatory Activities) that occurred in more than 5% of women in either treatment group included dysmenorrhea, headache, metrorrhagia, and tension headache. In total, 5 women in each group (2.1% of those receiving E2V/DNG and 2.2% of those receiving EE/LNG) prematurely discontinued the study medication due to TEAEs. The overall incidence of serious TEAEs was low (2 women [0.9%] in each group); serious TEAEs included helminthic infection, ovarian torsion, animal bite, and depression, none of which led to discontinuation of the study drug. There were no deaths in the study. 4. Discussion The results of the present phase IIIb, double-blind, double-dummy, parallel-group study showed that both E2V/DNG and EE/LNG led to considerable relief of dysmenorrheic complaints among women with primary dysmenorrhea, decreasing the number of days with dysmenorrheic pain from baseline to a comparable extent. In addition, both drugs were well tolerated. Although there are insufficient clinical trial data to confirm the efficacy of COCs for the treatment of primary dysmenorrhea, hormonal contraceptives have previously shown effectiveness in reducing both dysmenorrheic pain and use of rescue medication among adolescents and older women [13–15]. Hormonal contraceptives generally provide some relief from dysmenorrheic pain and may be recommended as a first-line treatment option for women with primary dysmenorrhea who require contraception [2,6]; however, COCs with an extended regimen and a shorter HFI (e.g. 24/4- and 26/2-day regimens) have also been shown to be beneficial for women with menstrual cyclerelated disorders, including dysmenorrhea [16]. Furthermore, in the HARMONY II trial, E2V/DNG provided a significantly greater reduction in the frequency and intensity of pelvic pain during the HFI compared with EE/LNG among otherwise healthy women aged 18–50 years who

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Fig. 2. Change from baseline in the number of days with dysmenorrheic pain among the study women who received estradiol valerate plus dienogest (E2V/DNG) or ethinylestradiol plus levonorgestrel (EE/LNG).

experienced these symptoms while taking COCs in a 21/7-day regimen [17]. Although “pelvic pain” does not reflect primary dysmenorrhea, this symptom was defined as a much broader disorder in the HARMONY II trial. Overall, E2V/DNG was shown to be superior to the comparator EE/LNG COC in reducing the intensity of pelvic pain. The superiority of E2V/DNG over another COC administered in a 21/7-day regimen was also shown in the similarly designed study HARMONY I [18]. In a previous study comparing E2V/DNG and EE/LNG, E2 V/DNG was shown to lead to shorter and lighter bleeding and a higher rate of absent withdrawal bleeding compared with EE/LNG in a conventional 21/7-day regimen [19]. It has also been shown to significantly reduce menstrual bleeding among women with heavy and/or prolonged menstrual bleeding without organic pathology [20]. Furthermore, the dynamic dosing regimen of E2V/DNG provides stable levels of estradiol throughout the 28-day cycle [7]. Therefore, on the basis of the assumption that fewer menstrual bleeding days might be associated with less dysmenorrheic pain, and the fact that E2V/DNG provides stable levels of E2 throughout the 28-day cycle and a shortened HFI of 2 days, it might be expected that E2V/DNG would have a favorable effect on primary dysmenorrhea compared with an established COC used in a 21/7-day regimen. In the present short-term study, administration of both E2V/DNG and EE/LNG led to considerable relief of dysmenorrheic complaints: both treatments decreased the mean number of days of dysmenorrheic pain by 4.6 and 4.2 days from baseline, respectively. This effect was accompanied by a reduction in the total points score for dysmenorrheic pain, the number of days with dysmenorrheic pain independent of vaginal bleeding, and rescue medication use; in addition, both study drugs were well tolerated. Despite these findings, however, there were no significant differences between the 2 treatment groups, and the superiority of E2V/DNG over EE/LNG was not demonstrated. Lastly, regarding rescue medication use, it should be noted that, because both treatment groups had to undergo 2 baseline cycles without study medication, it was expected that a considerable amount of pain medication would be used by these women. Therefore, to facilitate the accountability of pain medication for menstruation-related pelvic pain, rescue medication was distributed to the women in the form of ibuprofen, the intake of which was documented in the diary cards on a daily basis as a secondary efficacy variable. In brief, the median change in rescue medication use from baseline was –5 and –3 tablets in the E2V/DNG and EE/LNG groups, respectively. A limitation of the present study was its short duration of only 3 months. On the basis of the 26/2-day regimen of E2V/DNG and findings from other studies [16,17], E2V/DNG might prove to be statistically superior to EE/LNG and other 21/7-day regimen COCs when evaluated

over the longer term. Second, the study used a 4-point scale (none, mild, moderate, severe) for the self-assessment of dysmenorrheic pain instead of a validated questionnaire (e.g. Moos Menstrual Distress Questionnaire [21]) or a validated measure of pain such as a visual analog scale [22]. In conclusion, the present short-term study demonstrated that E2V/ DNG and EE/LNG had similar efficacy. Both treatments improved primary dysmenorrhea to a comparable extent, and the safety results were consistent with those expected for COCs with no apparent differences between E2V/DNG and EE/LNG.

Acknowledgments The study was funded by Bayer HealthCare, Berlin, Germany. Conflict of interest F.P. is a past speaker and advisory board member for Bayer HealthCare and PregLem. T.R. is a member of advisory boards of Bayer HealthCare and has received honoraria from Bayer for lectures. S.P., M.S., and U.M. are employees of Bayer HealthCare. Amy Evans of inScience Communications, Springer Healthcare, provided medical writing support (drafting and revisions) for the preparation of the manuscript. Funding for this writing support was provided by Bayer HealthCare.

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Estradiol valerate plus dienogest versus ethinylestradiol plus levonorgestrel for the treatment of primary dysmenorrhea.

To demonstrate the superiority of estradiol valerate plus dienogest (E(2)V/DNG) over ethinylestradiol plus levonorgestrel (EE/LNG) in reducing the num...
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