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

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).

Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, in women with endometriosis-associated pain: phase 2 safety and efficacy 24-week results.

BACKGROUND: Relugolix is a once-daily, oral, nonpeptide, gonadotropin-releasing hormone receptor antagonist. The aim of this study was to evaluate safety of relugolix over 24 weeks in women with endometriosis-associated pain. METHODS: This phase 2, randomized, open-label, parallel-group extension study was conducted in 101 clinics in Japan. Patients (premenopausal females ≥ 20 years) who completed the preceding 12-week relugolix phase 2 study continued to receive relugolix (10 mg, 20 mg, or 40 mg), placebo, or leuprorelin (3.75 mg) for an additional 12 weeks. Relugolix was administered orally once daily, and leuprorelin subcutaneously once every 4 weeks. The primary outcome was safety, including bone mineral density (BMD) and treatment-emergent adverse events (TEAEs). Secondary endpoints included visual analog scale (VAS) scores for endometriosis-associated pain. Analysis sets were defined as all patients who were administered the study drug. RESULTS: Of 487 randomized patients in the preceding study, 397 enrolled in this extension study and continued to receive placebo (n = 77), relugolix 10 mg (n = 84), relugolix 20 mg (n = 78), relugolix 40 mg (n = 89), or leuprorelin (n = 69). Baseline characteristics were similar between extension study patients and patients in the preceding study. Frequency of TEAEs including metrorrhagia, menorrhagia, and hot flush was similar in the relugolix 40-mg and leuprorelin groups. Mean (SD) change in BMD from baseline at Week 24 was - 0.2 (1.99)% for placebo; - 1.6 (2.34)%, - 2.6 (2.94)%, and - 4.9 (2.91)% for the relugolix 10-mg, 20-mg, and 40-mg groups, respectively; and - 4.4 (2.16)% for leuprorelin. Mean ± SD change from baseline in mean VAS score (mm) for pelvic pain at end of treatment was - 3.2 ± 12.16 for placebo; - 6.8 ± 10.56, - 9.0 ± 11.84, and - 11.9 ± 11.26 for the relugolix 10-mg, 20-mg, and 40-mg groups, respectively; and - 12.7 ± 12.57 for leuprorelin. Estradiol levels decreased with increasing relugolix dose and remained below postmenopausal levels throughout the 24-week relugolix 40-mg treatment period. CONCLUSIONS: Treatment with relugolix for 24 weeks was generally well tolerated and demonstrated similar pain reduction to leuprorelin in women with endometriosis. The dose-dependent loss in BMD observed with relugolix treatment was expected due to an induced hypoestrogenic state. Relugolix demonstrated a similar benefit/risk profile to injectable therapy in this phase 2 study. Trial registration NCT01452685 (ClinicalTrials.gov, registered 17/10/2011).

Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of three dose levels of relugolix, a gonadotropin-releasing hormone receptor antagonist, compared with placebo and leuprorelin in women with endometriosis-associated pain. DESIGN: Phase 2, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Hospitals and clinics. PATIENT(S): Adult premenopausal women with endometriosis who had dysmenorrhea and endometriosis-associated pelvic pain. INTERVENTION(S): During a 12-week treatment period, patients received relugolix 10 mg (n = 103), 20 mg (n = 100), or 40 mg (n = 103) as a daily oral dose; placebo (n = 97) as a daily oral dose; or leuprorelin 3.75 mg (n = 80) as a monthly subcutaneous injection. MAIN OUTCOME MEASURE(S): Primary endpoint was the change from baseline in mean visual analog scale score for pelvic pain during 28 days before the end of treatment. RESULT(S): The mean changes in mean visual analog scale score for pelvic pain were -3.8 mm in the placebo group; -6.2, -8.1, and -10.4 mm in the relugolix 10-mg, 20-mg, and 40-mg groups; respectively; and -10.6 mm in the leuprorelin group. The major adverse events with relugolix were hot flush, metrorrhagia, menorrhagia, and irregular menstruation, and bone mineral density decrease in a dose-response manner, which were also observed in the leuprorelin group with a frequency comparable with that in the relugolix 40-mg group. CONCLUSION(S): Oral administration of relugolix alleviated endometriosis-associated pain in a dose-response manner and was generally well tolerated. Relugolix 40 mg demonstrated efficacy and safety comparable with those of leuprorelin. CLINICAL TRIAL REGISTRATION NUMBER: NCT01458301.

