Joachim Marr

Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial

BACKGROUND Dienogest is a selective progestin that has been investigated in a clinical trial programme for the treatment of endometriosis. The current non-inferiority trial compared the efficacy and safety of dienogest against leuprolide acetate (LA) for treating the pain associated with endometriosis. METHODS Patients with confirmed endometriosis were randomized to treatment with dienogest (2 mg/day, orally) or LA (3.75 mg, depot i.m. injection, every 4 weeks) for 24 weeks. The primary efficacy variable was absolute change in pelvic pain from baseline to end of treatment, assessed by visual analogue scale (VAS). Safety variables included adverse event profile, laboratory parameters, bone mineral density (BMD), bone markers and bleeding patterns. RESULTS A total of 252 women were randomized to treatment with dienogest (n = 124) or LA (n = 128); 87.9 and 93.8% of the respective groups completed the trial. Absolute reductions in VAS score from baseline to Week 24 were 47.5 mm with dienogest and 46.0 mm with LA, demonstrating the equivalence of dienogest relative to LA. Hypoestrogenic effects (e.g. hot flushes) were reported less frequently in the dienogest group. As expected, bleeding episodes were suppressed less with dienogest than with LA. Changes in mean lumbar BMD between screening and final visit were +0.25% with dienogest and -4.04% with LA subgroups (P = 0.0003). Markers of bone resorption increased with LA but not dienogest. CONCLUSIONS Dienogest 2 mg/day orally demonstrated equivalent efficacy to depot LA at standard dose in relieving the pain associated with endometriosis, although offering advantages in safety and tolerability.

Suppression of ovarian activity with a drospirenone-containing oral contraceptive in a 24/4 regimen

BACKGROUND This study was conducted to compare ovarian activity of an oral contraceptive containing drospirenone (drsp) 3 mg plus ethinylestradiol (EE) 20 mcg administered in 24/4 regimen compared with the conventional 21/7 regimen, during intended use and following predefined dosing errors. STUDY DESIGN Women aged 18-35 years who ovulated or had a follicular diameter of >or=15 mm on or before Day 23 during a pretreatment cycle were admitted into this double-blind, randomized study. Participants underwent 3 treatment cycles with drsp 3 mg/EE 20 mcg in a 24/4 (n=52) or a 21/7 (n=52) regimen. In the third treatment cycle, the initial three pills in both groups were replaced with placebos. Ovarian activity was classified using the Hoogland scale during pretreatment and during Cycles 2 and 3. RESULTS Suppression of ovarian activity was more pronounced with the 24/4 regimen--the odds ratio for a lower Hoogland score (i.e., greater ovarian suppression) with the 24/4 regimen compared with the conventional 21/7 regimen were 6.01 (95% CI: 2.29-17.94) and 3.06 (95% CI: 1.44-6.65) for Cycles 2 and 3, respectively. More women in the 24/4 regimen group had no ovarian activity 87.8% vs. 56.0% during Cycle 2 and 55.1% vs. 30.0% during Cycle 3. The 24/4 regimen was associated with a more consistent suppression (less fluctuation) of endogenous estradiol. CONCLUSION The drsp 3 mg/EE 20 mcg oral contraceptive in a 24/4 regimen was associated with greater ovarian suppression (despite intentional dosing error), which results in decreased hormonal fluctuations, and may increase contraceptive efficacy with the low-dose formulation.

Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis

To analyze the secondary efficacy and safety outcomes from a recent trial comparing dienogest (DNG) with leuprolide acetate (LA) in women with endometriosis.

Folate status and homocysteine levels during a 24-week oral administration of a folate-containing oral contraceptive: a randomized, double-blind, active-controlled, parallel-group, US-based multicenter study

BACKGROUND This study investigated the effects of adding levomefolate calcium 0.451 mg (the calcium salt of L-5-methyltetrahydrofolate; Metafolin®) to an oral contraceptive containing ethinylestradiol (EE) 20 mcg/drospirenone (drsp) 3 mg on folate levels in healthy women seeking contraception. STUDY DESIGN In this randomized, double-blind, multicenter US-based study, women (18-40 years) received 24 weeks (six cycles) of EE/drsp/levomefolate calcium or EE/drsp for 24 days followed by 4 days of levomefolate calcium alone or placebo, respectively. The primary efficacy variables were red blood cell (RBC) and plasma folate levels at 24 weeks. RESULTS At week 24, increases from baseline in mean RBC (990 ± 390 nmol/L to 1406 ± 440 nmol/L) and plasma folate (45.0 ± 17.6 nmol/L to 60.8 ± 19.9 nmol/L) levels were observed in women who received EE/drsp/levomefolate calcium [per protocol set (n=262); all values are displayed as mean ± standard deviation]. In contrast, marginal fluctuations were observed with EE/drsp (p<.0001 for between-treatment differences at week 24). CONCLUSION Clinically significant increases in folate status were observed with EE/drsp/levomefolate calcium compared with EE/drsp alone in US women of childbearing age.

