The European Journal of Contraception & Reproductive Health Care

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1 The European Journal of Contraception & Reproductive Health Care ISSN: (Print) (Online) Journal homepage: Inhibition of ovulation by NOMAC/E 2, a novel monophasic oral contraceptive combining nomegestrol acetate and 17β-oestradiol: A doubleblind, randomised, dose-finding pilot study Nathalie Chabbert-Buffet, Didier Chassard, Edith Ochsenbein, Jean-Louis Thomas & Sophie Christin-Maitre To cite this article: Nathalie Chabbert-Buffet, Didier Chassard, Edith Ochsenbein, Jean-Louis Thomas & Sophie Christin-Maitre (2011) Inhibition of ovulation by NOMAC/E 2, a novel monophasic oral contraceptive combining nomegestrol acetate and 17β-oestradiol: A double-blind, randomised, dose-finding pilot study, The European Journal of Contraception & Reproductive Health Care, 16:2, 76-84, DOI: / To link to this article: Published online: 21 Feb Submit your article to this journal Article views: 204 View related articles Citing articles: 23 View citing articles Full Terms & Conditions of access and use can be found at

2 The European Journal of Contraception and Reproductive Health Care, April 2011;16:76 84 Inhibition of ovulation by NOMAC/E 2, a novel monophasic oral contraceptive combining nomegestrol acetate and 17b-oestradiol: A double-blind, randomised, dose-finding pilot study Nathalie Chabbert-Buffet*, Didier Chassard {, Edith Ochsenbein {, Jean-Louis Thomas { and Sophie Christin-Maitre x *Obstetrics and Gynaecology Unit, Hôpital Tenon AP-HP, and ER-9, UPMC Université Paris 06, Paris, France; { SGS Aster, Paris, France; { Laboratoire Théramex SAM, Monaco; and x AP-HP Endocrinology Department, Hôpital Saint Antoine and ER-9, UPMC Université Paris 06, Paris, France... ABSTRACT Objective To explore the optimal dose of the progestogen, nomegestrol acetate (NOMAC), required in a monophasic oral contraceptive, in combination with 1.5 mg 17b-oestradiol (E 2 ), to inhibit ovulation. Methods A double-blind, randomised study assessing 41 normally cycling women (aged years) over two screening cycles, one control cycle and one consecutive treatment cycle; 38 women completed the treatment period. Subjects received mg NOMAC/ 1.5 mg E 2 (n ¼ 9), 1.25 mg NOMAC/1.5 mg E 2 (n ¼ 10), 2.5 mg NOMAC/1.5 mg E 2 (n ¼ 10) or 2.5 mg NOMAC alone (n ¼ 9) for 21 days. Results During the treatment cycle, ovulation was suppressed in all treatment groups. The lowest plasma E 2 levels were observed with 2.5 mg NOMAC given alone. Addition of 1.5 mg E 2 to 2.5 mg NOMAC resulted in statistically significant increases in E 2 levels and decreases in mean follicle-stimulating hormone and luteinising hormone levels. In the three NOMAC/E 2 combination groups, a statistically significant inverse correlation was found between E 2 plasma levels and NOMAC dose. Conclusion The dose of 2.5 mg NOMAC was confirmed to be optimal to inhibit both ovulation and follicular maturation. The antigonadotropic effect of 2.5 mg NOMAC was reinforced when combined with 1.5 mg E 2. KEYWORDS 19-Norprogesterone; Oestradiol; Oral contraception; Progestogen; Antigonadotropic; Ovarian function; Nomegestrol acetate... Correspondence: Jean-Louis Thomas, Laboratoire Théramex, 6 Avenue Albert II, BP 59, Monaco. Tel: þ Fax: þ mmicheletti@theramex.mc ª 2011 The European Society of Contraception and Reproductive Health DOI: /