Efficacy and safety of once-weekly oral trelagliptin switched from once-daily dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: An open-label, phase 3 exploratory study.

INTRODUCTION: Trelagliptin, a novel once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor, has shown favorable efficacy and safety in type 2 diabetes mellitus patients. Trelagliptin was launched in Japan, and is expected to be initially used for switchover from a daily DPP-4 inhibitor in the clinical setting. Thus, the present study was carried out to explore the efficacy and safety of trelagliptin after a daily DPP-4 inhibitor was switched to it. MATERIALS AND METHODS: This was an open-label, phase 3 exploratory study to evaluate the efficacy and safety of trelagliptin in Japanese type 2 diabetes mellitus patients who had stable glycemic control on once-daily sitagliptin therapy. Eligible patients received trelagliptin 100 mg orally before breakfast once a week for 12 weeks. The primary end-point was blood glucose by the meal tolerance test, and additional end-points were glycemic control (efficacy) and safety. RESULTS: Altogether, 14 patients received the study drug. The blood glucose did not markedly change from baseline at major assessment points in the meal tolerance test, and a decrease in blood glucose was observed at several other assessment points. Adverse events were reported in 42.9% (6/14) of patients, but all adverse events were mild or moderate in severity, and most were not related to the study drug. No cases of death, serious adverse events or hypoglycemia were reported. DISCUSSION: It is considered possible to switch a once-daily DPP-4 inhibitor to trelagliptin in type 2 diabetes mellitus patients with stable glycemic control in combination with diet and exercise therapy without any major influences on glycemic control or safety.

Long-term safety and efficacy of a novel once-weekly oral trelagliptin as monotherapy or in combination with an existing oral antidiabetic drug in patients with type 2 diabetes mellitus: A 52-week open-label, phase 3 study.

AIMS/INTRODUCTION: Trelagliptin is a novel once-weekly oral dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus that was first approved in Japan. We evaluated long-term safety and efficacy of trelagliptin in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS: This was a phase 3, multicenter, open-label study to evaluate long-term safety and efficacy of trelagliptin. Patients with type 2 diabetes mellitus inadequately controlled despite diet/exercise or treatment with one of the existing oral antidiabetic drugs along with diet/exercise received trelagliptin 100 mg orally once weekly for 52 weeks as monotherapy or combination therapies. The primary end-points were the safety variables, and the secondary end-points were glycosylated hemoglobin and fasting plasma glucose. RESULTS: A total of 680 patients received the following antidiabetic therapies: trelagliptin monotherapy (n = 248), combination with a sulfonylurea (n = 158), a glinide (n = 67), an α-glucosidase inhibitor (n = 65), a biguanide (n = 70), or a thiazolidinedione (n = 72). During the study, 79.8% of the patients experienced at least one adverse event for monotherapy, 87.3% for combination with a sulfonylurea, 77.6% for a glinide, 81.5% for an α-glucosidase inhibitor, 64.3% for a biguanide, and 84.7% for a thiazolidinedione, respectively. Most of the adverse events were mild or moderate. The change in glycosylated hemoglobin from baseline at the end of the treatment period was -0.74 to -0.25% for each therapy. CONCLUSIONS: Once-weekly oral trelagliptin provides well-tolerated long-term safety and efficacy in both monotherapy and combination therapies in Japanese patients with type 2 diabetes mellitus.