Date: 2012-02-02
Type of information:
phase: 3
Announcement: publication of full results of PEARL I and II studies in the New England Journal of Medicine (NEJM)
Company: Preglem (Switzerland) member of the Richter Group (Hungary)
Product: Esmya® (ulipristal acetate)
Action mechanism: The active substance of Esmya® is ulipristal acetate, a selective progesterone receptor modulator, characterised by a tissue-specific partial progesterone antagonist effect. It acts by depriving uterine fibroids of growth stimulation due to progesterone.
Disease: pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age
Therapeutic area: Gynecology - Women's health
Country: Europe
Trial
details: PEARL I and II (PGL4001\'s – a code name for ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata) are two Phase 3 clinical trials conducted mainly in Europe.
PEARL I, a randomized, parallel-group, double-blind, placebo-controlled, phase 3 trial involved 242 patients. PEARL II, a randomized, parallel-group, double-blind, double-dummy, phase 3 trial comparing ulipristal acetate versus the injectable GnRH agonist (leuprolide acetate) involved 307 patients.
Both pivotal studies included premenopausal women, 18-50 years of age, with symptomatic fibroids, including heavy menstrual bleeding, eligible for hysterectomy. In addition to heavy menstrual bleeding, patients in PEARL I study had to be anaemic and therefore all subjects received concomitant oral administration of iron. The treatment periods of 12 weeks were followed by an end-of- treatment visit at week 13. Subjects still qualifying for surgery underwent hysterectomy, myomectomy, uterine artery embolization or endometrial ablation as determined by the investigator. All subjects were followed for 6 months after the end of treatment.
The primary objectives of PEARL I were to demonstrate superior efficacy of ulipristal acetate versus placebo, to reduce excessive uterine bleeding and to reduce total fibroid volume prior to surgery.
The primary efficacy objective of PEARL II was to demonstrate non- inferior efficacy of ulipristal acetate versus Gonadotropin Releasing Hormone (GnRH)-agonist to reduce, prior to surgery, excessive uterine bleeding caused by uterine fibroids. The co-primary safety objectives were to show a superior side-effect profile for ulipristal acetate versus leuprolide acetate in terms of serum estradiol levels at week 13 and the proportion of patients with moderate-to-severe hot flashes during treatment.
Latest
news: PregLem has announced full results of PEARL I and II studies, published simultaneously in the New England Journal of Medicine (NEJM). PEARL II, a double-blind, double-dummy, phase 3 trial comparing ulipristal acetate versus the injectable GnRH agonist (leuprolide acetate) showed:
PEARL I, a randomized, parallel-group, double-blind, placebo-controlled, phase 3 trial showed:
- Uterine bleeding was controlled in 91% of the women receiving ulipristal acetate 5 mg and in 92% of those receiving ulipristal acetate 10 mg, and 19% of those receiving placebo (P<0.001).
- The rates of amenorrhea were 73%, 82%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate.
- The median changes in total fibroid volume were ?21%, ?12%, and +3% (P = 0.002 ulipristal acetate 5 mg vs. placebo, and P = 0.006 ulipristal acetate 10 mg vs. placebo).
- As compared with placebo, both doses of ulipristal acetate led to reductions in pain (especially moderate or severe pain), as measured with the Short-Form McGill Pain Questionnaire.
- Ulipristal acetate induced benign histologic endometrial changes that had resolved by 6 months after the end of therapy.
- The rate of the occurrence of any adverse events did not differ significantly among the three groups. Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo.
- Uterine bleeding was controlled in 90% of patients receiving ulipristal acetate 5 mg and in 98% of those receiving ulipristal acetate 10 mg, and in 89% of those receiving leuprolide acetate. - Excessive bleeding control was demonstrated with statistical significance to be more rapid in patients receiving either ulipristal acetate 5 mg or ulipristal acetate 10 mg, than in those receiving leuprolide acetate.
- Median times to amenorrhea were 7 days for patients receiving ulipristal acetate 5 mg, 5 days for those receiving ulipristal acetate 10 mg, and 21 days for those receiving leuprolide acetate.
- All treatments reduced the volume of the three largest fibroids, with median reductions at week 13 of 36% in the group receiving ulipristal acetate 5 mg, 42% in the group receiving ulipristal acetate 10 mg, and 53% in the group receiving leuprolide acetate.
- For patients who did not undergo hysterectomy or myomectomy, ulipristal acetate showed a more sustained effect on the reduction of fibroids volume during the 6 months follow up without treatment than did leuprolide acetate.
- Moderate-to-severe hot flashes were reported for 11% of patients receiving ulipristal acetate 5 mg, for 10% of those receiving ulipristal acetate 10 mg and for 40% of those receiving leuprolide acetate (P<0.001 for each dose of ulipristal acetate vs. leuprolide acetate).
- There were no significant differences between the ulipristal acetate groups and the leuprolide acetate group in the proportion of patients reporting other adverse events or discontinuing treatment because of adverse events.
