Design of OASIS 1 and 2: phase 3 clinical trials assessing the efficacy and safety of elinzanetant for the treatment of vasomotor symptoms associated with menopause.

OBJECTIVE: Elinzanetant is a selective neurokinin-1,3 receptor antagonist in development for the treatment of vasomotor symptoms (VMS) associated with menopause. The pivotal, double-blind, randomized, placebo-controlled phase 3 studies Overall Assessment of efficacy and Safety of elinzanetant In patients with vasomotor Symptoms (OASIS) 1 and 2 will assess the efficacy and safety of elinzanetant in women with VMS. METHODS: The OASIS 1 and 2 pivotal studies are designed in accordance with regulatory guidance. Postmenopausal women with moderate/severe VMS are randomized to receive 120 mg elinzanetant or placebo once daily for 12 weeks, followed by a 14-week active treatment extension. Primary endpoints are the mean change in frequency and severity of moderate/severe VMS from baseline to weeks 4 and 12. Key secondary endpoints will assess the onset of action and effects on sleep disturbance and menopause-related quality of life. Primary and key secondary endpoints will be analyzed using a mixed model with repeated measures. Feedback from postmenopausal women with VMS was used during protocol development. RESULTS: Women confirmed the relevance of endpoints that assess the impact of VMS, sleep disturbance, and mood changes, and the need for new nonhormone treatments. Educational materials around study design, conduct and expected assessments and procedures were developed based on questions and concerns raised by women. CONCLUSIONS: The OASIS 1 and 2 pivotal phase 3 studies will enable assessment of the efficacy and safety of elinzanetant as a treatment for VMS, together with its effect on sleep disturbances, depressive symptoms, and menopause-related quality of life. Feedback from postmenopausal women with VMS was used to maximize patient centricity in the trials.

Absence of Drug-Drug Interaction of Anastrozole on Levonorgestrel Delivered Simultaneously by an Intravaginal Ring: Results of a Phase 2 Trial.

Intravaginal rings (IVRs) are an established option for continuous administration of drugs in women. The combination of anastrozole (ATZ) and levonorgestrel (LNG) in an IVR with an intended 4-week wearing period has been considered for long-term treatment of endometriosis-associated pelvic pain. A randomized, parallel-group, multicenter phase 2b study to assess the efficacy and safety of different dose combinations in women with symptomatic endometriosis has recently been performed. This paper will focus on the investigation of pharmacokinetic (PK) effects of ATZ on LNG using data collected from this study. Two hundred sixteen patients were randomized to the treatment group with IVRs releasing LNG 40 µg/day alone or in combination with ATZ 300 µg/day, 600 µg/day, or 1050 µg/day for 12 weeks. PK blood samples were taken before dosing and before IVR replacement or removal (days 28, 56, and 84). The primary PK parameter was the plasma concentration in apparent steady state of ATZ and LNG at the end of each IVR wearing period. Results of PK analysis demonstrate that ATZ concentrations increased proportionally with increasing dose (geometric mean values of 7.85, 15.48, and 22.61 µg/L at 300, 600, and 1050 µg/day nominal release, respectively). All point estimates for LNG concentration in apparent steady state ratios between the mono and combination IVR groups were close to 1, and the 90% confidence interval limits were in the 0.80 to 1.25 range (1.01 [0.85-1.19], 1.03 [0.88-1.20], 0.94 [0.80-1.10]). In conclusion, our data indicate there is no evidence of drug-drug interaction of ATZ on LNG.

Different Pearl Indices in studies of hormonal contraceptives in the United States: impact of study population.

