Relugolix for oral treatment of uterine leiomyomas: a dose-finding, randomized, controlled trial

Abstract

Background: Uterine leiomyomas are the most common neoplasm affecting women and frequently cause heavy menstrual bleeding and pain. Gonadotropin-releasing hormone (GnRH) receptor antagonists provide fast symptom relief and show promise as a medical (non-surgical) treatment option and as a presurgical treatment to reduce leiomyoma size. The aim of this study was to evaluate the efficacy and safety of three dose levels of oral relugolix, a small molecule GnRH receptor antagonist, in Japanese women with uterine leiomyomas and heavy menstrual bleeding.

Methods: This phase 2, multicenter, double-blind, parallel-group study was conducted at 36 sites in Japan in women with uterine leiomyomas and heavy menstrual bleeding, defined as a pictorial blood loss assessment chart (PBAC) score of ≥ 120 in one menstrual cycle. Patients were randomized 1:1:1:1 to relugolix 10, 20, or 40 mg, or placebo, orally once daily for 12 weeks. The primary endpoint was the proportion of patients with a total PBAC score of < 10 from week 6 to 12. A sample size of 50 patients per group was estimated to provide ≥ 95% power, based on the comparison of relugolix 40 mg with placebo using a chi-square test with a significance level of 5% (two-sided).

Results: From November 2011 to September 2012, 216 patients were randomized and 214 patients (99.1%) were analyzed. The proportion (difference vs. placebo) of patients that achieved the primary endpoint in the placebo and 10-, 20-, and 40-mg relugolix groups were 0%, 20.8% (95% confidence interval [CI]: 9.3-32.3, P < .001), 42.6% (95% CI: 29.4-55.8, P < .001), and 83.3% (95% CI: 73.4-93.3, P < .001), respectively. Though treatment-emergent adverse events were similar between the 20- and 40-mg groups, the incidence rates were more frequent compared with the placebo group. Most of these adverse events were mild or moderate in intensity.

Conclusions: Relugolix decreased menstrual blood loss in women with uterine leiomyomas in a dose-response manner, and was generally well tolerated.

Clinical trial registration: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01452659 , NCT01452659 (registered 17/10/2011); JAPIC Clinical Trial Information, https://www.clinicaltrials.jp , JapicCTI-111590 (registered 31/08/2011).

Keywords: Efficacy, Safety; Gonadotropin-releasing hormone antagonist; Japan; Leiomyoma; Menorrhagia; Randomized controlled trial; Relugolix.

Fig. 1

Study design. ^a Informed consent was obtained before day − 80. ^b Visits 2 and 3 occurred on days 1–5 of the menstrual cycle

Fig. 2

Patient disposition chart showing study participation. Of randomized patients, 214 (99.1%) were included in the full analysis and safety analysis sets. ^a Data for the primary endpoint were missing (n = 1). AE adverse event

Fig. 3

Primary efficacy endpoint: proportion of patients with a total pictorial blood loss assessment chart (PBAC) score < 10 at weeks 6–12. Error bars show 95% confidence intervals for differences vs. placebo. ***P < .001. Note: Differences were analyzed between each relugolix group and placebo group using chi-square tests according to the closed testing procedure, initially from the relugolix 40-mg group vs. the placebo group, to control the type I error rates in multiple comparison

Fig. 4

Secondary efficacy endpoints: proportion of patients with a total pictorial blood loss assessment chart (PBAC) score of 0 for weeks 6−12

Fig. 5

Proportion of patients with A maximum pain NRS score of 0 or 1 during the last 28 days before the last study dose, and B mean reduction in pain NRS score of > 50% from baseline to the last 28 days before the last study dose. Percentages are based on the number of patients with a maximum NRS score ≥ 4 at baseline. ***P < .001. NRS numerical rating scale, ns non-significant

Fig. 6

Median change in serum levels of estradiol. FFU final day of follow-up