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Safety and Efficacy of the Selective Progesterone Receptor Modulator Asoprisnil for Heavy Menstrual Bleeding With Uterine Fibroids: Pooled Analysis of Two 12-Month, Placebo-Controlled, Randomized Trials

Research output: Contribution to journalArticle

  • Elizabeth A. Stewart
  • Michael P Diamond
  • Alistair Williams
  • Bruce R. Carr
  • Richard E. Myers
  • R Feldman
  • W. Elger
  • C. Mattia-Goldberg
  • B. M. Schwefel
  • K. Chwalisz

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Original languageEnglish
Pages (from-to)1-12
JournalHuman Reproduction
Publication statusPublished - 13 Feb 2019


Study question: Can asoprisnil, a selective progesterone receptor modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? Summary answer: Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. What is known already: In a 3-month study, asoprisnil (5, 10, and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner. Study design, size, duration: In two phase 3, double-blind, randomized, placebo-controlled, multicenter studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg, or placebo (2:2:1) once daily for up to 12 months. Participants/materials, setting, methods: Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N=907). The primary efficacy endpoint was the percentage of women who met all 3 predefined criteria at 12 months, or final month for subjects who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume, and health-related quality of life (HRQL). Main results and the role of chance: In all, 90% and 93% of women in the asoprisnil 10 mg and 25 mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P<0.001). Similar results were observed at month 6 (P<0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66% to 78% in the asoprisnil 10 mg group and 83% to 93% in the asoprisnil 25 mg group, significantly higher than with placebo (3% to 12%, P<0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to −48% and −28%, respectively) and 25 mg (median changes up to −63% and −39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P<0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by approximately 2 mm in both asoprisnil groups compared with placebo (P<0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women. Limitations, reasons for caution: Most study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects. Wider implications of the findings: Daily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences.

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