LAUSR

OBJECTIVES To assess pharmacodynamic and pharmacokinetic outcomes of a novel copper (Cu) intrauterine system (IUS) releasing ulipristal acetate (UPA) in healthy women. STUDY DESIGN In this single-blinded, randomized proof-of-concept study, ovulatory women received one of three Cu-IUSs releasing low-dose UPA (5, 20 or 40 µg/d) for 12 weeks. The study included a baseline cycle, three 4-week treatment-cycles and two recovery cycles. Primary outcomes included effects of the IUS on bleeding profile, ovarian function, and the occurrence of progesterone receptor modulator associated endometrial changes (PAEC). Pharmacokinetics and safety profile were secondary outcomes. We compared outcomes in treatment-cycle 3 with baseline, using generalized linear mixed models with orthogonal contrasts. RESULTS We randomized 29 women (5µg/d=10, 20µg/d=10, 40µg/d=9). All had a successful IUS insertion; 27 completed the 12-week treatment period. Compared to baseline, the mean number of bleeding-only days at treatment-cycle 3 declined by 16.7% in the 5µg/d group (3.6 vs 3.0, p=0.66), 40.5% in the 20µg/d group (4.2 vs 2.5, p=0.14), and 77% in the 40µg/d group (3.9 vs 0.9, p=0.002). Most women reported reduction in the amount of bleeding: 4/8, 8/10, and 7/9 for the 5µg/d, 20µg/d, and 40µg/d groups, respectively. During IUS use, ovulation occurred in most cycles [5µg/d: 23/24 (96%), 20µg/d: 26/30 (87%), 40µg/d: 22/27 (81%)]. The frequency of PAEC at IUS removal was 1/10 (10%), 1/10 (10%) and 4/9 (44%) in the 5µg/d, 20µg/d, and 40µg/d groups, respectively. No serious adverse events (SAE) occurred. CONCLUSIONS Reduction in bleeding, low incidence of PAEC, and no SAEs are reassuring findings of the novel Cu-UPA-IUS. The 20µg/d seems the lowest dose promoting a favorable bleeding profile and limiting PAEC.