Short-term therapy with ulipristal acetate, a selective progesterone-receptor modulator, is superior to placebo and noninferior to leuprolide at controlling the bleeding, reducing the volume, and improving the pain of uterine fibroids, according to two reports in the Feb. 2 issue of the New England Journal of Medicine.
In two parallel international phase-III clinical trials, the duration of treatment with ulipristal acetate (PGL4001) was restricted to 13 weeks and limited to patients who were planning to undergo surgery for fibroids. "More data are needed to inform the benefits and risks of long-term treatment with ulipristal," as well as to compare the outcomes with therapy against those with surgery, said Dr. Jacques Donnez of the Cliniques Universitaires Saint-Luc Catholic University of Louvain, Brussels, and his associates in the PEARL I and PEARL II studies.
In the PEARL I (PGL4001 [Ulipristal Acetate] Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata) study, 242 premenopausal women with severe menorrhagia and associated anemia were randomly assigned to receive 5 mg ulipristal, 10 mg ulipristal, or placebo tablets once daily for 13 weeks. The study subjects were treated at 38 academic medical centers in six countries.
Excessive bleeding was controlled in 91% of the women who received the 5-mg dose and 92% of those who received the 10-mg dose, compared with only 19% of those who received placebo. Moreover, excessive bleeding was controlled rapidly – within 8 days – in more than 75% of women taking either dose of ulipristal, compared with only 6% of those taking placebo, the investigators said (N. Engl. J. Med. 2012;366:409-20).
"More data are needed to inform the benefits and risks of long-term treatment with ulipristal."
Most of the women in both ulipristal groups but few in the placebo group achieved amenorrhea after 4 weeks of treatment. Half of the patients receiving 5 mg and 70% of those receiving 10 mg of ulipristal became amenorrheic within 10 days.
At the same time, hemoglobin and hematocrit levels rose significantly higher in both ulipristal groups, compared with the placebo group. A significantly greater proportion of patients taking ulipristal showed reductions in fibroid volume of at least 25%, and more reported reduced pain.
The rate of adverse events was not significantly different among the three study groups. All patients showed modest changes in LDL and HDL cholesterol. There were no consistent effects on glucose, estradiol, corticotropin, or prolactin levels, and no differences between active treatment and placebo groups in liver function results or endometrial thickness.
Endometrial biopsies at the end of treatment showed nonphysiologic changes in 62% of women taking 5 mg ulipristal and 57% taking 10 mg ulipristal, compared with only 6% taking placebo. These changes had disappeared by the 6-month follow-up biopsy.
The PEARL II study was a noninferiority trial comparing the same two doses of daily oral ulipristal against once-monthly leuprolide injections for the preoperative treatment of fibroids in 307 women.
After 13 weeks of treatment, 90% of the patients receiving 5 mg ulipristal, 98% of those receiving 10 mg ulipristal, and 89% of those receiving leuprolide achieved control of excessive bleeding, indicating the noninferiority of both doses of ulipristal, Dr. Donnez and his colleagues said (N. Engl. J. Med. 2012;366:421-32).
Excessive bleeding was controlled much more rapidly with ulipristal than with leuprolide, and amenorrhea also was induced more rapidly. The median time to achieving amenorrhea was 7 days with 5 mg ulipristal, 5 days with 10 mg ulipristal, and 21 days with leuprolide, they reported.
All patients reported similar improvements in pain and quality of life, and all showed similar rebounds in hemoglobin levels.
All three treatments significantly reduced uterine volume, but leuprolide produced a significantly greater reduction (47%) than did either dose of ulipristal (20% and 22%).
Estradiol dropped to postmenopausal levels only in the women who received leuprolide. Accordingly, 40% of the leuprolide group reported moderate to severe hot flashes, compared with 11% of the women taking 5 mg ulipristal and 10% of those taking 10 mg ulipristal, Dr. Donnez and his colleagues wrote.
There were no significant differences among the three study groups in other adverse events. As in the PEARL I study, ulipristal induced benign endometrial changes that had disappeared at the 6-month follow-up.
Neither ulipristal nor leuprolide showed any clinically relevant effects on corticotropin, thyrotropin, prolactin, or glucose levels.
Both the PEARL I and PEARL II studies were funded by PregLem, manufacturer of ulipristal acetate. Dr. Donnez reported ties to PregLem, Serono, Merck, Organon, and Ferring; his associates reported ties to numerous industry sources.