A phase 2b multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of vaginal rings containing nomegestrol acetate or etonogestrel and 17ß-estradiol in the treatment of women with primary dysmenorrhea.

OBJECTIVE: To evaluate the effect of investigational vaginal rings containing nomegestrol acetate (NOMAC) plus 17ß-estradiol (E2) or etonogestrel (ENG) plus E2 in women with moderate to severe primary dysmenorrhea. STUDY DESIGN: This was a Phase 2b randomized, placebo-controlled, multicenter, double-blind study. We randomized participants to one of five treatment groups: four hormonal rings and one placebo ring. The investigational vaginal rings released 300 µg of E2 daily along with 700 µg or 900 µg of NOMAC or 100 µg or 125 µg of ENG. Each participant received 2 identical rings and was to insert each for 21 days followed by a 7-day ring-free period. The primary endpoint, as assessed by a daily electronic diary (e-Diary), was the change in menstrual pain score from baseline to the second in-treatment withdrawal bleeding episode (Cycle 2). The pain score was the mean of the three highest scores for menstrual cramping pain (0-4 point scale) recorded from the day before menses to the third day of bleeding. The primary hypothesis was that at least one investigational vaginal ring would demonstrate a statistically significant larger reduction from baseline in pain score compared to placebo. Secondary endpoints included total mean impact score (which assessed the negative impact on work/school, physical activities, leisure/social activities) and the amount and days of rescue medication (ibuprofen) used. CLINICAL TRIAL REGISTRATION NUMBER: NCT01670656. RESULTS: We randomized 439 participants. The mean pain score decreased from baseline to Cycle 2 in all groups; the decrease in all four treatment groups compared to placebo was statistically significant (p-values ≤0.002). All treatment groups had greater reductions than placebo in ibuprofen intake and greater improvement in impact scores; these differences were statistically significant for both endpoints for the ENG-E2 100/300 µg/day group, while the other groups were not statistically significant for one or both endpoints. CONCLUSION: All four investigational rings produced a statistically significantly larger reduction from baseline in mean menstrual pain score compared to placebo while pain medication use decreased. IMPLICATIONS: This placebo-controlled study provides evidence that vaginal contraceptive rings containing NOMAC-E2 or ENG-E2 improve moderate to severe dysmenorrhea, across all of doses studied. This adds to the evidence that hormonal contraceptives are effective treatments for dysmenorrhea.

Phase II dose-finding study on ovulation inhibition and cycle control associated with the use of contraceptive vaginal rings containing 17ß-estradiol and the progestagens etonogestrel or nomegestrol acetate compared to NuvaRing.

PURPOSE: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing® (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%. METHODS: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18-35 years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 µg 17ß-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 µg/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 µg/day), or the active control NuvaRing® (ENG/ethinylestradiol 120/15 µg), for three 28-day cycles. RESULTS: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16 nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 µg/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing® with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups. CONCLUSIONS: Contraceptive rings releasing 300 µg E2 and 75-125 µg/day of ENG or 500-900 µg/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing® was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control.

Pooled analysis of two randomized, open-label studies comparing the effects of nomegestrol acetate/17ß-estradiol and drospirenone/ethinyl estradiol on bleeding patterns in healthy women.

OBJECTIVES: To obtain more precise and detailed information regarding the bleeding patterns of nomegestrol acetate (NOMAC)/17ß-estradiol (E2) and drospirenone/ethinyl estradiol (DRSP/EE) and to identify whether baseline demographic characteristics were associated with unscheduled bleeding, absent scheduled bleeding, or amenorrhea. STUDY DESIGN: This analysis pooled results from two pivotal open-label, randomized trials that compared bleeding patterns of NOMAC/E2 and DRSP/EE. In the two studies 4317 women aged 18-50 years from 24 countries across the Americas, Europe, and Asia underwent treatment. RESULTS: 2835 women taking NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen and 938 women taking DRSP/EE (3 mg/30 µg) in a 21/7-day regimen had at least 1 evaluable cycle for vaginal bleeding analyses. The frequency of absent scheduled bleeding was higher (p<.0001) for women using NOMAC/E2 than DRSP/EE across all 11 cycles (cycles 2-12), ranging between 17.6% and 31.6% and between 3.4% and 5.8%, respectively. For women who had absent scheduled bleeding in cycles 2, 3, or 4 the incidence of absent scheduled bleeding in subsequent cycles was high and ranged between approximately 50%-60% for NOMAC/E2 and approximately 40%-50% for DRSP/EE. Amenorrhea increased over time with both regimens, being higher with NOMAC/E2. Both absent scheduled bleeding and amenorrhea with NOMAC/E2 were more common in older women, overweight women, switchers, and smokers; unscheduled bleeding was more common in starters, but had no association with age, body mass index, and smoking. CONCLUSIONS: NOMAC/E2 is associated with a higher prevalence of absent scheduled bleeding compared with DRSP/EE. Absent scheduled bleeding and amenorrhea were associated with age, body weight, switching and smoking. Unscheduled bleeding was more common in starters. IMPLICATIONS: Information about the factors associated with bleeding patterns may help clinicians provide guidance to women considering use of the NOMAC/E2 oral contraceptive.

