OBJECTIVE: To investigate the noninferiority of relugolix compared with 
leuprorelin acetate in reducing heavy menstrual bleeding associated with uterine 
leiomyomas.
METHODS: In a double-blind, double-dummy trial, premenopausal women with uterine 
leiomyomas and heavy menstrual bleeding defined as a pictorial blood loss 
assessment chart score of at least 120 were randomized in a 1:1 ratio to 
relugolix (40 mg, oral, once daily) or leuprorelin acetate (1.88 mg or 3.75 mg, 
monthly injection) for 24 weeks. The primary endpoint was the proportion of 
patients with a total pictorial blood loss assessment chart score of less than 
10 for weeks 6-12. Secondary endpoints included myoma and uterine volumes, and 
hemoglobin levels. A sample size of 144 patients per group (n=288) was estimated 
to provide at least 90% power to demonstrate noninferiority (prespecified 
noninferiority margin -15%; one-sided 0.025 level of significance).
RESULTS: From March 2016 to September 2017, 281 patients were randomized 
(relugolix, n=139, leuprorelin n=142). Demographic and baseline characteristics 
were well balanced; mean pictorial blood loss assessment chart score was 254.3 
in the relugolix group and 263.7 in the leuprorelin group. The proportion of 
patients with total pictorial blood loss assessment chart score of less than 10 
for weeks 6-12 was 82.2% in the relugolix group and 83.1% in the leuprorelin 
group, demonstrating noninferiority of relugolix compared with leuprorelin 
(relugolix-leuprorelin difference -0.9%; 95% CI: -10.10 to 8.35; prespecified 
noninferiority margin -15%; P=.001). Reductions in myoma and uterine volumes and 
increases in hemoglobin levels were comparable in the two groups. Relugolix was 
associated with an earlier effect on menstrual bleeding than leuprorelin 
(pictorial blood loss assessment chart score of less than 10, 64.2% vs 31.7% 
[relugolix-leuprorelin difference 32.5%; 95% CI: 20.95-44.13%] for weeks 2-6 and 
pictorial blood loss assessment chart score of 0, 52.6% vs 21.8% [30.7%; 95% CI: 
19.45-42.00%] for weeks 2-6) and faster recovery of menses after treatment 
discontinuation (relugolix median [Q1, Q3], 37 days [32.0, 46.0]; leuprorelin 
median, 65 days [54.0, 77.0]). Adverse events and bone mineral density loss were 
similar between relugolix and leuprorelin treatment groups.
CONCLUSION: In women with uterine leiomyomas, once-daily treatment with 
relugolix, an oral gonadotropin-releasing hormone antagonist, demonstrated 
noninferiority to monthly leuprorelin for improvement of heavy menstrual 
bleeding at 6-12 weeks of treatment, had a more rapid effect on menstrual 
bleeding, and was generally well tolerated.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02655237; JAPIC Clinical 
Trial Information, JapicCTI-163128.
FUNDING SOURCE: Takeda Pharmaceutical Company Limited and an affiliate of 
NovaQuest Capital Management LLC.