OBJECTIVE: To examine the impact of subject characteristics on efficacy as measured by the Pearl Index (PI) in clinical trials and to make study populations similar by matching. METHODS: Our analysis used US data from four large Phase III studies. We compared results from one fertility control patch study with pooled data from three studies with virtually identical design on oral hormonal contraceptives. First, we identified three characteristics that had the most impact on the PI. Second, we used these three variables and matched subjects from the patch study with those from the oral contraceptive (OC) studies. Finally, we calculated the PIs for matched and unmatched subjects from both the patch study and the OC studies. RESULTS: A total of 3706 subjects were included in our analysis. The variables 'Hispanic ethnicity', 'previous pregnancy' and 'previous use of hormonal contraceptives' had the most impact on the PI. The PIs for the matched patch cohort and the matched OC cohort were 2.97 and 2.48, respectively. Those for the unmatched patch cohort and the unmatched OC cohort were 10.17 and 0.90, respectively. CONCLUSION: Subject characteristics strongly influence the PI in clinical studies of hormonal contraceptives. In particular, Hispanic ethnicity, previous pregnancies and no previous use of hormonal contraceptives result in a higher PI. IMPLICATIONS: PIs from different clinical trials cannot be meaningfully compared unless subject characteristics that have most impact on the PI are similar or are made to be similar statistically as we did here by matching.

Effect of a low-dose contraceptive patch on efficacy, bleeding pattern, and safety: a 1-year, multicenter, open-label, uncontrolled study.

This Phase III, uncontrolled, open-label, multicenter study was conducted to investigate the contraceptive efficacy, bleeding pattern, and cycle control of a novel once-a-week contraceptive patch, delivering low-dose ethinyl estradiol (EE) and gestodene (GSD) at the same systemic exposure seen after oral administration of a combined oral contraceptive containing 0.02 mg EE/0.06 mg GSD. Participants were women aged 18 to 35 years, all of whom received the EE/GSD patch for 13 cycles each of 21 treatment days (one patch per week for 3 weeks) followed by a 7-day, patch-free interval. The primary efficacy variable was the occurrence of unintended pregnancies during the study period as assessed by life table analysis and the Pearl Index. Secondary efficacy variables were days with bleeding during four 90-day reference periods and during 1 treatment year, bleeding pattern, and cycle control. The Kaplan-Meier probability of contraceptive protection after 364 treatment days was 98.8% and the adjusted Pearl Index was 0.81. The percentage of participants with intracyclic bleeding/spotting decreased over time, from 11.4% to 6.8% in cycles 1 and 12, respectively. Almost all participants (range: 90.8%-97.6%) experienced withdrawal bleeding across the study period. Compliance was very high (mean: 97.9%; median: 100%). The most frequent adverse events were headache (9.5%) and application site reaction (8.5%); no clinically significant safety concerns were observed. Results suggest the EE/GSD patch is highly effective in preventing pregnancy. Menstrual bleeding pattern was favorable and within the ranges expected of a healthy female population. The patch was well tolerated and treatment compliance was high.

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

OBJECTIVE: To demonstrate the superiority of estradiol valerate plus dienogest (E(2)V/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 E(2)V/DNG (n = 253) or EE/LNG (n = 254) for three 28-daycycles. 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 E(2)V/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 E(2)V/DNG and EE/LNG groups, respectively (P = 0.34). CONCLUSION: Both E(2)V/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.

Efficacy and safety of a combined oral contraceptive containing estradiol valerate/dienogest: results from a clinical study conducted in North America.

BACKGROUND: This study investigated the efficacy and safety of a combined oral contraceptive (COC) containing estradiol valerate/dienogest (E2V/DNG). METHODS: This was a multicenter, noncomparative, 13-cycle (extended to 28 cycles) study conducted in the United States and Canada. Contraceptive efficacy was calculated as a Pearl Index for 13 cycles, based on all on-treatment pregnancies; bleeding patterns were calculated based on bleeding and spotting information recorded daily in diary cards. Safety events during a 16-month extension study were added to the 1-year data. RESULTS: In total, 499 women, aged 18-35 years, were enrolled, and 490 of them were included in the full analysis set for contraceptive efficacy. Five pregnancies occurred in the first year (unadjusted Pearl Index=1.64). In cycles 1-12, an average 23.5% of women had absent scheduled (withdrawal) bleeding. Among women with scheduled (withdrawal) bleeding, bleeding started after a median of 2 days after intake of the last DNG-containing pill. For safety, data included from 147 women followed over an additional 16 months were added to the original 13-cycle data set. Treatment-related adverse events (AEs) occurred in 51.8% of women; 14.9% discontinued because of AEs over the entire 28-month study period. CONCLUSION: A COC with E2V and DNG was shown to provide effective contraception in women aged 18-35 years in North America.