Comparative analysis of the effects of nomegestrol acetate/17 ß-estradiol and drospirenone/ethinylestradiol on premenstrual and menstrual symptoms and dysmenorrhea.

OBJECTIVES: To compare premenstrual and menstrual symptoms in healthy women using nomegestrol acetate/17ß-estradiol (NOMAC/E2) and drospirenone/ethinylestradiol (DRSP/EE) via the Moos Menstrual Distress Questionnaire Form C (MDQ-C). METHODS: Women completed the MDQ-C at baseline and after completion of cycles 1, 3, 6 and 13, for the premenstrual (four days before most recent flow) and menstrual (most recent flow) phases in two randomized controlled trials. Treatment effects of NOMAC/E2 and DRSP/EE on the t-scores of eight MDQ-C symptom domains from 3522 women were examined, and the effects of both treatments on the score for cramps from 1779 women with moderate to severe cramps at baseline. Longitudinal data analysis methods were applied in both analyses. RESULTS: NOMAC/E2 users experienced a significant improvement in Pain, Water Retention, Negative Affect, Impaired Concentration and Behaviour Change domain scores in the menstrual phase compared with DRSP/EE users (p < 0.001 for all comparisons). However, Arousal (emotional and mental) scores worsened with NOMAC/E2 but not with DRSP/EE. Women with moderate to severe cramps experienced an improvement in the cramps score with NOMAC/E2 and DRSP/EE. CONCLUSIONS: NOMAC/E2 was effective in reducing most premenstrual and menstrual symptoms, and was associated with significantly greater improvements in many MDQ-C domain scores compared with DRSP/EE. ( ClinicalTrials.gov: NCT00413062 and NCT00511199).

Efficacy, safety, and tolerability of a monophasic oral contraceptive containing nomegestrol acetate and 17ß-estradiol: a randomized controlled trial.

OBJECTIVE: To estimate the efficacy, cycle control, tolerability, and safety of a monophasic combined oral contraceptive containing nomegestrol acetate and 17ß-estradiol (E2) in comparison with drospirenone and ethinyl E2. METHODS: In a randomized, open-label, comparative multicenter trial, healthy women (n=2,281; age 18-50 years) at risk for pregnancy and in need of contraception were allocated in a 3:1 ratio to receive nomegestrol acetate (2.5 mg) and 17ß-E2 (1.5 mg) in a 24-4-day regimen (investigational drug) or drospirenone (3.0 mg) and ethinyl E2 (30 micrograms) in a 21-7-day regimen (comparator) for 13 consecutive, 28-day cycles. The primary end point was the Pearl Index. RESULTS: The Pearl Indices for 18- to 35-year-old women in the investigational (n=1,375) and comparator (n=463) groups were 1.27 (95% confidence interval [CI] 0.66-2.22) and 1.89 (95% CI 0.69-4.11), respectively. Respective 1-year cumulative pregnancy rates were 1.22 (95% CI 0.69-2.16) and 1.82 (95% CI 0.81-4.05). By the end of the trial, shorter, lighter scheduled bleeding or an absence of scheduled bleeding occurred with greater frequency (32.9%) in the investigational group, whereas unscheduled bleeding or spotting episodes were low (16.2% and 15.0% in the investigational and comparator groups, respectively). Acne prevalence decreased from approximately 33% at baseline to 22% and 14% at cycle 13 in the respective groups. In the investigational group, the most frequently reported adverse events were acne (16.4%), weight gain (9.5%), and irregular withdrawal bleeding (9.1%). CONCLUSION: Nomegestrol acetate and 17ß-E2 were well tolerated and provided excellent contraceptive efficacy and acceptable cycle control. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT00413062. LEVEL OF EVIDENCE: I.

Efficacy and tolerability of a monophasic combined oral contraceptive containing nomegestrol acetate and 17ß-oestradiol in a 24/4 regimen, in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 regimen.