3 INTRODUCTION Oral contraceptive pills that combine 17b-oestradiol (E 2 ) with a progestogen structurally related to progesterone (P) may have a more favourable metabolic and vascular profile than pills containing synthetic ethinylestradiol 1 3. However, early E 2 -containing combined oral contraceptives were associated with poor cycle control. The non-androgenic 19-norprogesterone derivative, nomegestrol acetate (NOMAC), is a highly selective progestogen that is structurally similar to endogenous P 4,5. Studies have demonstrated that it has a good safety profile in terms of carbohydrate metabolism, lipids and clotting factors when given alone or in combination with oral E NOMAC suppresses ovulation and alters the cervical mucus when given alone at doses of 1.25, 2.5 and 5 mg/day for days per cycle in premenopausal women While the 2.5 mg/day and 5 mg/day NOMAC doses decreased plasma E 2 levels, the 1.25 mg/day dose resulted in higher E 2 levels throughout the cycle compared with the other two dose groups, suggesting that 1.25 mg/day NOMAC alone is unable to fully inhibit follicular maturation 9. NOMAC at a dose of 5 mg/day did not show greater ovarian suppression than NOMAC 2.5 mg; a dose of 2.5 mg NOMAC was thus identified as the minimal effective dose to inhibit both ovulation and follicular maturation. A new monophasic oral contraceptive pill combining 1.5 mg E 2 with NOMAC is currently in development. The primary objective of this doseranging study was to explore the optimal dose of NOMAC required in combination with 1.5 mg E 2 to suppress ovarian function and particularly to inhibit ovulation, as assessed by P and luteinising hormone (LH) assays. Secondary objectives were to compare antigonadotropic effects of different doses of NOMAC in combination with 1.5 mg E 2, and of 2.5 mg NOMAC when used alone, as assessed by follicle-stimulating hormone (FSH) and E 2 levels. Cervical mucus scores, daily body temperature, and clinical and biological safety were also monitored. The selection of NOMAC doses and dosing regimen were based on the results of a previous clinical study demonstrating the antigonadotropic action of NOMAC 9.E 2 was given at a daily dose of 1.5 mg, which is known to produce serum concentrations of oestrogen similar to those observed during normal reproductive cycles 12. For the contraceptive combination assessed in this study, NOMAC was the primary component for ovulation inhibition and E 2 was added mainly to compensate for endogenous E 2 production. In previous studies, contraceptives combining another progestin (desogestrel) with E 2 given at 1.0 mg and 3.0 mg were tested in a 21/7 regimen and the results indicated that there was no advantage in tripling the dose of E 2 13,14. METHODS Design This was a Phase IIa, double-blind, randomised, parallel-group, dose-finding pilot study conducted at a single centre in Paris, France, according to Good Clinical Practice and in accordance with the ethical principles set out in the Declaration of Helsinki and its amendments. The protocol and all subsequent amendments were approved by an Independent Ethics Committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale). Written informed consent was obtained from all volunteers before they entered the study. The study comprised two screening cycles, one control ovulatory cycle, and one treatment cycle. The first day of menstruation was designated as day 1 of the cycle. Subjects Healthy premenopausal women aged years with normal ovulatory cycles ( days) who had given written informed consent were enrolled in the study. Participants were required to: agree not to become pregnant during the trial and to accept the use of condoms as the only authorised contraceptive method; be non-smokers or current smokers of 510 cigarettes/day; have a body mass index of kg/m 2 inclusive; have a normal gynaecological examination; have plasma P measurements during the luteal phase of the second screening cycle of 5 ng/ml for one measurement and 3 ng/ml for all three measurements taken 15. Oral contraceptive use was stopped at least two months before the start of the study. The European Journal of Contraception and Reproductive Health Care 77