Change to either a nonandrogenic or androgenic progestin-containing oral contraceptive preparation is associated with improved sexual function in women with oral contraceptive-associated sexual dysfunction.

INTRODUCTION: It is a commonly held belief that combined oral contraceptive (COC) pills containing an androgenic progestin may be less likely to impair sexual function than COCs containing an anti-androgenic progestin. AIM: The study aims to compare the effects of a COC containing a progestin with an anti-androgenic profile (estradiol valerate [E2 V]/dienogest [DNG]) to that of one with an androgenic progestin (ethinyl estradiol [EE]/levonorgestrel [LNG]) on sexual function in women with COC-associated sexual dysfunction. METHODS: In this multicenter, randomized, double-blind, noninferiority study, women with COC-associated female sexual dysfunction (FSD) were randomized to E2 V/DNG or EE/LNG for six cycles. The primary outcome was the change in the sum of Female Sexual Function Index (FSFI) desire and arousal component scores between baseline and cycle 6. Secondary outcome measures included changes to the FSFI domains, the Female Sexual Distress Scale (FSDS-R), Vaginal Health Assessment, the Atrophy Symptom Questionnaire, and the Psychological General Well Being Index over six treatment cycles. MAIN OUTCOME MEASURE: The main outcome is the change in the sum of FSFI desire and arousal component scores between baseline and cycle 6. RESULTS: Of 276 women screened, 213 received treatment and 191 completed the study. The mean increase in the sum of FSFI desire and arousal component scores was 5.90 (standard deviation [SD] 5.45) for E2 V/DNG and 5.79 (SD 6.17) for EE/LNG (change from baseline P < 0.0001, both groups). Both treatments showed equal efficacy and were associated with improvements in all domains of the FSFI, with no between-group differences. Both COCs reduced the distress associated with FSD, as indicated by reduced FSDS-R scores. CONCLUSION: In women with COC-associated FSD, switching to either E2 V/DNG or EE/LNG was associated with equivalent improvements in symptoms, challenging the perception that COCs containing anti-androgenic progestins have a detrimental effect on sexual function relative to those containing androgenic progestins.

Efficacy and bleeding profile of a combined oral contraceptive containing oestradiol valerate/dienogest: a pooled analysis of three studies conducted in North America and Europe.

OBJECTIVE: To summarise all clinical data on the contraceptive efficacy and bleeding profile associated with an oestradiol valerate (E2V) and dienogest (DNG) [E2V/DNG] combined oral contraceptive (COC) derived from Phase III trials. METHODS: Pooled analysis of three large-scale multicentre trials conducted in healthy women who received oral E2V/DNG for 7 to 28 cycles (28-day cycles). RESULTS: A total of 2266 women were included in this analysis. Overall, 19 pregnancies occurred over 13 cycles during 880,950 days of relevant exposure (Pearl Index [PI] of 0.79; upper limit of the two-sided 95% confidence interval [CI]: 1.23). Ten pregnancies attributed to method failure came about during 871,091 days of relevant exposure (adjusted PI of 0.42; upper limit of the two-sided 95% CI: 0.77). In women aged 18 to 35 years (n = 1687), the corresponding PI and adjusted PI were 1.01 (upper limit of the two-sided 95% CI: 1.59) and 0.51 (upper limit of the two-sided 95% CI: 0.97), respectively. In the first 13 cycles of treatment, 76 to 81% of women experienced scheduled withdrawal bleeding, and 13 to 23% experienced intracyclic bleeding. CONCLUSIONS: E2V/DNG provides reliable contraceptive efficacy in women aged 18 to 50 years.

Hormone withdrawal-associated symptoms: comparison of oestradiol valerate/dienogest versus ethinylestradiol/norgestimate.

