Objectives: To assess the safety and efficacy of four vilaprisan doses (0.5-4.0 mg) in women with uterine fibroids. Design: Randomized, double-blind, placebo-controlled, multicenter trial. Setting: Ninety-eight centers in 12 countries. Patient(s): Women aged 18-50 years with uterine fibroids and heavy menstrual bleeding were randomized equally to oral vilaprisan at 0.5, 1.0, 2.0, or 4.0 mg or placebo once daily. Intervention(s): Treatment for 12 weeks, 24-week follow-up. Main Outcome Measure(s): Primary end point was absence of scheduled or unscheduled bleeding/spotting. Key secondary efficacy end points included volume of menstrual blood loss and change in fibroid volume. Result(s): A total of 309 patients were randomized, and 300 received treatment. Complete absence of bleeding/spotting was observed in 30%, 56%, 54%, and 60% of patients in the vilaprisan 0.5, 1.0, 2.0, and 4.0 mg groups, respectively, versus 1.7% with placebo. After 12 weeks, >83% of women achieved amenorrhea (<2 mL/28 days) with R1.0 mg vilaprisan versus 9% with placebo. Heavy menstrual bleeding stopped (but returned at a lower volume after treatment cessation) with R1.0 mg vilaprisan treatment. Reductions in fibroid volume of up to 41% were observed. Most patients receiving vilaprisan reported improvements in symptom severity. No safety concerns were identified in general safety, endometrial safety (by biopsy), laboratory values, and ultrasound examinations. Conclusion(s): ASTEROID 1 supports the efficacy of vilaprisan for the treatment of heavy menstrual bleeding associated with uterine fibroids. Daily oral treatment with vilaprisan 0.5-4.0 mg was well tolerated, and vilaprisan 2.0 mg once daily has been selected for further investigation.

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We report population pharmacokinetic (popPK) and exposure-response (E-R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan.Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids.Methods: A popPK model was developed using data from Phase 1 and 2 studies (including ASTEROID 1 and 2). The relationship between vilaprisan exposure (steadystate AUC) and IA after oral administration of 0.5, 1, 2 or 4 mg/day over 3 months was analysed in ASTEROID 1 using logistic regression and qualified in ASTEROID 2 by comparing simulated and observed probability for IA after 2 mg/day. The exposure-E2 relationship was analysed visually.Results: Vilaprisan clearance was 22.7% lower in obese vs non-obese patients. The E-R relationship for IA in ASTEROID 1 was steep and consistent with ASTEROID 2, with a maximum probability (P max ) of 59% (95% CI: 49-68%). The exposure at which 50% of P max is obtained was 36.9 μg*h/L (95% CI: 27.7-48.7 μg*h/L). Simulations showed that 36% of the patients will be below 90% of P max for IA after 1 mg/day compared to 2% after 2 mg/day. E2 levels tended to decrease with increasing exposure. While E2 levels remained largely within the physiologic follicular phase range, the clinical relevance of this decrease will be evaluated in long-term studies.Conclusions: A 2 mg/day dose was selected for Phase 3 as E-R analyses show this dose results in a close to maximum probability for IA, without any safety concerns noted.

each: group (A) received 5 mg LE daily & CE 0.5 mg once weekly from first day of menstrual cycle for 6 weeks. Those in group (B) were prescribed only CE for the same dose & duration of trial. Regular follow-up visits were arranged, and changes in uterine & myoma size, volume and number were recorded at each visit for all patients. Adverse effects were recorded if any. Data analyzed and P-value considered to be significant if < 0.05. All analyses were performed using SPSS software. RESULTS: Treatments well tolerated in both groups with minor side effects. Five patients lost during follow-up period, three from (A) & two from (B) groups. Compared with baseline values, mean uterine volume was reduced significantly (P <0.05) in both groups and with significant difference between groups, more in group (A) than (B) (P <0.016). Total number of myomas was reduced significantly in both groups (P < 0.023). Group (A) patients expressed more myoma shrinkage in comparison to those in group (B) (P < 0.05). Reduction rate of tumor nodule varied from 43-78% in (A) group, while that in group (B) was between 38 to 58%. One patient in (A) group discontinued treatment because of headache, none in the other group. CONCLUSIONS: Combination of LE and CE in management of uterine myomas is safe and more effective than CE alone, leading to symptomatic improvements, and might be considered for short term treatments before surgery along with the opportunity to preserve fertility. References: A.M. Elbareg et al: (Effectiveness of dopamine agonist, Cabergoline (Dostinex), treatment on uterine myoma regression in comparison to effect of gonadotrophin-releasing hormone analogue (Zoladex). Fertility and Sterility,