4 Exclusion criteria included: blood donation in the three months prior to the study or intention to donate blood during or within three months of trial completion; a history of major medical or psychiatric illness or surgery; any acute or chronic systemic disease; current vascular pathology or history of thrombo-embolic disease, arterial hypertension, coronary artery disease, valvulopathy; thrombogenic cardiac rhythm disturbances, cerebrovascular disease, ocular pathology of vascular origin; cancer or progressive haematological disorder; epilepsy; full/partial hysterectomy or endometrium ablation, pregnancy, childbirth, breast-feeding, miscarriage or induced abortion in the past year. Screening took place over two spontaneous menstrual cycles. At visit 1, enrolled women underwent clinical and gynaecological examinations that included a cervical smear, vaginal bacteriology, pelvic transabdominal ultrasound (to confirm that the clinical examination was normal), and blood sampling for standard laboratory tests. All measured their basal rectal temperature and recorded it in a daily diary. Based on these data, participants entered a second screening cycle including visit 2 for cervical score assessment and three separate P assays to confirm ovulation. Visit 3 aimed at reviewing inclusion/exclusion criteria before subjects entered the control cycle. During the control cycle subjects attended visits 4 and 5 for gynaecological examination and cervical score assessment, and blood sampling was performed daily from day 5 until day 25. Women meeting all inclusion/exclusion criteria, and with confirmed ovulation at the end of the control cycle, were assigned to randomisation numbers in ascending order. The treatment cycle included one follow-up visit (visit 6) with blood sampling as in the control cycle. The second or final follow-up visit (visit 7) was scheduled at the beginning of the first post-treatment cycle. Prohibited medications included any hormonal treatment for gynaecological diseases, regular treatment with cyclosporine, and any treatment potentially causing hyperprolactinaemia within one month of study start; enzymatic inducers within two months of study start; and blood or plasma derivatives within the past year. Interventions Participants were randomised to one of four treatment groups: mg NOMAC/1.5 mg E 2, 1.25 mg NOMAC/1.5 mg E 2, 2.5 mg NOMAC/1.5 mg E 2 or 2.5 mg NOMAC alone (NOMAC/lactose). The study drug was administered orally each morning at the single study centre under the supervision of either the investigator or a physician under the direct supervision of the investigator, on days 1 21 of the 28-day treatment cycle. To maintain blinding, all four treatments were presented in identical, opaque masking capsules. Outcome measures Plasma levels of P, LH, FSH and E 2 were assessed during the control and treatment cycles. The primary outcome measure was inhibition of ovulation, defined as suppression of both the midcycle LH peak (510 miu/ml) and P secretion (53 ng/ml) during the luteal phase. Blood was sampled daily, in the morning after a 10-hour fast and just before drug administration, on days 5 to 25 of the control and treatment cycles, for measurement of plasma hormone levels. Samples were immediately centrifuged and stored at 208C. Hormone assays were carried out centrally using radioimmunoassays with commercial kits at the CEPHAC Research Centre, Saint-Benoît, France according to pre-established standard operating procedures and in compliance with French Good Laboratory Practice regulations. The mean recovery values for the quality control samples were: P, 102.0% (coefficient of variation [CV] 10.0%); E 2, 89.8% (CV 7.8%); LH, 103.8% (CV 5.3%) and FSH, 99.0% (CV 6.7%). Intrabatch and inter-batch precision was determined at three concentration levels for the quality control samples; the CVs were: P, 54% and 513%; E 2, 56% and 59%; LH, 54% and 56% and FSH, 54% and 