Table 2.

Summary of key findings of phase III clinical trials utilising UPA for management of HMB and fibroids.

Study	Type	Population	Intervention and comparator	Outcomes	Conclusion
PEARL I	Randomised Double blind Placebo controlled	Women with symptomatic fibroids; Age: 18–50 years; BMI: 18–40 kg/m2; PBAC score >100 (first 8 days of menstruation); At least one uterine fibroid >3 cm but <10 cm; Fibroid uterus: <6 weeks; Anaemia: Hb <10.2 g/dL; Eligible for surgery	Women were randomised in a ratio of 2:2:1 to 5 mg/day UPA (n = 96) 10 mg/day UPA (n = 98) Placebo (n = 48) Treatment duration 12–13 weeks All women received 80 mg/day oral iron	PBAC score <75 was achieved in 5 mg UPA group (91%) 10 mg UPA group (92%) Placebo (19%) Amenorrhoea (PBAC <2) in 10 days 5 mg UPA group (73%) 10 mg UPA group (82%) Placebo (6%) Median total change in fibroid volume 5 mg UPA group (−21.2%) 10 mg UPA group (−12.3%) Placebo (+3%) Self-reported pain scores improved compared to placebo Adverse effects comparable to placebo	Treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids.
PEARL II	Randomised Double Blind Double Dummy Active Comparator Controlled Noninferiority	Women with symptomatic fibroids; Age: 18–50 years BMI: 18–40 kg/m2; PBAC score >100 (first 8 days of menstruation); At least one uterine fibroid >3 cm but <10 cm; Fibroid uterus <16 weeks; Eligible for surgery	Women were randomised in a ratio of 1:1:1 to 5 mg/day UPA + placebo* (n = 97), 10 mg/day UPA + placebo (n = 104), placebo + Leuprorelin 3.75 mg IM monthly (n = 101) Treatment duration: 12–13 weeks *Placebo in UPA group - IM saline injection	PBAC score <75 was achieved in 5 mg UPA group (90%) 10 mg UPA group (98%) Leuprorelin (89%); Amenorrhoea (PBAC <2) was achieved 5 mg UPA group (75%) - Median time 7 days 10 mg UPA group (89%) - Median time 5 days Leuprorelin (80%) - Median time 21 days Median total change in fibroid volume 5 mg UPA group (−36%) 10 mg UPA group (−42%) Leuprorelin (−53%) Hot flushes (moderate to severe) 5 mg UPA group (11%) 10 mg UPA group (10%) Leuprorelin (40%) All three groups had improvements in pain and QoL scores	Treatment with ulipristal acetate for 13 weeks was noninferior to leuprolide acetate in controlling uterine bleeding and was associated with significantly lower risk of hot flushes.
PEARL III + Extension 1	PEARL III- Open label Extension 1 - Randomised double blind	Women with symptomatic fibroids; Age: 18–48 years; BMI: 18–40 kg/m2; Regular menstrual cycle; PBAC score >100 (first 8 days of menstruation); At least one uterine fibroid >3 cm but <10 cm; (FSH) <20 IU/L; Fibroid uterus <16 weeks; Eligible for surgery	PEARL III - UPA 10mg/day commenced in the first week of menstruation. Treatment duration 12 weeks (n = 209); Extension 1 - Up to 4 courses of 12 weeks of UPA treatment with drug free intervals, followed by randomised double blind treatment (1:1) to norethisterone acetate (NETA) or placebo for 10 days at the end of each treatment course. (n = 132)* *Participants recruited from the core PEARL III study	Amenorrhoea (PBAC <2) was achieved 1st UPA course (79.5%) - Median time 3.5 days 2nd UPA course (88.5%) - Median time 2 days 3rd UPA course (88.2%) - Median time 3 days 4th UPA course (89.7%) - Median time 3 days Median total change in fibroid volume 1st UPA course (−45.1%), n = 132 2nd UPA course (−63.2%), n = 131 3rd UPA course (−67%), n = 119 4th UPA course (−72.1%), n = 107 Hot flushes (moderate to severe) PAEC (6 weeks post treatment) 26% after course 1 25% after course 4 No effect of NETA on PAEC Improvement in pain scores appeared by the fifth week and was maintained during the four cycles. Quality-of-life scores were considerably reduced at the end of the treatment compared with scores at baseline and maintained throughout and at 3 months after cessation of treatment.	The study and its extensions (see subsequent section) demonstrates the safety and efficacy of repeated intermittent treatment of symptomatic fibroids with UPA.