Premenstrual dysphoric disorder symptom cluster improvement by cycle with the combined oral contraceptive ethinylestradiol 20 mcg plus drospirenone 3 mg administered in a 24/4 regimen

BACKGROUND A combined oral contraceptive comprising ethinylestradiol (EE) 20 mcg/drospirenone 3 mg in a 24/4 regimen has been clinically shown to alleviate the symptoms associated with premenstrual dysphoric disorder (PMDD). However, previous studies did not report data according to cycle-by-cycle improvement. STUDY DESIGN This was a subanalysis of a Phase III, double-blind, multicenter, United States-based study. Women with confirmed PMDD were randomized to EE 20 mcg/drospirenone 3 mg 24/4 or placebo for three treatment cycles. Ten of the 21 emotional and physical items on the Daily Record of Severity of Problems scale were grouped to define three symptom clusters: (a) negative emotions, (b) food cravings and (c) water retention-related symptoms. The change from baseline at each treatment cycle was compared between groups using a weighted analysis of covariance model. RESULTS The full analysis set comprised 449 women. Daily Record of Severity of Problems scores for each symptom cluster were significantly reduced from baseline with both EE 20 mcg/drospirenone 3 mg 24/4 and placebo (p<.0001 for all). The greatest symptom improvements were achieved within the first cycle of treatment and continued throughout cycles 2 to 3. The mean between-treatment difference was significant in favor of EE 20 mcg/drospirenone 3 mg 24/4 for all three symptom clusters in all three treatment cycles (p≤.0001 vs. placebo in percent change from baseline). CONCLUSION Ethinylestradiol 20 mcg/drospirenone 3 mg 24/4 improved commonly recognizable PMDD symptom clusters relating to negative emotions, food cravings and water retention-related symptoms to a significantly greater extent than placebo during all three cycles of treatment.

Contraceptive efficacy of a combined oral contraceptive containing ethinyloestradiol 20 μg/drospirenone 3 mg administered in a 24/4 regimen: a pooled analysis of four open-label studies

OBJECTIVE To determine the contraceptive efficacy of a low-dose combined oral contraceptive containing ethinyloestradiol (EE) 20 μg/drospirenone (drsp) 3mg administered for 24 days followed by a four-day hormone-free interval (24/4 regimen), by pooling data from four clinical trials. STUDY DESIGN Data on the occurrence of pregnancy during treatment in four open-label trials that enrolled healthy female volunteers aged 17-36 years, who received EE 20 μg/drsp 3mg in a 24/4 regimen for 7 or 13 cycles, were pooled. RESULTS Sixteen pregnancies occurred among 2386 women during 729,537 days (26,055 cycles) of treatment exposure, resulting in a Pearl Index (PI) of 0.80 (upper two-sided 95% confidence interval (CI) limit of 1.30). Of these pregnancies, seven were defined as method failures, resulting in an adjusted PI of 0.41 (upper two-sided 95% CI limit of 0.85), based on 616,607 days (22,022 cycles) of treatment. The Kaplan-Meier estimate for the one-year cumulative probability of contraceptive protection was 99.21%. CONCLUSIONS The EE 20 μg/drsp 3mg combined oral contraceptive administered in a 24/4 regimen has acceptable contraceptive efficacy.

Cycle control and bleeding pattern of a 24/4 regimen of drospirenone 3 mg/ethinylestradiol 20 μg compared with a 21/7 regimen of desogestrel 150 μg/ethinylestradiol 20 μg: a pooled analysis.

AbstractBackground and Objective: The degree of cycle control achieved with a hormonal contraceptive method is an important determinant of its acceptance and continuation. This study set out to compare the cycle control and bleeding profile of drospirenone (DRSP) 3 mg/ethinylestradiol (EE) 20 μg in a 24-active pill/4-inert pill (24/4) regimen (YAZ®) with those of desogestrel (DSG) 150 ®g/EE 20 ®g in a 21/7 regimen (Mercilon®), an established European combined oral contraceptive (COC). Methods: Bleeding data from women aged 17–36 years who received either DRSP 3 mg/EE 20 μg in a 24/4 regimen (n= 1285) or DSG 150 μg/EE 20 μg in a 21/7 regimen (n = 471) during four clinical studies were pooled and analysed over seven treatment cycles. Results: The maximum intensity of scheduled withdrawal bleeding was ‘normal bleeding’ for >50% of subjects in cycles 1–6 in both treatment groups. Moreover, the incidence of unscheduled intracyclic bleeding during cycles 2–7 was comparable between treatment types (10.2–14.9% in women treated with DRSP 3 mg/EE 20 μg 24/4 vs 8.6–13.8% in women treated with DSG 150 μg/EE 20 μg 21/7). Overall, similar bleeding patterns were observed with both treatments. Conclusion: DRSP 3 mg/EE 20 μg 24/4 is associated with a bleeding profile and cycle control that is comparable to that of an established, low-dose COC formulation.