OBJECTIVES: To determine the effect of oestradiol valerate/dienogest (E2V/DNG) versus ethinylestradiol/norgestimate (EE/NGM) on hormone-withdrawal associated symptoms (HWAS) in otherwise healthy women who had experienced at least one of these symptoms when using 21/7-day combined oral contraceptives (COCs). METHODS: This phase III, parallel-group study randomised 409 women aged 18 to 50 years to E2V/DNG or EE/NGM. The primary efficacy variable was the change from baseline to cycle 6 in the average of the three highest visual analogue scale values for headache and/or pelvic pain during cycle days 22 to 28. RESULTS: In total, 395 were included in the full analysis set (E2V/DNG, n = 191; EE/NGM, n = 204). E2V/DNG reduced the symptoms of headache or pelvic pain during cycle days 22 to 28 from baseline to cycle 6 to a significantly greater extent than EE/NGM (mean decrease 43.6 vs. 35.5 mm; p = 0.0024). Both treatments were well tolerated with a similar proportion of women experiencing adverse events that were considered at least possibly related to treatment (35% E2V/DNG vs. 34% EE/NGM). CONCLUSIONS: E2V/DNG reduces the frequency and intensity of headache and pelvic pain to a greater extent than EE/NGM, and may be a good option for women susceptible to HWAS with conventional 21/7-day COCs.

Estimation of menstrual blood loss volume based on menstrual diary and laboratory data.

BACKGROUND: Abnormal uterine bleeding is often investigated in clinical studies and critical to identify during gynecological consultation. The current standard for quantification of menstrual blood loss is the alkaline-hematin-method. However, this method is expensive and inconvenient for patients. Bleeding diaries, although widely used, provide only qualitative information on menstrual blood loss. Other methods have been developed, but still do not provide reliable quantitative data. METHODS: We estimated blood loss volume using data from two clinical studies in women suffering abnormal menstrual bleeding. These estimations were derived from mixed linear models based on diary data, hematological parameters and age. To validate the models, we applied our results to data from a third study with a similar patient population. RESULTS: The resulting best fitting model uses diary entries on bleeding intensity at a particular day, information on occurrence and frequency of single bleeding intensities in defined time windows, hemoglobin and ferritin values and age of the patient all as predictors of menstrual blood loss volume. Sensitivity and specificity for the diagnosis of excessive bleeding were 87% and 70%, respectively. Our model-based estimates reflect the subjective assessment by physicians and patients in the same way as the measured values do.When applying the model to an independent study, we found a correlation of 0.73 between estimated and measured values for the blood loss in a single day. Further models with reduced number of parameters (simplified for easier practical use) still showed correlation values between 0.69 and 0.73. CONCLUSIONS: We present a method for estimating menstrual blood loss volume in women suffering from prolonged or excessive menstrual bleeding. Our statistical model includes entries from bleeding diaries, laboratory parameters and age and produces results which correlate well with data derived by the alkaline-hematin-method. Therefore, this model may be used to estimate menstrual blood loss volume in both routine gynecological counseling and clinical studies.

Evaluation of the effects of rifampicin, ketoconazole and erythromycin on the steady-state pharmacokinetics of the components of a novel oral contraceptive containing estradiol valerate and dienogest in healthy postmenopausal women.

BACKGROUND: We evaluated the effects of cytochrome P450 3A4 (CYP3A4) induction and inhibition on steady-state pharmacokinetics of the components of a novel oral contraceptive (OC) containing estradiol valerate (E2V) and dienogest (DNG). STUDY DESIGN: CYP3A4 induction was assessed in an open-label, one-arm study. Sixteen healthy postmenopausal women received E2V 2 mg/DNG 3 mg (days 1-17) and concomitant rifampicin (600 mg, days 12-16). Ratios of the area under the serum concentration-time curve between 0 and 24 h [AUC(0-24 h)] and maximum serum concentration (C(max)) of E2 and DNG on days 17 and 11 (after and before rifampicin intervention) are presented. CYP3A4 inhibition was investigated in an open-label, parallel-group study in 24 healthy postmenopausal women receiving E2V 2 mg/DNG 3 mg (days 1-14) and concomitant ketoconazole (400 mg, n=12) or erythromycin (500 mg three times daily, n=12) on days 8-14. Mean ratios of AUC(0-24 h) and C(max) of E2 and DNG on days 7 and 14 are presented. RESULTS: Concomitant administration of rifampicin decreased systemic drug exposure and yielded geometric mean ratios for E2C(max) and AUC(0-24 h) of 75% and 56%, respectively. Corresponding mean ratios for DNG were 48% and 17%, respectively. Ketoconazole coadministration increased systemic drug exposure and yielded ratios of E2 of 165% and 157%, respectively, and ratios of DNG of 194% and 286%, respectively. Erythromycin coadministration also resulted in increased mean C(max) and AUC(0-24 h) of both E2 and DNG. Geometric mean ratios of C(max) and AUC(0-24 h) for E2 were 151% and 133%, respectively. Corresponding ratios for DNG were 133% and 162%, respectively. CONCLUSIONS: Significant drug-drug interactions are apparent when CYP3A4 modulators are coadministered with the components of a novel OC containing E2V/DNG. Coadministration of CYP3A4 modulators should be avoided where possible, and another type of contraception should be used when coadministration of CYP3A4 inducers like rifampicin is unavoidable.