58%, respectively. Measurement of LH and FSH was carried out on days 5 25 and P and E 2 measurements on days Plasma hormone levels were analysed by calculating the area under the curve (AUC) with the trapezoidal rule between days 12 and 22 for P and E 2 and between days 5 and 22 for FSH and LH in both the control and treatment cycles. The following values were also calculated: minimum (C min ), maximum (C max ) and average (C ave ¼ AUC/number of days) plasma concentrations, and the difference between C max and C min (C max 7 C min ). Midcycle cervical mucus scores were assessed during the control cycle (at visit 4, which took place 78 The European Journal of Contraception and Reproductive Health Care

5 between days 10 and 16) and the treatment cycle (visit 6, which took place between days 10 and 16) using a modified score that did not include ferning and could vary from 0 to 9. Safety was assessed by gynaecological and breast examination, weight, vital signs, recording of adverse events (AEs) according to the World Health Organisation Adverse Reaction Terminology bodysystem classification and changes in laboratory measurements. Standard blood chemistry and haematology, serologies, vaginal bacteriology and cervical smears were assessed centrally at the Laboratoire de Biologie Médicale THEBAULT, Choisy-le-Roi, France. Pelvic transabdominal ultrasounds carried out in the screening cycle were performed at the Centre d Imagerie Médicale du Grand Pavois, Paris, France. per-protocol population. The safety analysis was performed on the intent-to-treat population. A p-value was considered statistically significant. Paired t-tests were used to compare hormone levels during the control versus the treatment cycle within each treatment group. Analysis of variance (ANOVA) and analysis of covariance (ANCOVA) were used to compare hormone concentrations across treatment groups. Changes in cervical mucus scores within each treatment group between the control and the treatment cycle were assessed using the Friedman test and between-group comparisons using non-parametric ANCOVA. Linear regression analysis to determine the correlation coefficient (r) was performed on hormone levels according to NOMAC dose in the three groups receiving NOMAC combined with E 2 to determine any NOMAC dose effect on hormone levels. Statistical analyses The study was to include 48 subjects; this number was based on a sample size calculation with error risks of a ¼ 0.05 and b ¼ 0.20 that indicated that 12 subjects per group would be sufficient to demonstrate a statistical difference between two treatment groups of at least 40% in anovulatory cycles. The intent-to-treat population was defined as all randomised patients who received at least one dose of the study drug and the per-protocol population was defined as all randomised patients who completed the study and therefore received a full course of the study drug. Efficacy evaluations were carried out on the RESULTS Subject characteristics Overall, 41 women were randomised and 38 (92.7%) completed the treatment cycle. One subject (1.25 mg NOMAC/E 2 ) discontinued due to eczema (not related to treatment), one subject (1.25 mg NOMAC/E 2 ) discontinued due to mastalgia (related to treatment) and one subject (2.5 mg NOMAC/E 2 ) discontinued due to headache (related to treatment). Treatment group characteristics were similar at baseline (Table 1) with the exception of weight, which was higher in the 1.25 mg NOMAC/E 2 group. Table 1 Baseline demographic characteristics/gynaecological history (per-protocol population) NOMAC dose group mg/e mg/e mg/e mg alone Total (n ¼ 9) (n ¼ 10) (n ¼ 10) (n ¼ 9) (n ¼ 38) Age, mean (SD), years 26.2 (5.0) 26.6 (5.9) 25.2 (4.9) 26.8 (4.2) 26.2 (4.9) Weight, mean (SD), kg 58.2 (3.2) 64.2 (6.5)* 58.0 (6.4) 56.3 (7.0) 59.3 (6.5) BMI, mean (SD), kg/m (1.2) 22.9 (2.7) 21.1 (2.4) 20.8 (1.6) 21.5 (2.2) Age at first menstruation, 13.7 (12 15) 13.4 (11 17) 12.0 (10 16) 12.8 (10 16) 13.0 (10 17) mean (range), years Number of pregnancies, mean (range) 0.2 (0 2) 0.4 (0 4) 0.5 (0 3) 0.3 (0 3) 0.4 (0 4) *p ¼ 0.04 vs. other treatment groups. NOMAC ¼ nomegestrol acetate; E 2 ¼ 17b-oestradiol; SD ¼ standard deviation; BMI ¼ body mass index. The European Journal of Contraception and Reproductive Health Care 79