A historical cycle control comparison of two drospirenone-containing combined oral contraceptives: ethinylestradiol 30 μg/drospirenone 3 mg administered in a 21/7 regimen versus ethinylestradiol 20 μg/drospirenone 3 mg administered in a 24/4 regimen

OBJECTIVES To compare the bleeding patterns and cycle control of an oral contraceptive (OC) containing ethinylestradiol (EE) 30 μg/drospirenone (drsp) 3mg administered in a 21/7 regimen versus a lower-dose OC containing EE 20 μg/drsp 3mg administered in a 24/4 regimen, using data from two identically designed studies. MATERIALS AND METHODS In the first study, 326 healthy women (18-35 years) received EE 30 μg/drsp 3mg in a 21/7 regimen. In the second study, 1027 healthy women (17-36 years) received EE 20 μg/drsp 3mg in a 24/4 regimen. Participants recorded bleeding using daily completed diaries over 13 treatment cycles. RESULTS During cycles 1-12, the prevalence of scheduled withdrawal bleeding was lower with EE 20 μg/drsp 3mg 24/4 than with EE 30 μg/drsp 3mg 21/7 (82.0-91.7% versus 94.8-100.0% of women, respectively); moreover, a higher proportion of women reported a maximum intensity of light scheduled withdrawal bleeding with EE 20 μg/drsp 3mg 24/4 than with EE 30 μg/drsp 3mg 21/7 (30.9-39.0% versus 13.8-20.5% of women, respectively). In cycles 2-13, unscheduled intracyclic bleeding was reported by 7.7-13.8% of EE 20 μg/drsp 3mg 24/4 recipients and 3.8-7.9% of EE 30 μg/drsp 3mg 21/7 recipients; these were mainly single bleeding days. During reference periods 1-4, the mean number of bleeding episodes was similar between groups (3.1-3.3 episodes with EE 20 μg/drsp 3mg 24/4 versus 3.2 episodes with EE 30 μg/drsp 3mg 21/7). CONCLUSIONS A low-dose 24/4 regimen OC containing EE 20 μg/drsp 3mg is generally comparable in terms of bleeding to a higher-dose 21/7 regimen OC containing EE30 μg/drsp 3mg. Between-treatment differences in bleeding intensity and unscheduled intracyclic bleeding rates were observed.

Suppression of ovarian activity with a low-dose 21/7-day regimen oral contraceptive containing ethinylestradiol 20 mcg/drospirenone 3 mg in Japanese and Caucasian women ☆

BACKGROUND Two studies assessed the effect of a low-estrogen-dose 21/7-day oral contraceptive containing ethinylestradiol and drospirenone (EE 20 mcg/drsp 3 mg) on ovarian activity in Japanese and Caucasian women. STUDY DESIGN Study 1 was conducted in Japanese women (20-35 years), and Study 2 was conducted in Caucasian women (18-35 years). All women received EE 20 mcg/drsp 3 mg in a 21-day active pill regimen. The primary endpoint was the proportion of women with ovulation inhibition (Hoogland score <6; as assessed by transvaginal ultrasonography) during treatment cycle 2. RESULTS Japanese (n=23) and Caucasian (n=30) women received two cycles of study treatment. During treatment cycle 2, ovulation was inhibited in 100% and 92.9% of Japanese and Caucasian women, respectively. CONCLUSIONS EE 20 mcg/drsp 3 mg in a 21/7-day regimen provides comparable ovarian suppression in Japanese and Caucasian women, with normal ovarian function resuming shortly after treatment end in both populations.

P735 Contraceptive efficacy of a combined oral contraceptive containing ethinylestradiol 20 mcg/drospirenone 3 mg administered in 24/4 regimen: a pooled analysis of four, open-label studies

pregnancies is the source of disagreement among obstetricians and other healthcare providers. Others believe that an interval of 18–24 months between pregnancies is optimal for the health of the mother and fetus, but the scientific evidence for this is weak. It is still unclear whether short inter-pregnancy interval is a marker for poor pregnancy outcome or a direct risk factor for poor perinatal outcome. Objective: To determine the optimal length of interval between pregnancies that would prevent adverse perinatal outcome. Study design: Cross Sectional study. Methodology: Conducted from September 1 to December 31, 2002. A total of 216 women who had two consecutive singleton pregnancies of which the second of each pair is the current pregnancy and delivered during the study period were included in the study. The outcome of the second of each pair of pregnancies and the length of time between each pregnancy were determined. Statistical analysis: Fischer exact test, Chi-Square Test and Relative Risk at 95% confidence interval. Result: There was significant association between low birth weight infants and extremes of pregnancy interval: 4× risk for <1 year interval (RR =3.60 95%CI = 1.66–7.77) and 6× risk for >10yrs interval (RR=5.75 95%CI = 2.54–13.14) with p values of <0.001 and <0.03 respectively. Conclusion: There was significant association between long and short inter-pregnancy interval and low birth weight (LBW) infants.