Normalization of blood loss in women with heavy menstrual bleeding treated with an oral contraceptive containing estradiol valerate/dienogest.

BACKGROUND: The study was conducted to assess the efficacy of estradiol valerate/dienogest (E2V/DNG) administered using an estrogen step-down and progestogen step-up approach in a 28-day regimen in the treatment of heavy menstrual bleeding (HMB) using clinical end points allowing E2V/DNG to be compared with other available medical therapies. STUDY DESIGN: This was a pooled analysis of data from two identically designed randomized, placebo-controlled, multiple center studies conducted in Europe, Australia and North America that assessed the effectiveness of E2V/DNG in reducing menstrual blood loss (MBL) in women with HMB. Women aged ≥ 18 years with objectively confirmed HMB were randomized to E2V/DNG (n=220) or placebo (n=135) for seven treatment cycles. Outcomes analyzed included absolute reduction in MBL from baseline, proportion of women successfully treated (defined as MBL below 80 mL and ≥ 50% reduction in MBL), proportion with MBL below 80 mL and proportion with ≥ 50% reduction in MBL from baseline. RESULTS: At study end, 63.6% and 11.9% of patients were successfully treated with E2V/DNG and placebo, respectively, with 68.2% and 15.6% of women with MBL below 80 mL, and 70.0% and 17.0% with MBL reduction ≥ 50% (all p<.001). CONCLUSION: E2V/DNG is highly effective for the treatment of HMB and is associated with a high rate of treatment success.

Metabolic and haemostatic effects of estradiol valerate/dienogest, a novel oral contraceptive: a randomized, open-label, single-centre study.

BACKGROUND AND OBJECTIVE: The hormonal components of combined oral contraceptives (COCs) have various metabolic and haemostatic effects. The objective of this study was to compare the metabolic and haemostatic effects of a novel COC comprising estradiol valerate/dienogest (E(2)V/DNG) with ethinylestradiol/levonorgestrel (EE/LNG). METHODS: In a randomized, open-label study conducted in Germany over seven cycles, healthy women aged 18-50 years received E(2)V/DNG (E(2)V 3 mg on days 1-2, E(2)V 2 mg/DNG 2 mg on days 3-7, E(2)V 2 mg/DNG 3 mg on days 8-24, E(2)V 1 mg on days 25-26, placebo on days 27-28; n = 30) or EE/LNG (EE 0.03 mg/LNG 0.05 mg on days 1-6, EE 0.04 mg/LNG 0.075 mg on days 7-11, EE 0.03 mg/LNG 0.125 mg on days 12-21, placebo on days 22-28; n = 28). The primary variables were the mean intraindividual relative changes from baseline to cycle 7 in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels. Changes in other lipid parameters, haemostatic parameters, sex hormone-binding globulin (SHBG), cortisol-binding globulin (CBG), carbohydrate metabolism parameters, blood pressure and body weight were also assessed. RESULTS: Mean ± SD HDL cholesterol increased by 7.9% ± 21.8% with E(2)V/DNG and decreased by 2.3% ± 14.4% with EE/LNG. Mean ± SD LDL cholesterol decreased by 6.5% ± 15.9% with E(2)V/DNG and by 3.0% ± 17.4% with EE/LNG. Mean ± SD prothrombin fragment 1 + 2 and D-dimer levels remained essentially unchanged in the E(2)V/DNG group (-0.6% ± 30.3% and -2.1% ± 43.5%, respectively), but increased in the EE/LNG group (by 117.3% ± 358.0% and 62.9% ± 99.5%, respectively). Changes in other hepatic-induced parameters (SHBG, CBG) and carbohydrate metabolism were generally less pronounced with E(2)V/DNG versus EE/LNG. Body weight and blood pressure remained stable throughout the study in both treatment groups. Both formulations were well tolerated, with no serious adverse events reported. CONCLUSION: E(2)V/DNG had a minimal impact on metabolic and haemostatic parameters, and a more favourable effect than EE/LNG on lipid markers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00185224.