6 Antigonadotropic effects of NOMAC/E 2 During the control cycle, all 38 per-protocol subjects ovulated as shown by a midcycle LH peak, P secretion, their cervical mucus score and/or basal body temperature curve. Hormone levels in the control cycle were similar between the four treatment groups. During the treatment cycle, ovulation was inhibited in all subjects in all dose groups, as indicated by midcycle LH 510 miu/ml and P 53 ng/ml during the second half of the cycle in each individual. All mean plasma P levels were 0.8 ng/ml (Figure 1a), and the midcycle LH peak was suppressed (Figure 1b). Compared with the control cycle, there were statistically significant decreases in the treatment cycle in all four treatment groups in AUC, C max,c ave and C max C min for P. Values for AUC, C min,c max,c ave and C max C min during the treatment cycle are summarised in Table 2. Linear regression analysis indicated that suppression of P levels was significantly correlated with NOMAC dose in the NOMAC/E 2 dose groups, with the following correlation coefficients (r): C max r ¼ 0.47 (p ), C ave r ¼ 0.42 (p ) and C max C min r ¼ 0.43 (p ). Mean daily plasma P levels tended to be higher in the 2.5 mg NOMAC alone group compared with the 2.5 mg NOMAC/E 2 group, with a significant difference in C max (p 50.05). Suppression of the LH peak (510 miu/ml) was observed in all treatment groups in the treatment cycle (Figure 1b). Compared with the control cycle, there were statistically significant decreases in AUC, C max, C ave and C max C min in the treatment cycle in all four treatment groups. Daily LH plasma levels were consistently higher in the 2.5 mg NOMAC-alone group compared with the 2.5 mg NOMAC/E 2 group, with significant differences in C max (p ), AUC, C ave and C min (all p ) (Table 2). During the treatment cycle there was no FSH peak in any of the treatment groups and no statistically significant differences in FSH profiles (Figure 2a). In all treatment groups, the maximum FSH level was lower and the minimum level higher in the treatment Figure 1 Mean + standard error of the mean (SEM) daily plasma hormone levels in each treatment group during the control and nomegestrol acetate (NOMAC) treatment cycles (a) progesterone and (b) luteinising hormone. *p for 2.5 mg NOMAC/17b-oestradiol (E 2 ) versus 2.5 mg NOMAC alone; **p ¼ 0.01 for 2.5 mg NOMAC/E 2 versus 2.5 mg NOMAC alone. C ave ¼ average plasma concentration; C max ¼ maximum plasma concentration. 80 The European Journal of Contraception and Reproductive Health Care

7 Table 2 Hormone profiles during the treatment cycle NOMAC dose group Parameter mg/e mg/e mg/e mg alone p-value for 2.5 mg/e 2 Mean (SEM) (n ¼ 9) (n ¼ 10) (n ¼ 10) (n ¼ 9) vs 2.5 mg alone (ANOVA) Progesterone AUC 12-22, ng/ml*d 1.2 (0.3) 0.8 (0.3) 0.4 (0.1) 0.7 (0.2) p ¼ 0.06 C min, ng/ml 0.0 (0.0) 0.0 (0.0) 0.0 (0.0) 0.0 (0.0) p ¼ 0.31 C max, ng/ml 0.3 (0.1) 0.2 (0.1) 0.1 (0.0) 0.3 (0.1) p C ave, ng/ml 0.1 (0.0) 0.1 (0.0) 0.0 (0.0) 0.1 (0.0) p ¼ 0.06 C max C min, ng/ml 0.3 (0.1) 0.2 (0.0) 0.1 (0.0) 0.2 (0.1) p ¼ 0.05 LH AUC 5-22, mlu/ml*d 74.2 (9.2) 54.3 (9.2) 48.1 (8.9) 99.9 (11.2) p C min, mlu/ml 2.7 (0.5) 1.7 (0.4) 1.6 (0.4) 4.0 (0.6) p C max, mlu/ml 6.5 (0.7) 5.4 (0.7) 5.4 (0.6) 9.0 (1.3) p C ave, mlu/ml 4.1 (0.5) 3.0 (0.5) 2.7 (0.5) 5.6 (0.6) p C max C min, mlu/ml 3.9 (0.4) 3.7 (0.4) 3.8 (0.4) 5.1 (1.2) p ¼ 0.30 FSH AUC 5-22, mlu/ml*d (7.6) (9.3) 96.9 (13.5) (5.0) p C min, mlu/ml 4.4 (0.5) 5.0 (0.4) 4.1 (0.7) 5.8 (0.4) p ¼ 0.05 C max, mlu/ml 9.0 (0.5) 10.2 (0.6) 10.5 (0.4) 10.8 (0.2) p ¼ 0.45 C ave, mlu/ml 6.2 (0.4) 6.6 (0.5) 5.4 (0.8) 7. 