OBJECTIVES: The primary objective was to assess the efficacy, cycle control and tolerability of a monophasic combined oral contraceptive (COC) containing nomegestrol acetate (NOMAC) and 17ß-oestradiol (E2). Effects on acne were evaluated as a secondary objective. Results were compared to those of a COC containing drospirenone (DRSP) and ethinylestradiol (EE). METHODS: Women (aged 18-50 years) were randomised to receive NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n=1591) or DRSP/EE (3 mg/30 µg) in a 21/7-day regimen (n=535) for 13 cycles. RESULTS: Estimated Pearl Indices for NOMAC/E2 and DRSP/EE were 0.38 and 0.81 in women aged≤35 years and 0.31 and 0.66 for all women (18-50 years), respectively. Scheduled withdrawal bleedings were shorter and lighter among users of NOMAC/E2 and were sometimes absent altogether. Intracyclic bleeding/spotting was infrequent in both groups, and decreased over time. Type and frequency of adverse events were similar to those typically reported for COCs. CONCLUSIONS: These data show that NOMAC/E2 provides high contraceptive efficacy with acceptable cycle control as well as an overall adverse event profile similar to that of DRSP/EE.

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17 beta-oestradiol on ovarian function in comparison to a monophasic combined oral contraceptive containing drospirenone and ethinylestradiol.

OBJECTIVE: To compare the effects on ovarian activity of two oral contraceptives containing nomegestrol acetate (NOMAC)/17 beta-oestradiol (E2) or drospirenone (DRSP)/ethinylestradiol (EE). METHODS: In this open-label, randomised, six-cycle study, 32 subjects using NOMAC/E2 (2.5-1.5 mg; 24/4-day regimen) were compared to 16 subjects using DRSP/EE (3 mg-30 microg; 21/7-day regimen). Measurements included serum oestradiol, progesterone, follicle stimulating hormone (FSH) and luteinising hormone (LH), and ultrasonography of follicular diameter. RESULTS: No ovulations occurred during treatment. Progesterone was fully suppressed, with mean maximum values <2 nmol/l in both groups over all cycles. For NOMAC/E2, mean maximum follicular diameter decreased from 19.3 mm before treatment to between 6.9 and 8.2 mm during treatment, with no subject having a follicular diameter ≥15 mm. For DRSP/EE, a decrease from 19.6 to between 7.4 and 10.8 mm was observed, with two subjects (12.5%) having a maximum follicle diameter ≥15 mm. These findings were consistent with observed FSH reductions; full suppression of LH surges was observed in both groups. Post-treatment return of ovulation in both groups occurred on average 21 days after the last active tablet intake. CONCLUSIONS: NOMAC/E2 achieves consistent ovulation inhibition, with suppressive effects on the ovaries at least similar to those of DRSP/EE.

Ovulation incidence with oral contraceptives: a literature review.

BACKGROUND AND METHODOLOGY: Combined oral contraceptives (COCs) provide reliable and convenient contraception, although contraindications and tolerability issues may limit their use in some women. Progestogen-only pills (POPs) may be more suitable for some women, however, traditional POPs do not have the same contraceptive efficacy as COCs. A literature search was performed in order to assess the incidence of ovulation with available COCs, traditional POPs and with a desogestrel POP [Cerazette, 75 microg desogestrel (DSG)]. The following databases were searched: MEDLINE, EMBASE, Biosis, Derwent Drug File, Current Contents and the in-house Organon database 'Docs' (which contains all published reports of Organon products). Searches used free-text terms [e.g. Contraceptive$ in combination with (Ovulat$ adj Rate$), (Ovar$ adj Activ$) or (Escap$ adj Ovulat$)] and were limited to the search criteria 'Human' and 'from 1979 onwards'. The searches included publications up to July 2008. RESULTS: Many of the studies were hampered by inadequate ovulation criteria; however, the overall incidence of ovulation determined by the reports uncovered in the literature search was 2.0% [95% confidence interval (CI) 1.1-3.3] with COCs containing 30-35 microg ethinylestradiol (EE), 1.1% (95% CI 0.60-2.0) with 15-20 microg EE COCs, 4.6% (95% CI 2.8-6.9) with phasic COCs, 1.25% (95% CI 0.03-6.8) with Cerazette and 42.6% (95% CI 33.4-52.2) with traditional POPs. CONCLUSIONS: The findings indicate that COCs and the desogestrel POP are equally effective in suppressing ovulation, whilst the traditional POP formulations are less effective.