Effective treatment of heavy and/or prolonged menstrual bleeding without organic cause: pooled analysis of two multinational, randomised, double-blind, placebo-controlled trials of oestradiol valerate and dienogest.

OBJECTIVES: To evaluate the efficacy of oestradiol valerate/dienogest (E2V/DNG) for the treatment of heavy and/or prolonged menstrual bleeding without organic pathology based on the analysis of data from two identically designed double-blind, randomised studies. METHODS: Women aged ≥ 18 years with heavy and/or prolonged menstrual bleeding were randomised to E2V/DNG (n = 269) or placebo (n = 152) for 196 days. Objective changes in menstrual blood loss (MBL) volume were assessed using the alkaline haematin method. RESULTS: After six months of treatment, median MBL decreased by 88% with E2V/DNG compared with 24% with placebo. The greatest reduction was achieved at the first withdrawal bleed after treatment initiation and it was sustained with no loss of effect throughout treatment. CONCLUSION: E2V/DNG was more effective than placebo in reducing MBL in women with heavy and/or prolonged menstrual bleeding without organic pathology. The reduction was largely achieved as early as the first withdrawal bleed, with further gradual improvement throughout treatment.

Effect of extended-cycle regimen with an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on bleeding patterns, safety, acceptance and contraceptive efficacy.

BACKGROUND: The present study compared the efficacy and safety of a combined oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest (EE/DNG) in conventional and extended-cycle regimen over 1 year of treatment. STUDY DESIGN: In a phase III, randomized, prospective, open, two-arm, multicenter study, 1315 sexually active women (range, 18-40 years) were treated with EE/DNG either conventionally (21/7 days) or according to an extended-cycle regimen (84/7 days). Data were documented on volunteer diaries, and adverse events (AEs) were reported during five visits. RESULTS: In the extended-regimen group, the total number of days with bleeding progressively decreased over time, and overall, the volunteers had fewer numbers of days with bleeding/spotting compared to those treated conventionally. Intracyclic bleeding, on the other hand, was more frequent in the extended-cycle group, although its frequency considerably decreased over time. Both regimens offered reliable contraception, with an unadjusted Pearl Index of 0.489 for the conventional regimen and 0.495 for the extended regimen. The number of AEs was higher in the extended-cycle group, although the group differences tended to decrease over time. CONCLUSIONS: Extended-cycle use of EE/DNG was effective and mostly well tolerated, appearing to be a favorable option for women who need or wish to omit the pill-free interval.

Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel.

BACKGROUND: A novel estradiol-based combined oral contraceptive (COC) is currently available in many countries worldwide, including Europe and the US. Based on previous studies, it is expected that this estradiol-based COC will have a reduced hepatic effect compared with COCs containing ethinylestradiol with regard to proteins controlling the hemostatic balance. OBJECTIVE: The aim of this study was to compare the hemostatic effects of the estradiol valerate/dienogest COC with a monophasic low-estrogen dose COC containing ethinylestradiol/levonorgestrel. STUDY DESIGN: Healthy women aged 18-50 years were randomized to receive a COC containing estradiol valerate/dienogest (2 days estradiol valerate 3 mg, 5 days estradiol valerate 2 mg/dienogest 2 mg, 17 days estradiol valerate 2 mg/dienogest 3 mg, 2 days estradiol valerate 1 mg, 2 days placebo) or ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg in a crossover study design. Women received each treatment for three cycles, with two washout cycles between treatments. The primary efficacy variables were the intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three. RESULTS: Data from 29 women were assessed. Intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three were less pronounced with estradiol valerate/dienogest than with ethinylestradiol/levonorgestrel. CONCLUSION: The novel COC containing estradiol valerate/dienogest had similar or less pronounced effects on hemostatic parameters than ethinylestradiol/levonorgestrel.

Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial.

OBJECTIVE: To estimate the efficacy of a fixed estrogen step-down and progestin step-up 28-day estradiol (E2) valerate and dienogest oral contraceptive regimen in women with heavy menstrual bleeding, prolonged menstrual bleeding, or heavy and prolonged menstrual bleeding without organic pathology. METHODS: This double-blind, placebo-controlled study randomized women aged 18 years or older with prolonged, frequent, or heavy menstrual bleeding, objectively confirmed during a 90-day run-in phase, to treatment with E2 valerate and dienogest or placebo (2:1) for 196 days. Data from the last 90 days of treatment and the run-in phase were compared. The primary variable was the "complete response" rate (complete resolution of qualifying abnormal menstrual symptoms, including a 50% or greater reduction in pretreatment menstrual blood loss volume in women with heavy menstrual bleeding). Secondary variables included objective changes in menstrual blood loss volume (alkaline hematin methodology) and iron metabolism parameters. Overall, 180 women were needed to provide 90% power. RESULTS: There were no marked differences in the characteristics of E2 valerate and dienogest (n=120) and placebo (n=70) recipients. The proportion of "complete responders" in the evaluable group was significantly higher in E2 valerate and dienogest (35/80; 43.8%) compared with placebo (2/48, 4.2%, P<.001) recipients. The mean [standard deviation] reduction in menstrual blood loss with E2 valerate and dienogest from the run-in phase to the efficacy phase was substantial (-353 mL [309 mL]; mean -64.2%; median -70.6%) and significantly greater than that in placebo recipients (-130 mL [338 mL]; mean -7.8%; median -18.7%; P<.001). Significant improvements in hemoglobin, hematocrit, and ferritin were seen with E2 valerate and dienogest, but not with placebo. CONCLUSION: Oral E2 valerate and dienogest was highly effective compared with placebo in the treatment of women with heavy menstrual bleeding, prolonged menstrual bleeding, or heavy and prolonged menstrual bleeding without organic pathology. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00293059. LEVEL OF EVIDENCE: I.

Effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on lipid metabolism during 1 year of conventional or extended-cycle use.

BACKGROUND: The effects of extended regimens of combined oral contraceptives (COC) on lipid parameters are largely unknown. The present study compared the effects of a COC containing 30 mcg ethinyl estradiol and 2 mg dienogest (EE/DNG) in conventional and extended-cycle regimen over 1 year. STUDY DESIGN: Lipid parameters were measured in 59 women treated with EE/DNG either conventionally (21+7 days) or in extended-cycle regimen (84+7 days). Blood samples were taken in a control cycle and at 3 and 12 months of treatment. RESULTS: The mean levels of total cholesterol, HDL cholesterol and HDL(2) cholesterol underwent modest to moderate significant increases over time, while the significant increase in triglycerides and VLDL cholesterol was more pronounced with both regimens. LDL cholesterol decreased slightly in both regimen groups, whereas lipoprotein(a) was transiently decreased at 3 months only in the extended-cycle group. The changes reached a steady-state at latest at 3 months, but did not exceed the given normal ranges for any of the parameters. Notably, except for lipoprotein(a), the changes in mean lipid levels were not significantly different in the conventional and the extended-cycle regimen at 3 or 12 months of treatment. CONCLUSION: Use of EE/DNG in conventional or extended-cycle regimen resulted in comparable changes of lipid parameters.

Bleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel.

