Efficacy and Safety of repeated use of ulipristal acetate in uterine fibroids4 (PEARL IV part 1)
Long-term medical Medical Management Of Uterine Fibroids5 (PEARL IV part 2)
To investigate the efficacy and safety of repeated 12-week courses (3 months) of 5 or 10 mg daily of UPA (ulipristal acetate) for intermittent treatement of symptomatic uterine fibroids.
Design of PEARL IV
- A multicentre, randomised, double-blind, Phase III clinical study of UPA 5 mg or 10 mg daily for the long-term management of symptomatic uterine fibroids
- 4 courses of 12-week treatment with ulipristal acetate
- 451 patients recruited
- The main pivotal study on the intermittent use of Esmya®
Adapted from Donnez 2015, in press5 UPA, ulipristal acetate
PEARL IV: Primary efficacy endpoint
- percentage of subjects in amenorrhoea at the end of all four UPA courses7
PEARL IV: Secondary endpoints
of subjects in amenorrhoea at the end of each treatment course
|Median time to amenorrhoea during each individual treatment course|
with controlled bleeding
|Percentage of subjects with controlled bleeding in the last 56 days of each individual
|Percentage of subjects with controlled bleeding at the end of all 4 treatment courses|
|Change from baseline in the volume of the three largest myomas and uterus|
|QoL||Change from baseline in quality of life (UFS-QoL and EQ-5D)|
|Pain||Change from baseline in pain (VAS)|
EQ-5D, EuroQol 5-dimensional health status questionnaire
UFS-QoL, Uterine Fibroid Symptom and Quality of Life Questionnaire
UPA, ulipristal acetate
VAS, visual analogue scale
PEARL IV: Key inclusion criteria
|Premenopausal women aged 18−50 years|
|At least one uterine fibroid 3−12 cm diameter (none >12 cm diameter)|
|Regular menstrual cycles 22−35 days duration (FSH <= 20 mIU/mL)|
|Body mass index 18–40 kg/m2|
|Uterus volume upper limit equivalent to 16 weeks pregnancy|
|Excessive uterine bleeding (PBAC >100)|
FSH, follicle-stimulating hormone
PBAC, pictorial blood assessment chart
PEARL IV: Baseline characteristics
|Characteristic (full analysis set)||Esmya® (UPA 5 mg/day)
|UPA 10 mg/day (N=223)|
|Mean age, years (SD)||41.6
|Ethnic origin, n (%)||White||211
|Not reported||1 (0.4)||0|
|Mean weight, kg (SD)||69.2
|Mean BMI, kg/m2 (SD)||25.2
Adapted from Donnez 2015, in press 5
- Amenorrhoea†1 was achieved by 71.8%, 74.1%, 73.3%, and 69.6% in the Esmya® 5 mg group and 82.6%, 82.2%, 78.3%, and 74.5% in the 10 mg group, for treatment courses 1, 2, 3, and 3 respectively.
- Amenorrhoea was achieved after a median of 4-6 days for both groups across the treatment courses.
- The percentage of patients with controlled bleeding†2 in the last 56 days for individual treatment courses ranged from 73.3% to 93.4% across both treatment groups.
- Pain levels were reduced and maintained at the lower levels during all treatment courses and even during the off-treatment periods levels did not return to baseline.
- Quality of life scores indicated substantially reduced QoL at baseline, but mean scores were within the range of healthy participants at the end of each treatment course, and even during the off-treatment periods and the improvement was largely maintained at the 3-month follow-up after the final treatment course ‡§.
- Clinically significant reduction of ≥ 25% volume of the three largest fibroids was reported after each treatment course. In both groups, the percentage of subjects with a clinically significant reduction increased from course 1 to course 4. In the 5-mg group, the percentages increased from 62.3% after course 1 to 78.1% after course 4. Similarly, in the 10-mg group, the percentages increased from 66.5% to 80.5%.
- Further examination showed that at the end of four treatment courses, 73.5% of all subjects had a fibroid volume reduction of ≥ 25% and were in amenorrhea.
Safety and Tolerability
- The majority (97.6%) of adverse events were mild or moderate in nature and did not increase with successive treatment courses (≤ 11% in both cases).
- Headache and hot flushes were the most common adverse events reported during the study, but the incidences decreased after each treatment course.
- Breast pain/discomfort was observed in ≤ 3% of subjects, with a decrease in frequency for each successive treatment course (≤ 1% by treatment course 4).
- During the study, the median endometrial thickness remained between 7 and 8 mm. The percentage of subjects with endometrial thickness ≥ 16 mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses.
- The frequency of nonphysiological changes did not increase with repeated treatment. They were observed in 17.8% and 13.3% of biopsies after treatment courses 2 and 4, respectively, and were reversible after treatment cessation.
- There were no significant changes in laboratory parameters during the study.
†1 Amenorrhoea was defined as no bleeding for a continuous period of ≥35 days (1 day of spotting allowed).
†2 Controlled bleeding was defined as no episodes of heavy bleeding and a maximum of 8 d of bleeding during the last 56 d of a course of treatment.
‡ Quality of Life was measured by general EQ-5D questionnaire and the Uterine fibroid symptom and health-related quality of life (UFS-QoL) questionnaire.
§ Pain was measured with the short-form McGill pain questionnaire