6 (0.3) p C max C min, mlu/ml 4.6 (0.6) 5.2 (0.5) 6.4 (0.9) 5.0 (0.3) p ¼ 0.16 E 2 AUC 12-22, pg/ml*d (86.9) (49.8) (61.7) (43.0) p C min, pg/ml 46.4 (7.0) 46.5 (4.5) 39.0 (3.2) 16.4 (3.8) p C max, pg/ml (16.5) 89.5 (9.1) 73.2 (7.6) 68.0 (7.7) p ¼ 0.64 C ave, pg/ml 62.0 (7.9) 57.6 (4.5) 47.2 (5.6) 31.9 (3.9) p C max C min, pg/ml 65.8 (17.2) 43.0 (8.3) 34.2 (5.7) 51.6 (5.9) p ¼ 0.05 NOMAC ¼ nomegestrol acetate; SEM ¼ standard error of the mean; E 2 ¼ 17b-oestradiol; ANOVA ¼ analysis of variance; AUC ¼ area under the curve; C min ¼ minimum plasma concentration; C max ¼ maximum plasma concentration; C ave ¼ average plasma concentration; C max C min ¼ difference between C max and C min. cycle compared with the control cycle. The lowest levels of FSH were generally seen in the 2.5 mg NOMAC/E 2 group and the highest levels in the 2.5 mg NOMAC-alone group, with statistically significant differences in AUC and C ave (both p 50.05) between the 2.5 mg NOMAC-alone and 2.5 mg NOMAC/E 2 groups (Table 2). E 2 levels were significantly lower in the treatment cycles than in the control cycles. In the three groups in which NOMAC was coadministered with 1.5 mg E 2, the highest E 2 values were correlated with the lowest doses of NOMAC (Figure 2b) and statistical significance was reached in the regression analysis for C max : r ¼ 0.41 (p 50.05). The plasma E 2 level was lowest in the 2.5 mg NOMAC-alone treatment group; the combination of 2.5 mg NOMAC with E 2 resulted in consistently higher E 2 levels compared with 2.5 mg NOMAC alone (Figure 2b), with statistically significantly higher AUC, C ave (both p 50.05) and C min (p ) (Table 2). Cervical mucus scores Significant decreases were observed in cervical mucus score during the treatment cycle compared with the control cycle in all four treatment groups. There was no statistically significant difference between the four treatment groups during the treatment cycle in cervical mucus score (Table 3). The European Journal of Contraception and Reproductive Health Care 81

8 Safety Thirty-four subjects (82.9%) experienced at least one AE; there were no statistically significant differences between the treatment groups. No serious AEs were reported. In total, 84 AEs were reported, of which 51 (60.7%) were considered to be treatment related. The most common were gynaecological disorders (metrorrhagia, mastalgia and menorrhagia). No abnormal values were reported in haematology and biochemistry data, body weight or vital signs, and there were no differences between the four treatment groups in these parameters. DISCUSSION Figure 2 Mean + standard error of the mean (SEM) daily plasma hormone levels in each treatment group during the nomegestrol acetate (NOMAC) treatment cycle, (a) follicle-stimulating hormone (FSH) and (b) 17b-oestradiol (E 2 ). *p for 2.5 mg NOMAC/E 2 versus 2.5 mg NOMAC alone. C ave ¼ average plasma concentration. Monophasic combinations of 0.625, 1.25 and 2.5 mg NOMAC and 1.5 mg E 2 administered orally for 21 out of 28 days were effective in inhibiting ovulation in women of childbearing age. Marked reductions in P, LH and E 2 were observed in the treatment cycle in comparison to the control cycle. Although ovulation was suppressed in all treatment arms in this study, differences were observed in the hormone profiles across treatment groups. The high dose of NOMAC (2.5 mg) in combination with E 2 tended to give lower mean plasma levels of P, LH and E 2 than the lower NOMAC doses. These findings suggest that there were dose-related differences in suppression of gonadotropin secretion resulting in dose-related differences in inhibition of follicular development