BACKGROUND: This study compared the bleeding pattern, cycle control and safety of an oral contraceptive (OC) comprising estradiol valerate/dienogest (E2V/DNG; administered using a dynamic dosing regimen) with a monophasic OC containing ethinyl estradiol 20 mcg/levonorgestrel 100 mcg (EE/LNG). E2V releases estradiol (E2), which is identical to endogenously produced 17beta-estradiol. STUDY DESIGN: This was a randomized, multicenter, double-blind, double-dummy trial lasting seven cycles in healthy women aged 18-50 years. RESULTS: Overall, 798 women were randomized and received allocated treatment (399 per group). There were significantly fewer bleeding/spotting days reported by women who received E2V/DNG than those who received EE/LNG [17.3+/-10.4 vs. 21.5+/-8.6, respectively, p<.0001, Reference Period 1 (Days 1-90); and 13.4+/-9.vs. 15.9+/-7.1, respectively, p<.0001, Reference Period 2 (Days 91-180)]. Through Cycles 1-7, the occurrence of scheduled withdrawal bleeding per cycle was 77.7-83.2% with E2V/DNG and 89.5-93.8% with EE/LNG (p<.0001 per cycle). The duration and intensity of scheduled withdrawal bleeding were reduced with E2V/DNG vs. EE/LNG. The incidence of intracyclic bleeding was similar with E2V/DNG (10.5%-18.6%) and EE/LNG (9.9%-17.1%) (p>.05 per cycle). No unintended pregnancies occurred with E2V/DNG, but there was one unintended pregnancy with EE/LNG. Adverse drug reactions occurred in 10.0% and 8.5% of women taking E2V/DNG and EE/LNG, respectively. Overall, 79.4% of women were satisfied with E2V/DNG and 79.9% with EE/LNG. CONCLUSIONS: A novel OC composed of E2V/DNG is associated with an acceptable bleeding profile that is comparable to that of an EE-containing OC.

Effects of conventional or extended-cycle regimen of an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on various hemostasis parameters.

BACKGROUND: The study was conducted to investigate the effect of a combined oral contraceptive (COC) containing 30 mcg ethinylestradiol and 2 mg dienogest with two different regimens on various hemostasis variables. STUDY DESIGN: Hemostatic parameters were measured in 59 women treated with a monophasic COC containing 30 mcg ethinylestradiol and 2 mg dienogest (EE/DNG) either conventionally (13 cycles with 21 days of treatment+7 days without hormones) or with an extended-cycle regimen (4 extended cycles with 84 days of continuous administration of EE/DNG, followed by a hormone-free interval of 7 days). Blood samples were taken on Days 21-26 of the preceding control cycle and on Days 19-21 of the 3rd and 13th conventional cycle or on Days 82-84 of the first and fourth extended cycle. RESULTS: After 3 and 12 months, significant increases in fibrinogen (20%), factor VII antigen (50-60%), factor VII activity (45%), activated factor VII (30-45%) and factor VIII activity (10-20%) occurred in both treatment regimens. In both groups, there was a small but significant decrease in the level and activity of antithrombin, a 20-25% decrease in total and free protein S and a 15-20% rise in the level and activity of protein C, but no significant change of the thrombin-antithrombin complex. A significant over-time rise by about 25% of prothrombin fragment 1+2 occurred only in the extended-cycle group, but this effect did not differ significantly from that observed during conventional treatment. Plasminogen was elevated by 50% in both groups, while tissue-plasminogen activator (t-PA) activity rose by 15% in the conventional group and by 25-30% in the extended-cycle group. In both groups, t-PA antigen was reduced by about 30% and plasminogen activator inhibitor-1 by 40-60%. The levels of the plasmin-antiplasmin complex rose by 30-40% and those of D-dimers by 20-55%. The prothrombin time was slightly increased and the activated partial thromboplastin time was slightly decreased. CONCLUSION: In general, these results were in agreement with those observed during treatment with other COCs. The study demonstrated that during conventional and extended-cycle treatment with EE/DNG, a steady-state in the effects on hemostasis variables was reached within 3 months, and that the effects observed after 3 and 12 months of treatment did not substantially differ between conventional and extended-cycle regimen.