PEARL III + Extension 2	PEARL III- Open label	Women with symptomatic fibroids; Age: 18–48 years; BMI: 18–40 kg/m2; Regular menstrual cycle; PBAC score >100 (first 8 days of menstruation); At least one uterine fibroid >3 cm but <10 cm; Fibroid uterus <16 weeks; Eligible for surgery; Completed PEARL III core study and extension 1	Extension 2 - Up to four additional courses of 12 weeks of UPA treatment with drug free intervals - TOTAL up to 8 courses (n = 64) * *Participants recruited from the core PEARL III study + completed extension 1	PAEC (assessed post treatment) 21% after course 4 16% after course 8 No changes in laboratory results outside normal ranges at any time	The study and its extensions demonstrate the safety and efficacy of repeated intermittent treatment of symptomatic fibroids with UPA.
PEARL IV	Randomised Double Blind Parallel-Group	Women with symptomatic fibroids; Age: 18–50 years; BMI: 18–40 kg/m2; Regular menstrual cycle; PBAC score >100 (first 8 days of menstruation); At least one uterine fibroid ≥3 cm but ≤12 cm; FSH <20 IU/L; Fibroid uterus <16 weeks	Women were randomised in a ratio of 1:1 to 5 mg/day UPA (n = 230) 10 mg/day UPA (n = 221) Treatment duration - Up to four courses of 12 weeks each (84 days) with a drug free interval between courses; until the start of the second menstrual bleed after course completion Women were followed up at 3 months after the fourth treatment course	Amenorrhoea (PBAC <2) was achieved 5 mg UPA group Course 1 - 71.8% Course 2 - 74.1% Course 3 - 73.3% Course 4 - 69.6% All four courses combined - 48.7% 10 mg UPA group Course 1- 82.6% Course 2 - 82.2% Course 3 - 78.3% Course 4 - 74.5% All 4 courses combined - 60.5% Median change in volume of the 3 largest fibroids at follow up 5 mg UPA group (−65%) 10 mg UPA group (−67.4%) Placebo (−53%) PAEC 5 mg UPA group Baseline - 7.8% Course 2 (16.3%) & Course 4 (16.2%) 3 months post UPA - 9.0% 10 mg UPA group Baseline - 8.4% Course 2 (19.2%) & Course 4 (10.3%) 3 months post UPA - 6.3% Both groups had improvements in pain and QoL scores Headaches and hot flushes were the most commonly reported side effects and occurred in ≤11% of patients, with the frequency of these events decreasing with each successive treatment course.	The study demonstrates the safety and efficacy of repeated intermittent treatment of symptomatic fibroids with UPA.
VENUS II	Randomised Double Blind Placebo Controlled Partial Crossover	Women with symptomatic fibroids; Age: 18–50 years; Regular menstrual cycle; MBL ≥80 mL measured using the alkali hematin method (first 8 days of menstruation) Minimum one discrete leiomyoma seen by TVUS FS) <20 IU/L Fibroid uterus ≤20 weeks	Women were randomised (n = 432) 5 mg/day UPA 10 mg/day UPA Placebo Randomized to one of six treatment arms in a 1:1:2:1:2:1 ratio, with course 1, course 2 dosing of placebo, ulipristal 5 mg; placebo, ulipristal 10 mg; ulipristal 5 mg, 5 mg; ulipristal 5 mg, placebo; ulipristal 10 mg, 10 mg; ulipristal 10 mg, placebo Treatment duration - Two courses of 3 months each. There was a two menses drug-free interval in between courses. Women were followed up at 3 months after treatment completion	Amenorrhoea was achieved 5 mg UPA group Course 1 - 42% Course 2 - 40.5% 10 mg UPA group Course 1- 54.8% Course 2 - 57.3% Placebo Course 1- 0% Course 2 - 8% Improvement from baseline in UFS-QOL revised activities subscale: 5-mg UPA: 48% 10-mg UPA: 57% Placebo: 13%	Consistent with VENUS I and the European studies, both doses of UPA were superior to placebo in the proportion of women achieving amenorrhea and time to amenorrhea.