across the treatment groups, irrespective of the inhibitory effect on ovulation. Compared with 2.5 mg NOMAC alone, 2.5 mg NOMAC/E 2 was associated with significantly higher levels of E 2 and significantly lower levels of P, LH and FSH. These results indicate that the addition of 1.5 mg E 2 not only compensates for the suppression of endogenous estrogen secretion by 2.5 mg NOMAC alone, but also has a synergistic antigonadotropic action. Table 3 Cervical mucus scores during the control and treatment cycles NOMAC dose group mg/e mg/e mg/e mg alone (n ¼ 8) { (n ¼ 10) (n ¼ 10) (n ¼ 9) Control cycle, mean (SD) 7.3 (1.3) 7.1 (2.0) 6.5 (2.3) 6.1 (2.4) Treatment cycle, mean (SE) 1.5 (0.6)** 2.4 (0.5)** 1.5 (0.5)** 1.6 (0.4)* *p versus control cycle; **p 0.01 versus control cycle. { Cervical mucus score not established in one subject in the treatment cycle due to presence of blood during the examination. NOMAC ¼ nomegestrol acetate; E 2 ¼ 17b-oestradiol; SD ¼ standard deviation; SE ¼ standard error. 82 The European Journal of Contraception and Reproductive Health Care

9 Cervical mucus scores decreased significantly in the treatment cycle compared with the control cycle in all treatment groups. There were no statistically significant differences between treatment groups in cervical mucus scores. Overall, all administered doses of study drug were well tolerated; the AEs related to treatment were all non-serious and did not differ between treatment groups. As expected with this kind of study drug, the most frequent AEs were gynaecological disorders. As the pre-specified number of patients to be enrolled was not achieved owing to difficulties in subject recruitment, this is considered to be a preliminary study and has been followed by further studies involving larger populations treated for more than one cycle 16,17. As the aim of the present dosefinding study was to assess the effects of NOMAC on hormone profiles in combination with E 2 based on the results of the previous dose-ranging study performed with NOMAC alone 9, the same dosing regimen as in the previous study was chosen (21 days with a sevenday pill-free interval). In a study carried out after this one was completed, which compared once-daily 2.5 mg NOMAC/1.5 mg E 2 for either 24 days with a four-day placebo interval or 21 days with a sevenday placebo interval, there was no evidence of ovulation with either NOMAC/E 2 regimen. The objectives of this study were to assess the effects of the different regimens of this combination on follicular development and bleeding profile. The 24-day regimen was associated with greater inhibition of follicular growth and shorter duration of withdrawal bleeding than the 21-day regimen, suggesting a wider margin of contraceptive efficacy with the 24-day regimen of 2.5 mg NOMAC/1.5 mg E In summary, the monophasic combination of NOMAC/E 2 was effective in inhibiting ovulation in women of childbearing age when administered orally for 21 out of 28 days and had a synergistic antigonadotropic action. The higher dose of NO- MAC in combination with E 2 was shown to suppress both ovulation and follicular maturation, suggesting that the 2.5 mg NOMAC/1.5 mg E 2 dose combination may be the most appropriate for a novel, monophasic oral contraceptive preparation. ACKNOWLEDGEMENTS The authors acknowledge Helen Varley, PhD (Envision Scientific Solutions, Horsham, UK) for writing and editorial assistance, contracted by Théramex for these services. Declaration of interest: This report presents data generated from study 96-ESC/NOM-1-RD, which was funded by Théramex, part of the Merck-Serono division. Dr Nathalie Chabbert-Buffet has received consultancy fees from Servier, Aventis and Orion Pharma, and has acted as a clinical investigator in trials funded by Théramex, HRA Pharma and Organon. Didier Chassard has no conflicts of interest to declare. Prof. Sophie Christin-Maitre has received consultancy fees from Schering-Plough, Pierre Fabre, Procter & Gamble and Théramex, and has acted as a clinical investigator in trials funded by Théramex and Organon. Edith Ochsenbein is a previous employee of Théramex. Jean-Louis Thomas was an employee of Théramex at the time of the study and manuscript writing. AUTHORS CONTRIBUTIONS Conception and design: Jean-Louis Thomas Acquisition of data: Didier Chassard, Jean-Louis Thomas Analysis and interpretation of data: Nathalie Chabbert- Buffet, Jean-Louis Thomas, Edith Ochsenbein, Sophie Christin-Maitre Drafting or critically revising the article for important intellectual content: All authors Approval of the final version: All authors REFERENCES 1. Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update 2006;12: Mashchak CA, Lobo RA, Dozono-Takano R, et al. Comparison of pharmacodynamic properties of various estrogen formulations. AmJObstetGynecol1982;144: Calaf i Alsina J. After 50 years of ethinylestradiol, another oestrogen in combined oral contraceptives. Eur J Contracept Reprod Health Care 2010;15: Couzinet B, Young J, Brailly S, et al. The antigonadotropic activity of progestins (19-nortestosterone and The European Journal of Contraception and Reproductive Health Care 83

10 19-norprogesterone derivatives) is not mediated through the androgen receptor. J Clin Endocrinol Metab 1996;81: Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005;8 (Suppl. 1): Dorangeon P, Thomas JL, Choisy H, et al. Effects of nomegestrol acetate on carbohydrate metabolism. Diabete Metab 1993;19: Basdevant A, Pelissier C, Conard J, et al. Effects of nomegestrol acetate (5 mg/d) on hormonal, metabolic and hemostatic parameters in premenopausal women. Contraception 1991;44: Conard J, Basdevant A, Thomas JL, et al. Cardiovascular risk factors and combined estrogen-progestin replacement therapy: a placebo-controlled study with nomegestrol acetate and estradiol. Fertil Steril 1995;64: Bazin B, Thevenot R, Bursaux C, et al. Effect of nomegestrol acetate, a new 19-nor-progesterone derivative, on pituitary-ovarian function in women. Br J Obstet Gynaecol 1987;94: Chretien FC, Dubois R. Effect of nomegestrol acetate on spinability, ferning and mesh dimension of midcycle cervical mucus. Contraception 1991;43: Couzinet B, Young J, Kujas M, et al. The antigonadotropic activity of a 19-nor-progesterone derivative is exerted both at the hypothalamic and pituitary levels in women. J Clin Endocrinol Metab 1999;84: Anderson F. Kinetics and pharmacology of estrogens in pre- and postmenopausal women. Int J Fertil Menopausal Stud 1993;38(Suppl. 1): Wenzl R, Bennink HC, van Beek A, et al. Ovulation inhibition with a combined oral contraceptive containing 1 mg micronized 17 beta-estradiol. Fertil Steril 1993;60: Csemiczky G, Dieben T, Coeling Bennink HJ, Landgren BM. The pharmacodynamic effects of an oral contraceptive containing 3 mg micronized 17 beta-estradiol and mg desogestrel for 21 days, followed by mg desogestrel only for 7 days. Contraception 1996;54: Sullivan H, Furniss H, Spona J, et al. Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 microg) and ethinyl estradiol (15 microg) on ovarian activity. Fertil Steril 1999;72: Serfaty D, Christin-Maitre S, Ochsenbein E, et al. Comparison of two regimens of new monophasic oral contraceptive combining 17 beta-estradiol and nomegestrol acetate. Int J Gynecol Obstet 2009;107 (Suppl. 2): S Gaussem P, Alhenc-Gelas M, Thomas J-L, et al. Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17ß-estradiol, compared with those of levonorgestrel/ethinyl estradiol: A doubleblind, randomized study. Thromb Haemost 2011;105(3): [Epub ahead of print]. 84 The European Journal of Contraception and Reproductive Health Care

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